Biology of Interleukin-10

Cytokine & Growth Factor Reviews 21 (2010) 331–344
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Cytokine & Growth Factor Reviews

journal homepage: www.elsevier.com/locate/cytogfr
Biology of interleukin-10
Robert Sabat a,b,*, Gerald Grütz c,d, Katarzyna Warszawska a, Stefan Kirsch a, Ellen Witte a,
Kerstin Wolk a,b,1, Jens Geginat e,1
a
Interdisciplinary Group of Molecular Immunopathology, Dermatology/Medical Immunology, University Hospital Charité, Berlin, Germany
b
Research Center Immunosciences, University Hospital Charité, Charitéplatz 1, 10117 Berlin, Germany
c
Institute of Medical Immunology, University Hospital Charité, Berlin, Germany
d
GKSS Research Centre for Biomaterial Development, Teltow, Germany
e
Fondazione Istituto Nazionale di Genetica Molecolare (INGM), Milan, Italy
A R T I C L E I N F O A B S T R A C T
Article history: Interleukin (IL)-10 is the most important cytokine with anti-inflammatory properties besides TGF-b and
Available online 5 November 2010 IL-35. It is produced by activated immune cells, in particular monocytes/macrophages and T cell subsets
including Tr1, Treg, and Th1 cells. IL-10 acts through a transmembrane receptor complex, which is
Keywords: composed of IL-10R1 and IL-10R2, and regulates the functions of many different immune cells. In
IL-10 family monocytes/macrophages, IL-10 diminishes the production of inflammatory mediators and inhibits
Cytokine receptor antigen presentation, although it enhances their uptake of antigens. Additionally, IL-10 plays an
c-maf
important role in the biology of B cells and T cells. The special physiological relevance of this cytokine lies
AHR
Foxp3
in the prevention and limitation of over-whelming specific and unspecific immune reactions and, in
IL-27 consequence, of tissue damage. At the same time, IL-10 strengthens the ‘‘scavenger’’-function and
contributes to induced tolerance. This review provides an overview about the cellular sources, molecular
mechanisms, effects, and biological role of IL-10.
ß 2010 Elsevier Ltd. All rights reserved.
1. Introduction isms are associated with differential expression of IL-10 in vitro,

and a number of studies have investigated associations between IL-
In 1989, Mosmann and co-workers described a novel immune 10 polymorphisms and various diseases (see below). The IL-10
mediator that is secreted by mouse type 2 T-helper cell clones gene encodes a 178 amino acids long protein, which is secreted
(Th2) and inhibits the synthesis of interleukin (IL)-2 and interferon after cleavage of the 18 amino acids comprising signal peptide.
(IFN)-g in Th1 cell clones [1]. Originally named ‘‘cytokine synthesis Between human (h) and murine (m) IL-10, there is an approxi-
inhibitory factor’’ (CSIF), this mediator was accepted as ‘‘IL-10’’ in mately 75% identity in the amino acid sequence. The groups of
the everyday cytokine nomenclature. In the 21 years since its Wlodawer and Walter resolved the structure of hIL-10 using X-ray
discovery, numerous groups have intensively investigated the crystallography structure analysis [3–6]. Interestingly, the struc-
biology of IL-10. ture of IL-10 is similar to the IFN-g structure [7]. Human IL-10 is a
35 kD homodimer that is composed of two, non-covalently bonded
2. The IL-10 gene and protein monomers. The homodimer has two V-oriented domains, each of
which is composed of six helices: four (A–D) of one monomer and
The gene encoding human IL-10 is located on chromosome 1. It two (E0 and F0 ) of the other. Within the monomer, two disulfide
covers a total of 5.1 kb pairs and comprises five exons [2]. A large bridges exist (C30-C126 and C80-C132) that are essential for
number of polymorphisms [primarily single nucleotide poly- maintaining the structure and the biological activity of the
morphisms (SNPs)] have been identified in the IL-10 gene cytokine [8]. A detailed description of the IL-10 structure is
promoter. Some evidence exists that certain of these polymorph- published by A. Zdanov in this issue of CGFR. In addition to various
mammalian IL-10-related molecules (see below), four viral IL-10
homologues are known. They are produced by the Epstein–Barr
* Corresponding author at: Interdisciplinary Group of Molecular Immunopathol- virus, the equine Herpes type 2 virus, the Orf virus (parapoxvirus
ogy, Dermatology/Medical Immunology, Campus Charité Mitte, University Hospital ovis), and the Cytomegalovirus (reviewed in [9]). With the
Charité, Charitéplatz 1, D-10117 Berlin, Germany. Tel.: +49 30 450 518009;
exception of Cytomegalovirus’ IL-10, the similarity of the viral
fax: +49 30 450 518964.
E-mail address: [email protected] (R. Sabat).
and cellular IL-10s with respect to the amino acid sequence is very
1
Both authors contributed equally to this work. high. For instance, the sequence of the Epstein–Barr virus’ IL-10
1359-6101/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cytogfr.2010.09.002
332 R. Sabat et al. / Cytokine & Growth Factor Reviews 21 (2010) 331–344
(BCRF1) is 83% identical to that of hIL-10. This, apart from marginal activate the IL-10 and IL-21 gene promoters and induce the
differences predominantly in the N-terminal part, results in very generation of Tr1 cells [51,52]. The novel cytokine IL-21 (reviewed
similar protein structures [10]. The expression of the virus IL-10s in [53]) up-regulates the c-maf expression and enhances IL-10
appears during the lytic phase of virus infection. Virus IL-10s are secretion [50,54]. The expression of c-maf can also be induced by
suggested to act via the same receptor as cellular IL-10 does. When transforming growth factor (TGF)-b/IL-6 [55]. Tr1-like cells can
compared to hIL-10, however, an approximately 1000-fold lower also differentiate from Th1 cells [56,57], but how different types of
efficiency is observed for many effects [11]. Unfortunately, most Tr1-like cells are related to each other is unclear. IL-10 is
anti-hIL-10 antibodies and ELISAs cannot discriminate between hIL- additionally produced by naturally occurring T regulatory (Treg)
10 and Epstein–Barr virus derived IL-10. Recently, novel human cells [58]. Treg cells are mostly CD25+ and are generated in the
molecules with structural similarity to IL-10 have also been thymus, but also peripherally in response to tolerogenic stimuli.
identified. These are now combined in the so-called IL-10 family The development of Treg cells is dependent on TGF-b, all-trans
comprising IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26 [12]. retinoid acid, TCR signaling, and the engagement of common g-
Interestingly, their sequence relation is not reflected by a shared chain cytokine receptors ([59] and reviewed in [60]). TGF-b
biological function (reviewed in [9,13,14]). A detailed description of induces the expression of Foxp3 and IL-10, however, all-trans
the others IL-10 family members is published in this issue of CGFR. retinoid acids favor Foxp3 expression and inhibit IL-10 [61]. IL-2,
by means of signal transducer and activator of transcription
3. Cellular sources of IL-10 (STAT)5, enhances IL-10 production and is an important activator
of the Treg cells suppressive activity [62,63]. During infection or
Today it is known that the ability to synthesize IL-10 is not inflammation Treg cells can migrate from the blood to the inflamed
limited to certain T cell subsets, but is a characteristic of almost all tissues where they are activated and inhibit the migration of
leukocytes [15]. Very important sources in vivo appear to be mainly dendritic cells and the cytokine production of antigen-specific T
monocytes and macrophages as well as Th cells [16–19]. Moreover, cells. Then Treg cells can themselves migrate to draining lymph
dendritic cells, B cells, cytotoxic T cells, gd T cells, NK cells, mast nodes and inhibit the activation and proliferation of antigen-
cells, as well as neutrophilic and eosinophilic granulocytes specific T cells [64,65]. In mice, Foxp3 is a specific marker of Treg
synthesize IL-10 [20–28]. Which of these cells are mainly cells, however, in humans it is not always linked to regulatory
responsible for the presence of IL-10 in defined situations is function. Lastly, the very recently discovered Th17 and Th22 cells
dependent on the kind of stimulus, type of affected tissue, and time can also produce IL-10 ([66,67], R. Sabat unpublished, and
point in an immune process (see below and reviewed in [29]). reviewed in [60,68]). Interestingly, IL-27 reduces the RORgt
Monocytes and macrophages secrete IL-10 after activation with expression and inhibits the development of Th17 cells [46,69].
various endogenous as well as exogenous mediators such as However, in stable Th17 cells IL-27 together with IL-23 can induce
bacterial lipopolysaccharide (LPS) [via activation of toll-like IL-10 secretion without exerting a negative influence on IL-17
receptor (TLR) 4, TRAF3, NF-kB p65/p50, and ERK kinase)] and expression [69]. Therefore, each currently known Th population
catecholamines (via activation of protein kinase A and CREB-1/ can produce IL-10, although in slightly different amounts (Fig. 1).
ATF-1) by inducing of IL-10 gene transcription [20,21,23–28,30– IL-10 production can be inhibited by IL-4 and IFN-g [21,70,71].
34]. Monocytes and macrophages also secrete IL-10 during Additionally, IL-10 is self-inhibiting [70]. Very recently, it was even
clearance of apoptotic cells in a process that is dependent on postulated that many CCR6+ memory T cells secrete IL-10 under
CD36 and p38 mitogen-activated protein (MAP) kinase [35]. In steady-state conditions after recognition of cross-reactive antigens
addition to the transcriptional level, Sharma et al. recently [72].
suggested that IL-10 expression is also regulated on the
posttranscriptional level by microRNAs [36]. 4. The IL-10 receptor
T cells secrete IL-10 predominantly following T cell receptor
triggering and the activation of ERK1 and ERK2 MAP kinases [37]. IL-10’s pleiotropic activities are mediated by a specific cell
Furthermore, IL-10 secretion correlated with the expression of c- surface receptor complex. This IL-10 receptor (IL-10R) is composed
maf transcription factor [37]. The antigen-primed T cells in vivo of two different chains, IL-10R1 and IL-10R2 (Fig. 2). Both chains
show a higher basal probability to transcribe IL-10 than naı̈ve T belong to the class II cytokine receptor family (CRF2). CRF2
cells, although the antigen-primed T cells still demonstrate mostly members are usually transmembrane glycoproteins, whose
mono-allelic IL-10 expression [38]. Among antigen-primed T cells, extracellular domains typically consist of about 210 amino acids,
Th2 cells were originally believed to be the principal source of IL- form two fibronectin type III domains, and have several conserved
10. In these cells, interferon-regulatory factor (IRF) 4 furthers the amino acid positions that are important for their secondary
IL-10 expression [39]. However, today it is clear that Th1 cells structure. In contrast, their intracellular domains vary in length
produce at least similar amounts of IL-10 as does Th2 cells [37,40– and do not demonstrate striking sequence similarity (reviewed in
43]. In Th1 cells IL-12 augments IL-10 production by increasing [73]). The Moore group cloned the mIL-10R1 in 1993 [74]. A year
phosphatidylinositol-3 kinase activity, which leads to inactivation later, the same group published the sequence of the hIL-10R1,
of the constitutively active serine/threonine kinase glycogen which, on the amino acid level, is 60% identical and 73% similar to
synthase kinase-3beta and enhances c-jun levels [44]. Stimulation the murine chain [75]. The IL-10R1 is a 90–110 kD, glycosylated
of Th1 cells with IL-27 elevates IL-10 production and slightly protein, whose encoding gene is located on chromosome 11
enhances IFN-g expression [45,46]. In 1997 so-called type 1 [75,76]. Polymorphisms within the human IL-10R1 gene have also
regulatory T cells (Tr1) were identified as a subset of CD4+ cells been described [77,78]. More recently, a protein known since 1993
that produces high levels of IL-10, low levels of IL-2 and no IL-4 as CRF2-4 was identified as the IL-10R2 [79]. The gene for this chain
[47]. Tr1 cells are Foxp3-negative cells that are characterized by (i) can be found on human chromosome 21. The affinity of IL-10 to the
a weak proliferation, (ii) nearly selective synthesis of IL-10, and (iii) IL-10R complex is markedly higher (50–250 pM) than to the
their ability to suppress the function of antigen-presenting cells isolated IL-10R1 (500–620 pM). Binding of IL-10 to its receptor
(APCs) as well as antigen-specific effector T cells via a cytokine- complex consists of two steps (Fig. 2). IL-10 first binds to IL-10R1.
dependent mechanism. They develop from naı̈ve T cells under the The IL-10/IL-10R1 interaction changes the cytokine conformation
influence of IL-27 [46,48–50] that induces the aryl hydrocarbon allowing the association of the IL-10/IL-10R1 complex with IL-
receptor (AHR) [51]. AHR binds c-maf and they synergistically 10R2 [80–82]. IL-10R2 alone is unable to bind IL-10 [81,83]. The
[()TD$FIG] R. Sabat et al. / Cytokine & Growth Factor Reviews 21 (2010) 331–344 333
Fig. 1. CD4+ T cells as IL-10 sources.
molecular basis of the interaction between human IL-10 and IL- stimulation of tissue cells with IFN-g or TNF-a leads to increased
10R1 has been characterized in detail [3,84]. An IL-10 epitope that mRNA expression of IL-10R2 [88,90,96]. While IL-10R1 is specific
becomes available after its conformational change has been for the IL-10 receptor complex, IL-10R2 is simultaneously part of
proposed to represent the binding site for IL-10R2 [81–83,85]. receptor complexes of other ligands. In fact, its role was recently
IL-10R1 is mainly found on immune cells. Its expression is demonstrated in transmitting the effects of the newly discovered
generally low, varying between 100 and 800 molecules per cell cytokines IL-22, IL-26, IL-28, and IL-29 [97–100]. This explains the
([86,87], and R. Sabat, unpublished]. Interestingly, monocytes and broad expression of IL-10R2 in a series of cell types, which do not
macrophages exhibit the highest IL-10R expression ([15,88,89] and express IL-10R1. We recently demonstrated for IL-22 and IL-10
R. Sabat, unpublished]. The expression is adjustable, but only few that this IL-10R2 sharing does not appear to be associated with
regulating factors are known so far. The activation of monocytes binding competition for IL-10R2 and mutual limitation of the
with LPS slightly strengthens the mRNA expression of both IL-10R1 biological effects of the different mediators [81]. Given the fact that
(2 h) and IL-10R2 (18 h) in these cells [88,90]. IL-10R1 is expressed there is apparently no co-expression of IL-22R1 and IL-10R1 in any
at higher levels on CD4+ memory than on naı̈ve T cells [91] and the cell type [81,90], the reason for the lacking interference is likely the
expression of both components of the IL-10R complex decreases nonexistent binding between either cytokine and IL-10R2 in the
following stimulation in T cells as well as in B and NK cells [88,90]. absence of the R1 chain for the competing cytokine [81].
In the case of T cells, this is dependent on the strength of cellular IL-10 mainly uses the Janus kinase family members and STAT
activation [88,90]. Very low levels of IL-10R1 expression have also transcription factors to mediate its effects, i.e. principally like IFNs
been described for a few non-immune cell lines [92,93]. Here, [101]. In fact, the binding of IL-10 to its receptor activates two
cellular activation enhances its expression. In general, the IL-10R1 members of the Janus kinase family: Jak1 (associated with the IL-
expression levels correlate with the strengths of the effects of IL-10 10R1) and Tyk2 (associated with the IL-10R2) (Fig. 2) [102].
on immune cells [94,95]. In contrast to IL-10R1, IL-10R2 is widely Afterwards, two tyrosines (Tyr 446 and Tyr 496) of IL-10R1 are
and strongly expressed in most cells and tissues [81,88,90]. The phosphorylated by these kinases, to which the transcription factor
[()TD$FIG]
Fig. 2. IL-10–IL-10R interaction. The cellular IL-10R is a complex composed of the CRF2 members IL-10R1 and IL-10R2. IL-10 first binds IL-10R1. This interaction apparently
leads to a conformation change of the cytokine creating a binding site for IL-10R2. The close proximity of both receptor components leads to the reciprocal activation of the
receptor-associated Janus kinases Jak1 (associated with IL-10R1) and Tyk2 (associated with IL-10R1). Following the tyrosine phosphorylation of the cytoplasmatic part of IL-
10R1, STAT3 molecules are bound and phosphorylated by the Janus kinases. Additionally, STAT1 and, in certain cell types, STAT5 molecules are activated. STAT homo- or
heterodimers immigrate into the nucleus where they bind to the STAT binding elements of various promoters in order to induce transcription of the corresponding genes.
STAT3 binds via its SH2 domain and in turn becomes itself effects on various cell populations including thymocytes, T cells, B
phosphorylated [102,103]. Additionally, STAT1 and, in certain cell cells, NK cells, monocytes, macrophages, mast cells, as well as
types, STAT5 molecules are activated in IL-10-treated cells neutrophilic and eosinophilic granulocytes were illuminated.
[102,104]. These transcription factors build homo- and hetero- According to the latest knowledge, it appears that above all
dimers that migrate into the cell nucleus and bind to the STAT monocytes/macrophages are the main target cells of the inhibitory
binding elements of various promoters in order to induce IL-10 effects. Interestingly, the IL-10R signaling in monocytes
transcription of the corresponding genes. In contrast to earlier causes transcriptional activation of several hundred genes: In our
studies, there is emerging evidence that, instead of STAT molecule recent gene chip analysis, we found the expression of about 1600
dimerization induced by SH2 tyrosine phosphorylation, the STAT genes up-regulated and of about 1300 genes down-regulated
molecules are already present as dimers in the cytoplasm and will [114]. IL-10 influences three important functions of the mono-
undergo a conformational switch upon activation by the Janus cytes/macrophages: the release of immune mediators, the antigen
kinases [105–108]. The suppressor of cytokine signaling 3 (SOCS3) presentation, and the phagocytosis. Simply said, it suppresses all
is one of the genes whose expression is induced by IL-10. SOCS3 functions of monocytes/macrophages that are responsible for a
belongs to a protein family that binds Janus kinases and inhibits positive role of these cells in both innate and specific immunity. At
their activity [109]. SOCS3 induction appears to be responsible for the same time, it enhances the inhibitory, tolerance inducing, and
the termination of IL-10 effects [110]. ‘scavenger’ functions of these cells. In fact, IL-10 inhibits the
In addition to the two IL-10R1 intracellular tyrosines described release of pro-inflammatory mediators from monocytes/macro-
above, another region of IL-10R1 is essential for inhibiting the phages and therefore inhibits the LPS- and IFN-g-induced
production of inflammatory mediators, specifically a region near secretion of TNF-a, IL-1b, IL-6, IL-8, G-CSF, and GM-CSF
the C-terminus of the chain that contains two serines [111]. [70,115]. Additionally, it enhances the release of anti-inflammato-
Despite intensive research, many aspects of the IL-10 signal ry mediators such as IL-1 receptor antagonist and soluble TNF-a
cascade (e.g. the role of other kinases such as phosphatidylinositol- receptors [116–118]. Thereby, IL-10 drastically reduces the action
3 kinase or p70 S6 kinase that are activated after IL-10 treatment) of important mediators that mostly play a role in innate immunity
are still unclear [112]. The intracellular part of IL-10R1 also (reviewed in [119]). Furthermore, IL-10 inhibits antigen presenta-
contains a region, which, when removed from the cell, makes it 100 tion of monocytes/macrophages. It reduces the constitutive as well
times more sensitive to IL-10. Which mediators play a role in this is as the IFN-g-induced cell surface expression of major histocom-
still unclear [113]. patibility complex class II (MHC II) molecules and of co-stimulating
(e.g. CD86) and adhesion (e.g. CD54) molecules [120–122].
5. Biological effects of IL-10 Moreover, IL-10 inhibits the synthesis of IL-12 [123], thereby,
hampering the development of Th1 immunity. The direct
The biological effects of IL-10 are incredibly multifaceted and inhibitory influence on APCs is then indirectly enhanced by
were intensively investigated in the last years. In doing this, the repression of CD4+ T cells. For example, the IL-10-induced
R. Sabat et al. / Cytokine & Growth Factor Reviews 21 (2010) 331–344 335
inhibition of IL-12 synthesis in APCs results in reduced IFN-g [148]. In eosinophilic granulocytes, IL-10 inhibits the LPS-induced
production in T cells. Further, IL-10 itself reduces IFN-g production synthesis of numerous pro-inflammatory mediators such as TNF-
in Th1 cells (see below). An IFN-g deficit then amplifies the a, GM-CSF, and CXCL8 [149]. Furthermore, the LPS-caused increase
deactivation of APCs [124]. IL-10 also reduces the secretion of IL-23 of vitality in both neutrophilic and eosinophilic granulocytes is
by macrophages [125], which is essential for the existence of Th17 diminished by IL-10 [149,150].
cellular immunity. As mentioned above, IL-10 enhances the IL-10 together with IL-4 suppresses the mast cell development
phagocytosis of monocytes/macrophages [126]. It increases the induced by IL-3 and stem cell factor (SCF) [26]. Furthermore, an
expression of various receptors that are responsible for the uptake incubation of mast cells with IL-10 inhibits the spontaneous and
of opsonized and non-opsonized microorganisms. In fact, IL-10- antigen-induced TNF-a, GM-CSF, and nitric oxide production in
treated monocytes demonstrate an enhanced expression of IgG-Fc these cells [151,152]. IL-10 also diminishes the expression of IgE
receptors (CD64, CD32, CD16) and also of molecules such as CD14, receptor and its signaling molecules like Syk, Fyn, and Akt [153].
which play an important role in the uptake of non-opsonized Consistent with these observations, IL-10 overexpression reduces
material [127–129]. Interestingly, IL-10 concurrently inhibits the the IgE-mediated anaphylactic response in vivo [153].
killing of microorganisms that have been taken up [130]. This Notably, IL-10 also has important non-inhibitory functions on
increased phagocytosis of pathogens could theoretically enhance several immune cells. Thus, it prevents the apoptosis of B cells,
the risk for an attack by complement activity. It seems however enhances their proliferation, differentiation, and MHC II expression
that IL-10 minimizes this danger: it protects human monocytes in addition to playing a positive role in immunoglobulin class
and macrophages from complement lysis [131]. IL-10 has an switching [154–157]. Moreover, IL-10 stimulates the cytotoxic
inhibitory influence on the chemotaxis of monocytes, although it is activity of the NK cells [86]. Additionally, it increases the IL-2-
very weak [132]. It also significantly influences the further induced production of cytokines such as IFN-g, GM-CSF, and TNF-a
differentiation of monocytes because it enhances the final in these cells. It also increases the IL-2-induced proliferation of the
differentiation of these cells into macrophages [127,133] or even CD56-bright subpopulation of NK cells [86].
into inhibitory APCs [134] and at the same time inhibits the The human cytokine is also biologically active in the mouse,
appearance of myeloid dendritic cells [133]. The function of although mIL-10 has no effects on the function of human cells [75].
plasmacytoid dendritic cells (reviewed in [135]) is only minimally The Epstein–Barr virus-encoded IL-10 homologue BCRF1 has a
influenced by IL-10; for example it slightly inhibits the production spectrum of immunological effects similar to that of the human
of type I IFNs in these cells [136,137]. cytokine. However, a series of positive effects cannot be detected.
As mentioned above, IL-10 also acts directly on T cells, For example, the expression of MHC II on murine B cells was not
independent of its inhibitory effect on APCs. IL-10 inhibits both increased by BCRF1 [155,158]. Additionally, a 1000-fold higher
the proliferation and the cytokine synthesis of CD4+ T cells, concentration of viral IL-10 is necessary in comparison to human
including the production of IL-2 and IFN-g by Th1 and of IL-4 and IL-10 in order to produce most effects such as the inhibition of the
IL-5 by Th2 [41,138]. Interestingly, IL-10 is not able to suppress the IL-2 release. This is probably due to a lower affinity of viral IL-10 to
IL-17 production in Th17 cells [139]. In addition, IL-10 apparently IL-10R1. Furthermore, it seems that in contrast to hIL-10 virus IL-
has no direct inhibitory influence on CD8+ T cells [140]. Upon CD4+ 10s bind different IL-10R1 variants (SNP-dependent amino acid
T cell activation in vitro, the presence of IL-10 causes these cells to changes) with different affinities [159].
develop a regulatory phenotype [47,138]. In this manner, Tr1 cells
arise that secrete IL-10 and suppress antigen-specific effector T cell 6. Molecular basis of IL-10’s immunosuppressive effects
responses via a cytokine-dependent mechanism. Although the in
vitro generation of Tr1 can be induced by the pre-treatment of APCs The exact molecular mechanisms of immunosuppressive
with IL-10, the presence of IL-10 in the APC-independent effects of IL-10 on APCs (the inhibition of cytokine production
stimulation of CD4+ T cells, or by further regimens (see below), and antigen presentation) and T cells (the suppression of cytokine
it appears that the effects of IL-10 on APCs play a more important production and proliferation) are still a matter of debate despite a
role in the development of Tr1 than the direct influence on the long research activity in this field.
CD4+ T cells. Additionally, the presence of IL-27 and co- There is however general agreement that STAT3 activation by
engagement of complement receptor CD46 during activation can IL-10 receptor engagement is essential for the anti-inflammatory
also promote the differentiation of naı̈ve T cells to the Tr1 subset effects of IL-10 in cells of myeloid origin. This was demonstrated
[48,50,141]. It is believed that in contrast to Tr1 cells, IL-10 is most convincingly in STAT3-deficient mice [160] and confirmed by
generally not so important for the in vitro suppressive activity of several in vitro studies [161,162]. Most interestingly, there is
Treg cells (reviewed in [142]). However, in 2008 Ito et al. described evidence also from patients with hyper-IgE syndrome, harboring a
two subsets of Treg cells in the human thymus and the periphery dominant negative STAT3 mutation, who show a defective IL-10
defined by the expression of ICOS [143]. Whereas the ICOS+ Treg inhibition of LPS-induced TNF-a [163]. Whether STAT3 activation
cells use IL-10 to suppress DC function and TGF-b to suppress T cell accounts also for direct inhibitory effects on T cells remains to be
function, the ICOS Treg cells used TGF-b only. Furthermore, demonstrated, in particular because cytokines driving pro-
Collison et al. recently postulated that the contact between Treg inflammatory Th17 induction, such as IL-6 and IL-23, act also
and other T cells is important for the induction of IL-35 and the mainly via activation of STAT3. This is reflected by the fact that
active state of the Treg cells although the inhibiting activity of the hyper-IgE syndrome patients with STAT3 mutations also have a
Treg cells is IL-35- and IL-10-dependent [144]. However, Treg cell- strongly reduced Th17 population [164].
produced IL-10 only slightly limits immune responses in the colon New protein synthesis induced by STAT3 activation seems to be
and the lung in vivo [145]. necessary for the anti-inflammatory effects of IL-10 in monocytes/
Similar to monocytes, in neutrophilic granulocytes IL-10 makrophages although anti-inflammatory effects dependent and
inhibits the release of pro-inflammatory mediators. Thereby, it independent of new protein synthesis have been described in
inhibits the production of TNF-a and IL-1b that are induced by LPS neutrophils [165]. This prompted several studies on identifying
or by phagocytosis of bacteria [146]. Additionally, IL-10 inhibits genes which are induced by IL-10 by gene profiling [114,166,167].
the secretion of various chemokines attracting neutrophilic However, from these studies no clear candidate has emerged
granulocytes [147]. The synthesis of cyclooxygenase-2 and the which would be a key mediator of anti-inflammatory effects of IL-
resulting production of prostaglandin E2 are also inhibited by IL-10 10. It appears that some IL-10-induced gene expressions would
[()TD$FIG]
Fig. 3. Interference of IL-10 with LPS-induced gene expression. The engagement of the TLR4 receptor complex by LPS induces pro-inflammatory responses (e.g. expression of
TNF-a) mainly via the Myd88-dependent pathway (depicted in green colours) which triggers cytokine gene transcription via NF-kB and p38 MAPK. The MAPK p38 also
controls TNF-a mRNA stability and translation via MK2 which deactivates the AU-rich element binding protein Tristetraprolin (TTP) by phosphorylation. IL-10-induced
STAT3 activation is essential to induce the expression of several genes that have been implicated in the inhibition of LPS responses (depicted in red). Abin-3, which is active
only in human cells, has been described to interfere with NF-kB activation and thereby prevents translocation of the activating p65/p50 heterodimers into the nucleus. DUSP-
11 inhibits p38 MAPK activation and thereby might prevent deactivation of TTP which then can initiate degradation of cytokine mRNAs via binding to AU-rich elements in
their 30 UTR. The IkB family members bcl-3 and IKBNS might favor the transport of p50 into the nucleus and, by an unknown mechanism, guide the binding of p50/p50
homodimers to NF-kB sites of specific promoters. Consequently, the binding of transcriptionally active p65/p50 heterodimers at these sites NF-kB sites is prevented.
rather lead to effect-specific inhibition as discussed in more detail fact that IL-10 inhibits miR-155 induction by TLRs [185]. This
below. microRNA targets the phosphatase SHIP1 mRNA [186], and
Monocytic cells (monocytes, macrophages, dendritic cells) therefore SHIP1 levels are elevated which has been shown in
produce several pro-inflammatory mediators after the recognition another context to affect TLR signaling events [187].
of pathogens e.g. by means of TLR family members. Engaged TLRs Murray claimed that the anti-inflammatory effects of IL-10 in
trigger signal transduction cascades via several adaptor molecules murine macrophages are mainly mediated at the level of
of which MyD88 is the most common one used. This leads to the transcriptional activation of TNF-a gene [188]. There have been
activation of the transcription factor NF-kB and several MAP several mechanisms suggested by which such a transcriptional
kinases (p38, ERK, JNK) (Fig. 3) (reviewed in [168–170]). IL-10 in repression of pro-inflammatory cytokines could be realized. First,
turn is known to inhibit the TLR-triggered production of pro- IL-10 was suggested to induce nuclear translocation and DNA
inflammatory mediators (see above). There are contrasting reports binding of the transcriptionally inactive p50/p50 homodimers of
whether IL-10 would interfere with TLR-induced signaling events NF-kB leading to reduced transcription of NF-kB dependent gene
(reviewed in [171]). Of the IL-10-induced gene expression SOCS3 expression [189]. However, Cao et al. demonstrated that p50/p50
initially seemed to be the most promising candidate particularly homodimers are not transcriptionally inactive and specifically
since deficiency of its kinsman SOCS1 (which itself does not seem induce the expression of IL-10 [190]. Therefore the possibility
to be clearly induced by IL-10) augmented the LPS response and arises that these inhibitory effects of p50/p50 homodimers could
mortality due to an interference with the Myd88-independent result from an autocrine IL-10 feedback loop, which would down-
pathway and inhibition of type I IFN [172–174]. However, SOCS3- regulate cytokine expression via an alternative mechanism.
deficient mice exhibited a normal capacity of IL-10 to inhibit TNF- From gene expression profiling, several factors emerged which
a production [175–177]. Some phosphatases, which deactivate have been described to repress NF-kB activity (Bcl-3 [191], IKBNS
specific MAP kinases (e.g. DUSP1/MKP1), have been reported to be [192], Abin3 [193], ETV3, and SBNO2 (Fig. 3) [194]). However,
regulated by IL-10 [178] and were also shown to be negative formal proof that absence of these factors would abrogate the IL-10
regulators of LPS-signaling (Fig. 3) [179–182]. However, formal inhibitory effect was provided only so far for Bcl-3. Interestingly,
proof that genetic deficiencies of these phosphatases would Bcl-3 and IKBNS might mediate the above mentioned recruitment
abrogate the inhibitory capacity of IL-10 is still lacking [180] or of p50/p50 homodimers, but only to specific cytokine promoters.
even disproved for TNF-a regulation [179]. Some recent papers Whereas Bcl-3 regulates TNF-a and IL-23p19 but not IL-6
suggested that translation of MyD88 [183] or ubiquitination and expression [191,195], IKBNS is affecting only IL-6 and IL-12/IL-
thereby degradation of MyD88-dependent signaling molecules 23p40 but not TNF-a transcription. On the other hand, the IL-10
(IRAK-1, IRAK-4 and TRAF6) [184] might be regulated by IL-10. induced gene B-ATF, which can repress AP-1 activity, does
Another level of regulation of TLR signaling could arise from the apparently neither affect TNF-a nor IL-6 expression [171].
There have been several reports supporting the idea that there temporary immunodeficiency occurring after trauma, major
is a post-transcriptional element in the inhibitory capacity of IL-10 surgery, burns, or shock, and which has a high risk of bacterial/
[196–199]. However, this may be dependent on the timing of the mycological infections with lethal outcomes [214–219]. It seems
IL-10 challenge [200]. Many cytokines including IL-10 itself and that macrophage-derived IL-10 is also jointly responsible for age-
growth factors contain AU-rich elements (AREs) which are associated immune deficiency [220].
targeted by ARE-binding proteins thereby regulating mRNA In diseases with a relative or absolute IL-10 deficiency, a
stability and translation. The TLR-activated p38 MAPK pathway persistent immune activation exists. This is the case in chronic-
has been shown to regulate mRNA-decay of TNF-a via inactivation inflammatory bowel diseases (e.g. Crohn’s disease), psoriasis,
of TTP by MK2-mediated phosphorylation (reviewed in [201]). rheumatoid arthritis, and after organ transplantation [221–224].
Some publications suggest that IL-10 would interfere with this The IL-10 promoter was found to have discrete SNPs in different
pathway either by interfering with p38 MAPK signaling [199,202] individuals, similar to promoters of other cytokines ([225] and
or by regulating the expression of the ARE-binding proteins TTP reviewed in [226,227]). Interestingly, the transcription factor Sp1
[203] or HuR [202,204] (Fig. 3). was shown to bind to one of these SNPs and to enhance IL-10
As mentioned above, IL-10 is thought to be responsible for the transcription in response to LPS [228]. However, it should be noted
inhibition of Th1, Th2, and Th17 immunity. Some of the negative that the association of SNPs in the IL-10 promoter and the amount
effects of IL-10 on T cell activation are the result of the of secreted IL-10 is dependent on many facts e.g. cell type,
immunosuppressive effects on APCs. The IL-10-induced inhibition stimulation time, and kind of stimulus [191,229]. Nevertheless,
of antigen presentation causes a down-regulation of Th1 as well as correlations between certain haplotypes of the IL-10 and IL-10R1
Th2 and Th17 responses. Interestingly, Koppelman et al. [205] genes and the occurrence and/or course of various diseases were
demonstrated that, in IL-10-treated monocytes, mature peptide- described [230–235]. In fact, in Lupus erythematosus, not only was
bound MHC II molecules accumulate in intracellular vesicles and the correlation statistically significant between the haplotype and
are prevented from reaching the cell membrane. The Steimle group the occurrence of disease, but also between the type of antibody
recently explained this phenomenon [206]. They found that in and the severity of the clinical condition [230,232,236]. Addition-
human primary monocytes IL-10 induces the membrane-associ- ally, an increased incidence of certain variations of the IL-10
ated RING-CH (MARCH) 1, a member of the ubiquitin ligase family. promoter is described in differing courses of the EBV infection
MARCH1 down-regulates the surface expression of MHC II [237]. Furthermore, an IL-10 ‘higher producing’ haplotype was
molecules in transfected cells. Furthermore, they found ubiquiti- found to be significantly associated with a reduced risk of
nated forms of MHC II molecules both in IL-10-treated monocytes developing melanoma [234]. Also, the immune reaction against
and in cells transfected with MARCH1. Consequently, the transplants appears to be influenced by polymorphisms in the
knockdown of MARCH1 by means of siRNA reverses IL-10-induced promoter region of various cytokines. After heart transplantations,
MHC II down-regulation in primary monocytes. those recipients defined by their promoter type to be ‘‘TNF-a high/
In addition to antigen presentation, cytokine production, which IL-10 low’’—producers are more often confronted with organ
would favor the development of Th1 cells, is reduced greatly as rejection [235]. In the first six months after kidney transplanta-
discussed above. Interestingly, even the IFN-g production in pre- tions, however, those defined as ‘‘TNF-a high/IL-10 high’’—
activated T cells is indirectly inhibited by IL-10 via its down- producers had most frequently multiple rejection episodes,
regulating effect on the APC IL-12 and IL-18 production [207]. In whereas the ‘‘TNF-a low/IL-10 low’’ producer genotype was
addition to the indirect influence on T cell activation, there have protective [238]. This slight discrepancy makes clear that the role
been some reports about a direct inhibition of CD4+ T ells when of IL-10 promoter polymorphisms in the pathogenesis of certain
stimulated by low numbers of triggered T cell receptors [208,209]. diseases have to be further investigated.
It has been proposed that this would be mainly due to an inhibitory
affect of IL-10 on the CD28 co-stimulatory pathway, namely a 8. Biological relevance of IL-10
reduced CD28 tyrosine phosphorylation and thereby reduced
recruitment of phosphatidylinositol 3-kinase p85 [209]. However, The biological relevance of IL-10 is better understandable if the
our own observations demonstrated that IL-10 can also inhibit timeline of released cytokines after cell activation is kept in mind.
T cell receptor-induced IFN-g production in CD28-negative T cells IL-10 is a rather late cytokine being produced after the pro-
suggesting an additional mechanism independent of CD28 inflammatory mediators. Thereby, it has a special physiological
signaling [139]. significance in limiting and preventing an excessive immune
response and in limiting collateral damage. Concurrently, it
7. Role of IL-10 in immune-mediated diseases strengthens the ‘‘scavenger’’ functions of the immune system
which is important after a conflict with antigens, and it contributes
There are numerous investigations that describe an important to the peripheral tolerance during antigen persistence.
role of IL-10 in the pathogenesis of various diseases. These diseases Its relevance can be seen in both IL-10-deficient (Table 1) and
can be subdivided into: IL-10-over-expressing animals [239]. Such IL-10-deficient mice,
when bred under normal conditions, develop lethal intestinal
(a) Diseases with relative or absolute IL-10 over-production and inflammation as a sign of an excessive immune reaction to the
(b) Diseases with a relative or absolute IL-10 deficiency. intestinal antigens of otherwise commensal bacteria [240].
Notably, a similar phenotype is observed in mice where only
In diseases with an IL-10 over-production, undesired immuno- CD4+ T cells are unable to secrete IL-10 [17]. This inflammation can
suppressive effects of IL-10 and the growth of some tumors can be be reduced by a sterile environment and the application of IL-10 or
observed. Lupus erythematosus, EBV-associated lymphomas, and Treg cells [240]. Moreover, IL-10 produced by macrophages is
skin malignomas such as melanoma belong to this group of necessary for the Treg cells-mediated prevention of colitis
diseases [210–212]. Furthermore, an elevated production of IL-10 induced by transferred CD4+CD45RB+ T cells [16,59]. In fact, in
during infections causes unfavorable progress. For example, a IL-10(/)Rag1(/) mice, Treg cells failed to maintain Foxp3
genetically dependent increased production of IL-10 is strongly expression and regulatory activity. Consequently, IL-10R1-defi-
associated with active lesions of cutaneous leishmaniasis [213]. IL- cient Treg cells also failed to maintain Foxp3 expression, which
10 also plays a decisive role in the formation of immune paralysis, a suggests that IL-10 released from myeloid cells acts in a paracrine
Table 1
Effects of IL-10 knockout on different mouse models.
Model Phenotype IL-10 knockout (mouse) References
Inflammatory bowel disease Spontaneous inflammatory bowel disease [16,240]

LPS inflammation Uncontrolled production of TNF-a [17,19,242,243]
High mortality rate
Collagen-induced arthritis More susceptible [244,250]
More severe course of the disease
Experimental autoimmune encephalomyelitis More severe course of the disease [244]
OVA-induced asthma Reduced immunopathology [265]
Influenza virus infection Enhanced clearance of pathogens [260,266]
Improved survival
Cytomegalovirus infection Enhanced clearance of pathogens [267]
Severe inflammation
Lymhocytic choriomeningitis virus infection Enhanced clearance of pathogens [268]
Chlamydia pneumoniae infection Enhanced clearance of pathogens [269,270]
Severe inflammation
Mycobacterium tuberculosis/bovis infection Enhanced clearance of pathogens [248,271]
Severe immunopathology
Systemic Escherichia coli infection Enhanced clearance of pathogens [272]
High mortality rate
Systemic Candida albicans infection Enhanced clearance of pathogens [273]
Toxoplasma gondii infection Lethal inflammatory response [17,43,274,275]
Leishmania major infection Enhanced clearance of pathogens [40,255,257,276]
Plasmodium chabaudi chabaudi infection Enhanced immunopathology [277–279]
Higher rate of mortality
Trypanosoma cruzi infection Enhanced clearance of Pathogens [280,281]
Earlier mortality
Schistosoma mansoni infection Enhanced inflammation [282,283]
Higher rate of mortality
manner on Treg cells to maintain Foxp3 expression [16]. Together in [262]). For example, Th1 cell-derived IL-10 mainly inhibits Th17
with the observation that IL-10-deficient Tregs cells have slight cells and is responsible for the death of mice that were challenged
defects in controlling intestinal immune responses [145], this with high doses of influenza [260]. IL-10 produced by NK cells
points to a crucial role for IL-10 in the maintenance of gut inhibits protective immunity in mice models of visceral leishman-
homeostasis and tolerance to commensal bacteria in the mouse. In iasis [259].
the human, IL-10 appears to have a similar role since patients with The knowledge regarding IL-10 effects forces us to think about
defective IL-10R expression also develop a severe form of IBD modulation of IL-10 activity as a potential therapy for chronic
[241]. The second very impressive example is systemic endotox- infection (by decrease of IL-10 activity) or chronic inflammatory
emia (LPS shock). Following application of modest LPS doses, mice diseases (by enhancement of IL-10 activity). We could hope for
deficient in IL-10 production showed an uncontrolled TNF-a enhanced clearance of pathogens as a result of inhibition of IL-10
secretion and a high mortality rate [242]. Subsequent studies with effects, however, we also have to anticipate higher TNF-a, IFN-g,
cell-specific IL-10- and IL-10R1-deficient animals clearly demon- and IL-17 levels, more distinct inflammation, and severe immu-
strated that in this model protective IL-10 is produced by nopathology. The inhibition of IL-10 effects may be achieved by
macrophages and/or neutrophils and acts on these cells in an means of application of anti-IL-10 or anti-IL-10R1 antibodies as
autocrine loop [17,19,243]. Furthermore, this anti-inflammatory well as by induction of autoantibodies against these molecules
and immunosuppressive role of IL-10 is seen in many local and (reviewed in [263]). On the other hand, the fact that IL-10 mediates
systemic inflammatory processes and some infections the therapeutic effects of some immunosuppressive therapies such
[22,25,40,43,244–253]. For example, Langerhans cell-derived IL- as extracorporeal photopheresis [264] supports the reasons for
10 is required for suppression of hapten-specific CD4 and CD8 T using IL-10 as an immunosuppressive drug. However, before that,
cells and optimal inhibition of contact-hypersensitivity in mice we have to clear up how strong the inhibitory influence of IL-10
[249]. IL-10 produced by Th1 cells were shown to prevent actually is on Th17 cells, Th22 cells, myeloid DCs, and plasmacytoid
immunopathology upon infection with intracellular pathogens, DCs as well as how important IL-10 is for the development of Tr1
such as the protozoan Leishmania major during chronic cutaneous cells in vivo. Can we hope that by means of IL-10 application in
leishmaniasis [40] and the protozoan Toxoplasma gondii during patients we can generate Tr1 cells?
systemic infection [43]. In the murine model of listeriosis, after TCR-
mediated interactions with Listeria-elicited macrophages, by means
Acknowledgments
of IL-10, gd T cells control the expansion and TNF-a secretion from
CD8+ T cell as well as protect the animals against liver injury [25].
The authors thank Elisabeth Wallace and Brigitte Ketel for the
Furthermore, IL-10 produced by B cells suppresses pathogenic
assistance.
inflammation in experimental autoimmune encephalomyelitis
(EAE) [22] and decreases virus-specific CD8+ T cell responses during
murine cytomegalovirus infection in the spleen [252]. References
On the other hand, organisms whose APCs or other cells
[1] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV.
produce an increased amount of IL-10 are not able to control both Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J
various infections and tumor growth ([239,254–261] and reviewed Exp Med 1989;170:2081–95.
[2] Kim JM, Brannan CI, Copeland NG, Jenkins NA, Khan TA, Moore KW. Structure [31] Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, et al.
of the mouse IL-10 gene and chromosomal localization of the mouse and Specificity in Toll-like receptor signalling through distinct effector functions
human genes. J Immunol 1992;148:3618–23. of TRAF3 and TRAF6. Nature 2006;439:204–7.
[3] Josephson K, Logsdon NJ, Walter MR. Crystal structure of the IL-10/IL-10R1 [32] Meisel C, Vogt K, Platzer C, Randow F, Liebenthal C, Volk HD. Differential
complex reveals a shared receptor binding site. Immunity 2001;15:35–46. regulation of monocytic tumor necrosis factor-alpha and interleukin-10
[4] Walter MR, Nagabhushan TL. Crystal structure of interleukin 10 reveals an expression. Eur J Immunol 1996;26:1580–6.
interferon gamma-like fold. Biochemistry 1995;34:12118–25. [33] Platzer C, Meisel C, Vogt K, Platzer M, Volk HD. Up-regulation of monocytic IL-
[5] Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, Weatherbee J, Wlodawer A. 10 by tumor necrosis factor-alpha and cAMP elevating drugs. Int Immunol
Crystal structure of interleukin-10 reveals the functional dimer with an unex- 1995;7:517–23.
pected topological similarity to interferon gamma. Structure 1995;3:591–601. [34] Suberville S, Bellocq A, Fouqueray B, Philippe C, Lantz O, Perez J, et al.
[6] Zdanov A, Schalk-Hihi C, Wlodawer A. Crystal structure of human interleukin- Regulation of interleukin-10 production by beta-adrenergic agonists. Eur J
10 at 1.6 A resolution and a model of a complex with its soluble receptor. Immunol 1996;26:2601–5.
Protein Sci 1996;5:1955–62. [35] Chung EY, Liu J, Homma Y, Zhang Y, Brendolan A, Saggese M, et al. Interleukin-
[7] Savan R, Ravichandran S, Collins JR, Sakai M, Young HA. Structural conserva- 10 expression in macrophages during phagocytosis of apoptotic cells is
tion of interferon gamma among vertebrates. Cytokine Growth Factor Rev mediated by homeodomain proteins Pbx1 and Prep-1. Immunity
2009;20:115–24. 2007;27:952–64.
[8] Windsor WT, Syto R, Tsarbopoulos A, Zhang R, Durkin J, Baldwin S, et al. [36] Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A, et al.
Disulfide bond assignments and secondary structure analysis of human and Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a.
murine interleukin 10. Biochemistry 1993;32:8807–15. Proc Natl Acad Sci USA 2009;106:5761–6.
[9] Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the [37] Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, O’Garra A.
interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765. Interleukin-10 production by Th1 cells requires interleukin-12-induced
[10] Zdanov A, Schalk-Hihi C, Menon S, Moore KW, Wlodawer A. Crystal structure STAT4 transcription factor and ERK MAP kinase activation by high antigen
of Epstein–Barr virus protein BCRF1, a homolog of cellular interleukin-10. J dose. Immunity 2009;31:209–19.
Mol Biol 1997;268:460–7. [38] Calado DP, Paixao T, Holmberg D, Haury M. Stochastic monoallelic expression
[11] Liu Y, de Waal Malefyt R, Briere F, Parham C, Bridon JM, Banchereau J, et al. of IL-10 in T cells. J Immunol 2006;177:5358–64.
The EBV IL-10 homologue is a selective agonist with impaired binding to the [39] Ahyi AN, Chang HC, Dent AL, Nutt SL, Kaplan MH. IFN regulatory factor 4
IL-10 receptor. J Immunol 1997;158:604–13. regulates the expression of a subset of Th2 cytokines. J Immunol
[12] Volk H, Asadullah K, Gallagher G, Sabat R, Grutz G. IL-10 and its homologs: 2009;183:1598–606.
important immune mediators and emerging immunotherapeutic targets. [40] Anderson CF, Oukka M, Kuchroo VJ, Sacks D. CD4(+)CD25()Foxp3() Th1
Trends Immunol 2001;22:414–7. cells are the source of IL-10-mediated immune suppression in chronic
[13] Sabat R, Wallace E, Endesfelder S, Wolk K. IL-19 and IL-20: two novel cytokines cutaneous leishmaniasis. J Exp Med 2007;204:285–97.
with importance in inflammatory diseases. Expert Opin Ther Targets [41] Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S.
2007;11:601–12. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2)
[14] Wolk K, Sabat R. Interleukin-22: a novel T- and NK-cell derived cytokine that T cell clones and inhibits their antigen-specific proliferation and cytokine
regulates the biology of tissue cells. Cytokine Growth Factor Rev 2006;17: production. J Immunol 1993;150:353–60.
367–80. [42] Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, et al.
[15] Wolk K, Kunz S, Asadullah K, Sabat R. Cutting edge: immune cells as sources Suppression of autoimmune inflammation of the central nervous system
and targets of the IL-10 family members? J Immunol 2002;168: by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol
5397–402. 2007;8:1372–9.
[16] Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. [43] Jankovic D, Kullberg MC, Feng CG, Goldszmid RS, Collazo CM, Wilson M, et al.
Interleukin 10 acts on regulatory T cells to maintain expression of the Conventional T-bet(+)Foxp3() Th1 cells are the major source of host-pro-
transcription factor Foxp3 and suppressive function in mice with colitis. tective regulatory IL-10 during intracellular protozoan infection. J Exp Med
Nat Immunol 2009;10:1178–84. 2007;204:273–83.
[17] Roers A, Siewe L, Strittmatter E, Deckert M, Schluter D, Stenzel W, et al. T cell- [44] Garcia CA, Wang H, Benakanakere MR, Barrett E, Kinane DF, Martin M. c-jun
specific inactivation of the interleukin 10 gene in mice results in enhanced T controls the ability of IL-12 to induce IL-10 production from human memory
cell responses but normal innate responses to lipopolysaccharide or skin CD4+ T cells. J Immunol 2009;183:4475–82.
irritation. J Exp Med 2004;200:1289–97. [45] Anderson CF, Stumhofer JS, Hunter CA, Sacks D. IL-27 regulates IL-10 and IL-
[18] Seki S, Osada S, Ono S, Aosasa S, Habu Y, Nishikage T, et al. Role of liver NK 17 from CD4+ cells in nonhealing Leishmania major infection. J Immunol
cells and peritoneal macrophages in gamma interferon and interleukin-10 2009;183:4619–27.
production in experimental bacterial peritonitis in mice. Infect Immun [46] Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, et al.
1998;66:5286–94. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin
[19] Siewe L, Bollati-Fogolin M, Wickenhauser C, Krieg T, Muller W, Roers A. 10. Nat Immunol 2007;8:1363–71.
Interleukin-10 derived from macrophages and/or neutrophils regulates the [47] Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, et al. A
inflammatory response to LPS but not the response to CpG DNA. Eur J CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents
Immunol 2006;36:3248–55. colitis. Nature 1997;389:737–42.
[20] Blanco P, Palucka AK, Pascual V, Banchereau J. Dendritic cells and cytokines in [48] Batten M, Kljavin NM, Li J, Walter MJ, de Sauvage FJ, Ghilardi N. Cutting edge:
human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. J Immunol
2008;19:41–52. 2008;180:2752–6.
[21] Chomarat P, Rissoan MC, Banchereau J, Miossec P. Interferon gamma inhibits [49] Murugaiyan G, Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL.
interleukin 10 production by monocytes. J Exp Med 1993;177:523–7. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J
[22] Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate Immunol 2009;183:2435–43.
autoimmunity by provision of IL-10. Nat Immunol 2002;3:944–50. [50] Pot C, Jin H, Awasthi A, Liu SM, Lai CY, Madan R, et al. Cutting edge: IL-27
[23] Grant LR, Yao ZJ, Hedrich CM, Wang F, Moorthy A, Wilson K, et al. Stat4- induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory
dependent, T-bet-independent regulation of IL-10 in NK cells. Genes Immun receptor ICOS that coordinately act together to promote differentiation of IL-
2008;9:316–27. 10-producing Tr1 cells. J Immunol 2009;183:797–801.
[24] Mehrotra PT, Donnelly RP, Wong S, Kanegane H, Geremew A, Mostowski HS, [51] Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, et al. The aryl
et al. Production of IL-10 by human natural killer cells stimulated with IL-2 hydrocarbon receptor interacts with c-Maf to promote the differentiation
and/or IL-12. J Immunol 1998;160:2637–44. of type 1 regulatory T cells induced by IL-27. Nat Immunol 2010;11:
[25] Rhodes KA, Andrew EM, Newton DJ, Tramonti D, Carding SR. A subset of IL- 854–61.
10-producing gammadelta T cells protect the liver from Listeria-elicited, [52] Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B, Laroni A, et al. Activation of
CD8(+) T cell-mediated injury. Eur J Immunol 2008;38:2274–83. the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like
[26] Speiran K, Bailey DP, Fernando J, Macey M, Barnstein B, Kolawole M, et al. and Foxp3(+) regulatory T cells. Nat Immunol 2010;11:846–53.
Endogenous suppression of mast cell development and survival by IL-4 and [53] Monteleone G, Pallone F, Macdonald TT. Interleukin-21 (IL-21)-mediated
IL-10. J Leukoc Biol 2009;85:826–36. pathways in T cell-mediated disease. Cytokine Growth Factor Rev
[27] Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF. The development 2009;20:185–91.
and function of regulatory B cells expressing IL-10 (B10 cells) requires [54] Spolski R, Kim HP, Zhu W, Levy DE, Leonard WJ. IL-21 mediates suppressive
antigen receptor diversity and TLR signals. J Immunol 2009;182: effects via its induction of IL-10. J Immunol 2009;182:2859–67.
7459–72. [55] Xu J, Yang Y, Qiu G, Lal G, Wu Z, Levy DE, et al. c-Maf regulates IL-10
[28] Zhang X, Majlessi L, Deriaud E, Leclerc C, Lo-Man R. Coactivation of Syk kinase expression during Th17 polarization. J Immunol 2009;182:6226–36.
and MyD88 adaptor protein pathways by bacteria promotes regulatory [56] Gabrysova L, Nicolson KS, Streeter HB, Verhagen J, Sabatos-Peyton CA,
properties of neutrophils. Immunity 2009;31:761–71. Morgan DJ, et al. Negative feedback control of the autoimmune response
[29] Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to through antigen-induced differentiation of IL-10-secreting Th1 cells. J Exp
infection. J Immunol 2008;180:5771–7. Med 2009;206:1755–67.
[30] Banerjee A, Gugasyan R, McMahon M, Gerondakis S. Diverse Toll-like recep- [57] Haringer B, Lozza L, Steckel B, Geginat J. Identification and characterization of
tors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in IL-10/IFN-gamma-producing effector-like T cells with regulatory function in
hemopoietic cells. Proc Natl Acad Sci USA 2006;103:3274–9. human blood. J Exp Med 2009;206:1009–17.
[58] Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, Rudensky AY, [87] Jurlander J, Lai CF, Tan J, Chou CC, Geisler CH, Schriber J, et al. Characterization
et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and of interleukin-10 receptor expression on B-cell chronic lymphocytic leuke-
Foxp3 precursor cells in the absence of interleukin 10. Nat Immunol mia cells. Blood 1997;89:4146–52.
2007;8:931–41. [88] Kunz S, Wolk K, Witte E, Witte K, Doecke WD, Volk HD, et al. Interleukin (IL)-
[59] Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria 19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct
macrophages and dendritic cells differentially induce regulatory and inter- from classical ILs. Exp Dermatol 2006;15:991–1004.
leukin 17-producing T cell responses. Nat Immunol 2007;8:1086–94. [89] Wolk K, Witte K, Witte E, Proesch S, Schulze-Tanzil G, Nasilowska K, et al.
[60] Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and Maturing dendritic cells are an important source of IL-29 and IL-20 that may
restraining inflammation. Cell 2010;140:845–58. cooperatively increase the innate immunity of keratinocytes. J Leukoc Biol
[61] Maynard CL, Hatton RD, Helms WS, Oliver JR, Stephensen CB, Weaver CT. 2008;83:1181–93.
Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction [90] Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases the
of Foxp3 and Il10 genes in developing regulatory T cells. J Exp Med innate immunity of tissues. Immunity 2004;21:241–54.
2009;206:343–57. [91] Geginat J, Sallusto F, Lanzavecchia A. Cytokine-driven proliferation and
[62] Brandenburg S, Takahashi T, de la Rosa M, Janke M, Karsten G, Muzzulini T, differentiation of human naive, central memory, and effector memory
et al. IL-2 induces in vivo suppression by CD4(+)CD25(+)Foxp3(+) regulatory CD4(+) T cells. J Exp Med 2001;194:1711–9.
T cells. Eur J Immunol 2008;38:1643–53. [92] Seifert M, Gruenberg BH, Sabat R, Donner P, Gruetz G, Volk HD, et al.
[63] Tsuji-Takayama K, Suzuki M, Yamamoto M, Harashima A, Okochi A, Otani T, Keratinocyte unresponsiveness towards interleukin-10: lack of specific bind-
et al. The production of IL-10 by human regulatory T cells is enhanced by IL-2 ing due to deficient IL-10 receptor 1 expression. Exp Dermatol 2003;12:137–
through a STAT5-responsive intronic enhancer in the IL-10 locus. J Immunol 44.
2008;181:3897–905. [93] Weber-Nordt RM, Meraz MA, Schreiber RD. Lipopolysaccharide-dependent
[64] McLachlan JB, Catron DM, Moon JJ, Jenkins MK. Dendritic cell antigen induction of IL-10 receptor expression on murine fibroblasts. J Immunol
presentation drives simultaneous cytokine production by effector and regu- 1994;153:3734–44.
latory T cells in inflamed skin. Immunity 2009;30:277–88. [94] Crepaldi L, Gasperini S, Lapinet JA, Calzetti F, Pinardi C, Liu Y, et al. Up-
[65] Zhang N, Schroppel B, Lal G, Jakubzick C, Mao X, Chen D, et al. Regulatory T regulation of IL-10R1 expression is required to render human neutrophils
cells sequentially migrate from inflamed tissues to draining lymph nodes to fully responsive to IL-10. J Immunol 2001;167:2312–22.
suppress the alloimmune response. Immunity 2009;30:458–69. [95] Ding Y, Qin L, Zamarin D, Kotenko SV, Pestka S, Moore KW, et al. Differential
[66] Vanden Eijnden S, Goriely S, De Wit D, Willems F, Goldman M. IL-23 up- IL-10R1 expression plays a critical role in IL-10-mediated immune regulation.
regulates IL-10 and induces IL-17 synthesis by polyclonally activated naive T J Immunol 2001;167:6884–92.
cells in human. Eur J Immunol 2005;35:469–75. [96] Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, et al. IL-22 and IL-
[67] McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClana- 20 are key mediators of the epidermal alterations in psoriasis while IL-17 and
han T, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T IFN-gamma are not. J Mol Med 2009;87:523–36.
cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol [97] Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al.
2007;8:1390–7. IFN-lambdas mediate antiviral protection through a distinct class II cytokine
[68] Wolk K, Witte E, Witte K, Warszawska K, Sabat R. Biology of interleukin-22. receptor complex. Nat Immunol 2003;4:69–77.
Semin Immunopathol 2010;32:17–31. [98] Sheikh F, Baurin VV, Lewis-Antes A, Shah NK, Smirnov SV, Anantha S, et al.
[69] Diveu C, McGeachy MJ, Boniface K, Stumhofer JS, Sathe M, Joyce-Shaikh B, Cutting edge: IL-26 signals through a novel receptor complex composed of IL-
et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 20 receptor 1 and IL-10 receptor 2. J Immunol 2004;172:2006–10.
cells. J Immunol 2009;182:5748–56. [99] Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore
[70] de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10 TE, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol
(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory 2003;4:63–8.
role of IL-10 produced by monocytes. J Exp Med 1991;174:1209–20. [100] Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, et al. Interleukin (IL)-
[71] Frasca L, Nasso M, Spensieri F, Fedele G, Palazzo R, Malavasi F, et al. IFN- 22, a novel human cytokine that signals through the interferon receptor-
gamma arms human dendritic cells to perform multiple effector functions. J related proteins CRF2-4 and IL-22R. J Biol Chem 2000;275:31335–9.
Immunol 2008;180:1471–81. [101] Gough DJ, Levy DE, Johnstone RW, Clarke CJ. IFNgamma signaling—does it
[72] Rivino L, Gruarin P, Haringer B, Steinfelder S, Lozza L, Steckel B, et al. CCR6 is mean JAK-STAT? Cytokine Growth Factor Rev 2008;19:383–94.
expressed on an IL-10-producing, autoreactive memory T cell population [102] Finbloom DS, Winestock KD. IL-10 induces the tyrosine phosphorylation of
with context-dependent regulatory function. J Exp Med 2010;207:565–77. tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3
[73] Kotenko SV. The family of IL-10-related cytokines and their receptors: complexes in human T cells and monocytes. J Immunol 1995;155:1079–90.
related, but to what extent? Cytokine Growth Factor Rev 2002;13:223–40. [103] Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber
[74] Ho AS, Liu Y, Khan TA, Hsu DH, Bazan JF, Moore KW. A receptor for interleukin 10 RD. Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphory-
is related to interferon receptors. Proc Natl Acad Sci USA 1993;90:11267–71. lated docking sites in the interleukin-10 receptor intracellular domain. J Biol
[75] Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW. Expression cloning and Chem 1996;271:27954–61.
characterization of a human IL-10 receptor. J Immunol 1994;152:1821–9. [104] Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM.
[76] Taniyama T, Takai S, Miyazaki E, Fukumura R, Sato J, Kobayashi Y, et al. The IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and
human interleukin-10 receptor gene maps to chromosome 11q23.3. Hum Stat5) and their distinct combinatorial assembly in the promoters of selected
Genet 1995;95:99–101. genes. FEBS Lett 1996;394:365–70.
[77] Gasche C, Grundtner P, Zwirn P, Reinisch W, Shaw SH, Zdanov A, et al. Novel [105] Haan S, Kortylewski M, Behrmann I, Muller-Esterl W, Heinrich PC, Schaper F.
variants of the IL-10 receptor 1 affect inhibition of monocyte TNF-alpha Cytoplasmic STAT proteins associate prior to activation. Biochem J
production. J Immunol 2003;170:5578–82. 2000;345(Pt 3):417–21.
[78] Hofer H, Neufeld JB, Oesterreicher C, Grundtner P, Wrba F, Gangl A, et al. Bi- [106] Kretzschmar AK, Dinger MC, Henze C, Brocke-Heidrich K, Horn F. Analysis of
allelic presence of the interleukin-10 receptor 1 G330R allele is associated Stat3 (signal transducer and activator of transcription 3) dimerization by
with cirrhosis in chronic HCV-1 infection. Genes Immun 2005;6:242–7. fluorescence resonance energy transfer in living cells. Biochem J
[79] Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S. Identification 2004;377:289–97.
and functional characterization of a second chain of the interleukin-10 [107] Novak U, Ji H, Kanagasundaram V, Simpson R, Paradiso L. STAT3 forms stable
receptor complex. EMBO J 1997;16:5894–903. homodimers in the presence of divalent cations prior to activation. Biochem
[80] Reineke U, Schneider-Mergener J, Glaser RW, Stigler RD, Seifert M, Volk HD, Biophys Res Commun 1998;247:558–63.
et al. Evidence for conformationally different states of interleukin-10: bind- [108] Schroder M, Kroeger KM, Volk HD, Eidne KA, Grutz G. Preassociation of
ing of a neutralizing antibody enhances accessibility of a hidden epitope. J nonactivated STAT3 molecules demonstrated in living cells using biolumi-
Mol Recognit 1999;12:242–8. nescence resonance energy transfer: a new model of STAT activation? J
[81] Wolk K, Witte E, Reineke U, Witte K, Friedrich M, Sterry W, et al. Is there an Leukoc Biol 2004;75:792–7.
interaction between interleukin-10 and interleukin-22? Genes Immun [109] Piessevaux J, Lavens D, Peelman F, Tavernier J. The many faces of the SOCS
2005;6:8–18. box. Cytokine Growth Factor Rev 2008;19:371–81.
[82] Yoon SI, Logsdon NJ, Sheikh F, Donnelly RP, Walter MR. Conformational [110] Ito S, Ansari P, Sakatsume M, Dickensheets H, Vazquez N, Donnelly RP, et al.
changes mediate interleukin-10 receptor 2 (IL-10R2) binding to IL-10 and Interleukin-10 inhibits expression of both interferon alpha- and interferon
assembly of the signaling complex. J Biol Chem 2006;281:35088–96. gamma-induced genes by suppressing tyrosine phosphorylation of STAT1.
[83] Logsdon NJ, Jones BC, Josephson K, Cook J, Walter MR. Comparison of Blood 1999;93:1456–63.
interleukin-22 and interleukin-10 soluble receptor complexes. J Interferon [111] Riley JK, Takeda K, Akira S, Schreiber RD. Interleukin-10 receptor signaling
Cytokine Res 2002;22:1099–112. through the JAK-STAT pathway. Requirement for two distinct receptor-derived
[84] Reineke U, Sabat R, Volk HD, Schneider-Mergener J. Mapping of the interleu- signals for anti-inflammatory action. J Biol Chem 1999;274:16513–21.
kin-10/interleukin-10 receptor combining site. Protein Sci 1998;7:951–60. [112] Crawley JB, Williams LM, Mander T, Brennan FM, Foxwell BM. Interleukin-10
[85] Yoon SI, Jones BC, Logsdon NJ, Harris BD, Deshpande A, Radaeva S, et al. stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required
Structure and mechanism of receptor sharing by the IL-10R2 common chain. for the proliferative but not the antiinflammatory effects of the cytokine. J
Structure 2010;18:638–48. Biol Chem 1996;271:16357–62.
[86] Carson WE, Lindemann MJ, Baiocchi R, Linett M, Tan JC, Chou CC, et al. The [113] Ho AS, Wei SH, Mui AL, Miyajima A, Moore KW. Functional regions of the
functional characterization of interleukin-10 receptor expression on human mouse interleukin-10 receptor cytoplasmic domain. Mol Cell Biol
natural killer cells. Blood 1995;85:3577–85. 1995;15:5043–53.
[114] Jung M, Sabat R, Kratzschmar J, Seidel H, Wolk K, Schonbein C, et al. [140] Groux H, Bigler M, de Vries JE, Roncarolo MG. Inhibitory and stimulatory
Expression profiling of IL-10-regulated genes in human monocytes and effects of IL-10 on human CD8+ T cells. J Immunol 1998;160:3188–93.
peripheral blood mononuclear cells from psoriatic patients during IL-10 [141] Kemper C, Chan AC, Green JM, Brett KA, Murphy KM, Atkinson JP. Activation
therapy. Eur J Immunol 2004;34:481–93. of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1
[115] Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits phenotype. Nature 2003;421:388–92.
cytokine production by activated macrophages. J Immunol 1991;147:3815–22. [142] Baecher-Allan C, Viglietta V, Hafler DA. Human CD4+CD25+ regulatory T cells.
[116] Hart PH, Hunt EK, Bonder CS, Watson CJ, Finlay-Jones JJ. Regulation of surface Semin Immunol 2004;16:89–98.
and soluble TNF receptor expression on human monocytes and synovial fluid [143] Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, et al. Two functional
macrophages by IL-4 and IL-10. J Immunol 1996;157:3672–80. subsets of FOXP3+ regulatory T cells in human thymus and periphery.
[117] Jenkins JK, Malyak M, Arend WP. The effects of interleukin-10 on interleukin- Immunity 2008;28:870–80.
1 receptor antagonist and interleukin-1 beta production in human mono- [144] Collison LW, Pillai MR, Chaturvedi V, Vignali DA. Regulatory T cell suppres-
cytes and neutrophils. Lymphokine Cytokine Res 1994;13:47–54. sion is potentiated by target T cells in a cell contact, IL-35- and IL-10-
[118] Joyce DA, Gibbons DP, Green P, Steer JH, Feldmann M, Brennan FM. Two dependent manner. J Immunol 2009;182:6121–8.
inhibitors of pro-inflammatory cytokine release, interleukin-10 and inter- [145] Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory
leukin-4, have contrasting effects on release of soluble p75 tumor necrosis T cell-derived interleukin-10 limits inflammation at environmental inter-
factor receptor by cultured monocytes. Eur J Immunol 1994;24:2699–705. faces. Immunity 2008;28:546–58.
[119] Kruglov AA, Kuchmiy A, Grivennikov SI, Tumanov AV, Kuprash DV, Nedos- [146] Cassatella MA, Meda L, Bonora S, Ceska M, Constantin G. Interleukin 10 (IL-
pasov SA. Physiological functions of tumor necrosis factor and the conse- 10) inhibits the release of proinflammatory cytokines from human polymor-
quences of its pathologic overexpression or blockade: mouse models. phonuclear leukocytes. Evidence for an autocrine role of tumor necrosis
Cytokine Growth Factor Rev 2008;19:231–44. factor and IL-1 beta in mediating the production of IL-8 triggered by lipo-
[120] Creery WD, Diaz-Mitoma F, Filion L, Kumar A. Differential modulation of B7-1 polysaccharide. J Exp Med 1993;178:2207–11.
and B7-2 isoform expression on human monocytes by cytokines which [147] Kasama T, Strieter RM, Lukacs NW, Burdick MD, Kunkel SL. Regulation of
influence the development of T helper cell phenotype. Eur J Immunol neutrophil-derived chemokine expression by IL-10. J Immunol
1996;26:1273–7. 1994;152:3559–69.
[121] de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C, et al. [148] Niiro H, Otsuka T, Izuhara K, Yamaoka K, Ohshima K, Tanabe T, et al.
Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expres-
T cell proliferation by diminishing the antigen-presenting capacity of mono- sion in human neutrophils. Blood 1997;89:1621–8.
cytes via downregulation of class II major histocompatibility complex ex- [149] Takanaski S, Nonaka R, Xing Z, O’Byrne P, Dolovich J, Jordana M. Interleukin
pression. J Exp Med 1991;174:915–24. 10 inhibits lipopolysaccharide-induced survival and cytokine production by
[122] Willems F, Marchant A, Delville JP, Gerard C, Delvaux A, Velu T, et al. human peripheral blood eosinophils. J Exp Med 1994;180:711–5.
Interleukin-10 inhibits B7 and intercellular adhesion molecule-1 expression [150] Keel M, Ungethum U, Steckholzer U, Niederer E, Hartung T, Trentz O, et al.
on human monocytes. Eur J Immunol 1994;24:1007–9. Interleukin-10 counterregulates proinflammatory cytokine-induced inhibi-
[123] D’Andrea A, Aste-Amezaga M, Valiante NM, Ma X, Kubin M, Trinchieri G. tion of neutrophil apoptosis during severe sepsis. Blood 1997;90:3356–63.
Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-pro- [151] Arock M, Zuany-Amorim C, Singer M, Benhamou M, Pretolani M. Interleukin-10
duction by suppressing natural killer cell stimulatory factor/IL-12 synthesis inhibits cytokine generation from mast cells. Eur J Immunol 1996;26:166–70.
in accessory cells. J Exp Med 1993;178:1041–8. [152] Lin TJ, Befus AD. Differential regulation of mast cell function by IL-10 and
[124] Billiau A, Matthys P. Interferon-gamma: a historical perspective. Cytokine stem cell factor. J Immunol 1997;159:4015–23.
Growth Factor Rev 2009;20:97–113. [153] Kennedy Norton S, Barnstein B, Brenzovich J, Bailey DP, Kashyap M, Speiran K,
[125] Schuetze N, Schoeneberger S, Mueller U, Freudenberg MA, Alber G, Strau- et al. IL-10 suppresses mast cell IgE receptor expression and signaling in vitro
binger RK. IL-12 family members: differential kinetics of their TLR4-mediat- and in vivo. J Immunol 2008;180:2848–54.
ed induction by Salmonella enteritidis and the impact of IL-10 in bone [154] Burdin N, Rousset F, Banchereau J. B-cell-derived IL-10: production and
marrow-derived macrophages. Int Immunol 2005;17:649–59. function. Methods 1997;11:98–111.
[126] Buchwald UK, Geerdes-Fenge HF, Vockler J, Ziege S, Lode H. Interleukin-10: [155] Go NF, Castle BE, Barrett R, Kastelein R, Dang W, Mosmann TR, et al. Interleukin
effects on phagocytosis and adhesion molecule expression of granulocytes and 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-
monocytes in a comparison with prednisolone. Eur J Med Res 1999;4:85–94. linked immunodeficiency B cells. J Exp Med 1990;172:1625–31.
[127] Calzada-Wack JC, Frankenberger M, Ziegler-Heitbrock HW. Interleukin-10 [156] Levy Y, Brouet JC. Interleukin-10 prevents spontaneous death of germinal
drives human monocytes to CD16 positive macrophages. J Inflamm center B cells by induction of the bcl-2 protein. J Clin Invest 1994;93:424–8.
1996;46:78–85. [157] Rousset F, Peyrol S, Garcia E, Vezzio N, Andujar M, Grimaud JA, et al. Long-
[128] Spittler A, Schiller C, Willheim M, Tempfer C, Winkler S, Boltz-Nitulescu G. IL-10 term cultured CD40-activated B lymphocytes differentiate into plasma cells
augments CD23 expression on U937 cells and down-regulates IL-4-driven CD23 in response to IL-10 but not IL-4. Int Immunol 1995;7:1243–53.
expression on cultured human blood monocytes: effects of IL-10 and other [158] Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE, Kastelein R, Fiorentino DF,
cytokines on cell phenotype and phagocytosis. Immunology 1995;85:311–7. et al. Isolation and expression of human cytokine synthesis inhibitory factor
[129] te Velde AA, de Waal Malefijt R, Huijbens RJ, de Vries JE, Figdor CG. IL-10 cDNA clones: homology to Epstein–Barr virus open reading frame BCRFI. Proc
stimulates monocyte Fc gamma R surface expression and cytotoxic activity. Natl Acad Sci USA 1991;88:1172–6.
Distinct regulation of antibody-dependent cellular cytotoxicity by IFN-gam- [159] Gruber SG, Gloria Luciani M, Grundtner P, Zdanov A, Gasche C. Differential
ma, IL-4, and IL-10. J Immunol 1992;149:4048–52. signaling of cmvIL-10 through common variants of the IL-10 receptor 1. Eur J
[130] Roilides E, Anastasiou-Katsiardani A, Dimitriadou-Georgiadou A, Kadiltso- Immunol 2008;38:3365–75.
glou I, Tsaparidou S, Panteliadis C, et al. Suppressive effects of interleukin-10 [160] Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, et al.
on human mononuclear phagocyte function against Candida albicans and Enhanced Th1 activity and development of chronic enterocolitis in mice
Staphylococcus aureus. J Infect Dis 1998;178:1734–42. devoid of Stat3 in macrophages and neutrophils. Immunity 1999;10:39–49.
[131] Koch N, Jung M, Sabat R, Kratzschmar J, Docke WD, Asadullah K, et al. IL-10 [161] El Kasmi KC, Holst J, Coffre M, Mielke L, de Pauw A, Lhocine N, et al. General
protects monocytes and macrophages from complement-mediated lysis. J nature of the STAT3-activated anti-inflammatory response. J Immunol
Leukoc Biol 2009;86:155–66. 2006;177:7880–8.
[132] Vicioso MA, Garaud JJ, Reglier-Poupet H, Lebeaut A, Gougerot-Pocidalo MA, [162] Williams L, Bradley L, Smith A, Foxwell B. Signal transducer and activator of
Chollet-Martin S. Moderate inhibitory effect of interleukin-10 on human neutro- transcription 3 is the dominant mediator of the anti-inflammatory effects of
phil and monocyte chemotaxis in vitro. Eur Cytokine Netw 1998;9:247–53. IL-10 in human macrophages. J Immunol 2004;172:567–76.
[133] Allavena P, Piemonti L, Longoni D, Bernasconi S, Stoppacciaro A, Ruco L, et al. [163] Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-
IL-10 prevents the differentiation of monocytes to dendritic cells but pro- negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE
motes their maturation to macrophages. Eur J Immunol 1998;28:359–69. syndrome. Nature 2007;448:1058–62.
[134] Schoenbein C, Docke WD, Wolk K, Belbe G, Hoflich C, Jung M, et al. Long-term [164] Woellner C, Gertz EM, Schaffer AA, Lagos M, Perro M, Glocker EO, et al.
interleukin-10 presence induces the development of a novel, monocyte- Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J
derived cell type. Clin Exp Immunol 2008;151:306–16. Allergy Clin Immunol 2010;125:424–32. e428.
[135] Fitzgerald-Bocarsly P, Dai J, Singh S. Plasmacytoid dendritic cells and type I IFN: [165] Rossato M, Cencig S, Gasperini S, Cassatella MA, Bazzoni F. IL-10 modulates
50 years of convergent history. Cytokine Growth Factor Rev 2008;19:3–19. cytokine gene transcription by protein synthesis-independent and depen-
[136] Duramad O, Fearon KL, Chan JH, Kanzler H, Marshall JD, Coffman RL, et al. IL- dent mechanisms in lipopolysaccharide-treated neutrophils. Eur J Immunol
10 regulates plasmacytoid dendritic cell response to CpG-containing immu- 2007;37:3176–89.
nostimulatory sequences. Blood 2003;102:4487–92. [166] Lang R, Patel D, Morris JJ, Rutschman RL, Murray PJ. Shaping gene expression
[137] Waibler Z, Anzaghe M, Konur A, Akira S, Muller W, Kalinke U. Excessive CpG in activated and resting primary macrophages by IL-10. J Immunol
1668 stimulation triggers IL-10 production by cDC that inhibits IFN-alpha 2002;169:2253–63.
responses by pDC. Eur J Immunol 2008;38:3127–37. [167] Williams L, Jarai G, Smith A, Finan P. IL-10 expression profiling in human
[138] Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long- monocytes. J Leukoc Biol 2002;72:800–9.
term antigen-specific anergic state in human CD4+ T cells. J Exp Med [168] Basak S, Hoffmann A. Crosstalk via the NF-kappaB signaling system. Cytokine
1996;184:19–29. Growth Factor Rev 2008;19:187–97.
[139] Naundorf S, Schroder M, Hoflich C, Suman N, Volk HD, Grutz G. IL-10 [169] Schmid JA, Birbach A. IkappaB kinase beta (IKKbeta/IKK2/IKBKB)—a key
interferes directly with TCR-induced IFN-gamma but not IL-17 production molecule in signaling to the transcription factor NF-kappaB. Cytokine Growth
in memory T cells. Eur J Immunol 2009;39:1066–77. Factor Rev 2008;19:157–65.
[170] Wertz IE, Dixit VM. Ubiquitin-mediated regulation of TNFR1 signaling. [199] Kontoyiannis D, Kotlyarov A, Carballo E, Alexopoulou L, Blackshear PJ, Gaestel
Cytokine Growth Factor Rev 2008;19:313–24. M, et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF
[171] Grutz G. New insights into the molecular mechanism of interleukin-10- mRNA translation and limit intestinal pathology. EMBO J 2001;20:3760–70.
mediated immunosuppression. J Leukoc Biol 2005;77:3–15. [200] Denys A, Udalova IA, Smith C, Williams LM, Ciesielski CJ, Campbell J, et al.
[172] Baetz A, Frey M, Heeg K, Dalpke AH. Suppressor of cytokine signaling (SOCS) Evidence for a dual mechanism for IL-10 suppression of TNF-alpha produc-
proteins indirectly regulate toll-like receptor signaling in innate immune tion that does not involve inhibition of p38 mitogen-activated protein kinase
cells. J Biol Chem 2004;279:54708–15. or NF-kappa B in primary human macrophages. J Immunol 2002;168:4837–
[173] Gingras S, Parganas E, de Pauw A, Ihle JN, Murray PJ. Re-examination of the 45.
role of suppressor of cytokine signaling 1 (SOCS1) in the regulation of toll-like [201] Gaestel M. MAPKAP kinases – MKs – two’s company, three’s a crowd. Nat Rev
receptor signaling. J Biol Chem 2004;279:54702–7. Mol Cell Biol 2006;7:120–30.
[174] Nakagawa R, Naka T, Tsutsui H, Fujimoto M, Kimura A, Abe T, et al. SOCS-1 [202] Rajasingh J, Bord E, Luedemann C, Asai J, Hamada H, Thorne T, et al. IL-10-
participates in negative regulation of LPS responses. Immunity 2002;17:677–87. induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression
[175] Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, et al. of p38 MAP kinase activation and inhibition of HuR expression. FASEB J
SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 2003;4:540– 2006;20:2112–4.
5. [203] Schaljo B, Kratochvill F, Gratz N, Sadzak I, Sauer I, Hammer M, et al. Triste-
[176] Lang R, Pauleau AL, Parganas E, Takahashi Y, Mages J, Ihle JN, et al. SOCS3 traprolin is required for full anti-inflammatory response of murine macro-
regulates the plasticity of gp130 signaling. Nat Immunol 2003;4:546–50. phages to IL-10. J Immunol 2009;183:1197–206.
[177] Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, et al. IL-6 [204] Krishnamurthy P, Lambers E, Verma S, Thorne T, Qin G, Losordo DW, et al.
induces an anti-inflammatory response in the absence of SOCS3 in macro- Myocardial knockdown of mRNA-stabilizing protein HuR attenuates post-MI
phages. Nat Immunol 2003;4:551–6. inflammatory response and left ventricular dysfunction in IL-10-null mice.
[178] Hammer M, Mages J, Dietrich H, Schmitz F, Striebel F, Murray PJ, et al. Control FASEB J 2010;24:2484–94.
of dual-specificity phosphatase-1 expression in activated macrophages by IL- [205] Koppelman B, Neefjes JJ, de Vries JE, de Waal Malefyt R. Interleukin-10 down-
10. Eur J Immunol 2005;35:2991–3001. regulates MHC class II alphabeta peptide complexes at the plasma membrane
[179] Chi H, Barry SP, Roth RJ, Wu JJ, Jones EA, Bennett AM, et al. Dynamic of monocytes by affecting arrival and recycling. Immunity 1997;7:861–71.
regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase [206] Thibodeau J, Bourgeois-Daigneault MC, Huppe G, Tremblay J, Aumont A,
1 (MKP-1) in innate immune responses. Proc Natl Acad Sci USA Houde M, et al. Interleukin-10-induced MARCH1 mediates intracellular
2006;103:2274–9. sequestration of MHC class II in monocytes. Eur J Immunol
[180] Hammer M, Mages J, Dietrich H, Servatius A, Howells N, Cato AC, et al. Dual 2008;38:1225–30.
specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes [207] Schroder M, Meisel C, Buhl K, Profanter N, Sievert N, Volk HD, et al. Different
and protects mice from lethal endotoxin shock. J Exp Med 2006;203:15–20. modes of IL-10 and TGF-beta to inhibit cytokine-dependent IFN-gamma
[181] Salojin KV, Owusu IB, Millerchip KA, Potter M, Platt KA, Oravecz T. Essential production: consequences for reversal of lipopolysaccharide desensitization.
role of MAPK phosphatase-1 in the negative control of innate immune J Immunol 2003;170:5260–7.
responses. J Immunol 2006;176:1899–907. [208] de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of
[182] Zhao Q, Wang X, Nelin LD, Yao Y, Matta R, Manson ME, et al. MAP kinase human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2
phosphatase 1 controls innate immune responses and suppresses endotoxic production and proliferation. J Immunol 1993;150:4754–65.
shock. J Exp Med 2006;203:131–40. [209] Joss A, Akdis M, Faith A, Blaser K, Akdis CA. IL-10 directly acts on T cells by
[183] Dagvadorj J, Naiki Y, Tumurkhuu G, Hassan F, Islam S, Koide N, et al. specifically altering the CD28 co-stimulation pathway. Eur J Immunol
Interleukin-10 inhibits tumor necrosis factor-alpha production in lipopoly- 2000;30:1683–90.
saccharide-stimulated RAW 264.7 cells through reduced MyD88 expression. [210] Grondal G, Kristjansdottir H, Gunnlaugsdottir B, Arnason A, Lundberg I,
Innate Immun 2008;14:109–15. Klareskog L, et al. Increased number of interleukin-10-producing cells in
[184] Chang J, Kunkel SL, Chang CH. Negative regulation of MyD88-dependent systemic lupus erythematosus patients and their first-degree relatives and
signaling by IL-10 in dendritic cells. Proc Natl Acad Sci USA spouses in Icelandic multicase families. Arthritis Rheum 1999;42:1649–54.
2009;106:18327–32. [211] Stewart JP, Behm FG, Arrand JR, Rooney CM. Differential expression of viral
[185] McCoy CE, Sheedy FJ, Qualls JE, Doyle SL, Quinn SR, Murray PJ, et al. IL-10 and human interleukin-10 (IL-10) by primary B cell tumors and B cell lines.
inhibits miR-155 induction by toll-like receptors. J Biol Chem Virology 1994;200:724–32.
2010;285:20492–8. [212] Yue FY, Dummer R, Geertsen R, Hofbauer G, Laine E, Manolio S, et al.
[186] O’Connell RM, Chaudhuri AA, Rao DS, Baltimore D. Inositol phosphatase Interleukin-10 is a growth factor for human melanoma cells and down-
SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer
2009;106:7113–8. 1997;71:630–7.
[187] Sly LM, Rauh MJ, Kalesnikoff J, Song CH, Krystal G. LPS-induced upregulation [213] Salhi A, Rodrigues Jr V, Santoro F, Dessein H, Romano A, Castellano LR, et al.
of SHIP is essential for endotoxin tolerance. Immunity 2004;21:227–39. Immunological and genetic evidence for a crucial role of IL-10 in cutaneous
[188] Murray PJ. The primary mechanism of the IL-10-regulated antiinflammatory lesions in humans infected with Leishmania braziliensis. J Immunol
response is to selectively inhibit transcription. Proc Natl Acad Sci USA 2008;180:6139–48.
2005;102:8686–91. [214] Berres ML, Schnyder B, Yagmur E, Inglis B, Stanzel S, Tischendorf JJ, et al.
[189] Driessler F, Venstrom K, Sabat R, Asadullah K, Schottelius AJ. Molecular Longitudinal monocyte human leukocyte antigen-DR expression is a prog-
mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: nostic marker in critically ill patients with decompensated liver cirrhosis.
a role for p50. Clin Exp Immunol 2004;135:64–73. Liver Int 2009;29:536–43.
[190] Cao S, Zhang X, Edwards JP, Mosser DM. NF-kappaB1 (p50) homodimers [215] Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, et al.
differentially regulate pro- and anti-inflammatory cytokines in macro- Monocyte deactivation in septic patients: restoration by IFN-gamma treat-
phages. J Biol Chem 2006;281:26041–50. ment. Nat Med 1997;3:678–81.
[191] Kuwata H, Watanabe Y, Miyoshi H, Yamamoto M, Kaisho T, Takeda K, et al. IL- [216] Steinhauser ML, Hogaboam CM, Kunkel SL, Lukacs NW, Strieter RM, Standi-
10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production ford TJ. IL-10 is a major mediator of sepsis-induced impairment in lung
in macrophages. Blood 2003;102:4123–9. antibacterial host defense. J Immunol 1999;162:392–9.
[192] Hirotani T, Lee PY, Kuwata H, Yamamoto M, Matsumoto M, Kawase I, et al. [217] Woiciechowsky C, Asadullah K, Nestler D, Eberhardt B, Platzer C, Schoning B,
The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccha- et al. Sympathetic activation triggers systemic interleukin-10 release in
ride-induced IL-6 production in macrophages of the colonic lamina propria. J immunodepression induced by brain injury. Nat Med 1998;4:808–13.
Immunol 2005;174:3650–7. [218] Wolk K, Docke WD, von Baehr V, Volk HD, Sabat R. Impaired antigen
[193] Weaver BK, Bohn E, Judd BA, Gil MP, Schreiber RD. ABIN-3: a molecular basis presentation by human monocytes during endotoxin tolerance. Blood
for species divergence in interleukin-10-induced anti-inflammatory actions. 2000;96:218–23.
Mol Cell Biol 2007;27:4603–16. [219] Wolk K, Hoflich C, Zuckermann-Becker H, Docke WD, Volk HD, Sabat R.
[194] El Kasmi KC, Smith AM, Williams L, Neale G, Panopoulos AD, Watowich SS, Reduced monocyte CD86 expression in postinflammatory immunodeficien-
et al. Cutting edge: a transcriptional repressor and corepressor induced by cy. Crit Care Med 2007;35:458–67.
the STAT3-regulated anti-inflammatory signaling pathway. J Immunol [220] Chiu BC, Stolberg VR, Chensue SW. Mononuclear phagocyte-derived IL-10
2007;179:7215–9. suppresses the innate IL-12/IFN-gamma axis in lung-challenged aged mice. J
[195] Muhlbauer M, Chilton PM, Mitchell TC, Jobin C. Impaired Bcl3 up-regulation Immunol 2008;181:3156–66.
leads to enhanced lipopolysaccharide-induced interleukin (IL)-23P19 gene [221] Asadullah K, Sterry W, Stephanek K, Jasulaitis D, Leupold M, Audring H, et al.
expression in IL-10(/) mice. J Biol Chem 2008;283:14182–9. IL-10 is a key cytokine in psoriasis. Proof of principle by IL-10 therapy: a new
[196] Bogdan C, Paik J, Vodovotz Y, Nathan C. Contrasting mechanisms for sup- therapeutic approach. J Clin Invest 1998;101:783–94.
pression of macrophage cytokine release by transforming growth factor-beta [222] DeBruyne LA, Li K, Chan SY, Qin L, Bishop DK, Bromberg JS. Lipid-mediated
and interleukin-10. J Biol Chem 1992;267:23301–8. gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by
[197] Brown CY, Lagnado CA, Vadas MA, Goodall GJ. Differential regulation of the inhibiting donor-specific cellular and humoral immune responses. Gene Ther
stability of cytokine mRNAs in lipopolysaccharide-activated blood mono- 1998;5:1079–87.
cytes in response to interleukin-10. J Biol Chem 1996;271:20108–12. [223] Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M. Immunoregulatory
[198] Kishore R, Tebo JM, Kolosov M, Hamilton TA. Cutting edge: clustered AU-rich role of interleukin 10 in rheumatoid arthritis. J Exp Med 1994;179:1517–27.
elements are the target of IL-10-mediated mRNA destabilization in mouse [224] van Montfrans C, Camoglio L, van Deventer SJ. Immunotherapy of Crohn’s
macrophages. J Immunol 1999;162:2457–61. disease. Mediators Inflamm 1998;7:149–52.
[225] Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the human IL10 gene and [252] Madan R, Demircik F, Surianarayanan S, Allen JL, Divanovic S, Trompette A,
further characterization of the 50 flanking sequence. Immunogenetics et al. Nonredundant roles for B cell-derived IL-10 in immune counter-
1997;46:120–8. regulation. J Immunol 2009;183:2312–20.
[226] Smith AJ, Humphries SE. Cytokine and cytokine receptor gene polymorph- [253] Walsh KP, Brady MT, Finlay CM, Boon L, Mills KH. Infection with a helminth
isms and their functionality. Cytokine Growth Factor Rev 2009;20:43–59. parasite attenuates autoimmunity through TGF-beta-mediated suppression
[227] Dutra WO, Moreira PR, Souza PE, Gollob KJ, Gomez RS. Implications of of Th17 and Th1 responses. J Immunol 2009;183:1577–86.
cytokine gene polymorphisms on the orchestration of the immune response: [254] Almeida AS, Lago PM, Boechat N, Huard RC, Lazzarini LC, Santos AR, et al.
lessons learned from oral diseases. Cytokine Growth Factor Rev Tuberculosis is associated with a down-modulatory lung immune response
2009;20:223–32. that impairs Th1-type immunity. J Immunol 2009;183:718–31.
[228] Larsson L, Johansson P, Jansson A, Donati M, Rymo L, Berglundh T. The Sp1 [255] Anderson CF, Lira R, Kamhawi S, Belkaid Y, Wynn TA, Sacks D. IL-10 and TGF-beta
transcription factor binds to the G-allele of the 1087 IL-10 gene polymor- control the establishment of persistent and transmissible infections produced by
phism and enhances transcriptional activation. Genes Immun 2009;10:280–4. Leishmania tropica in C57BL/6 mice. J Immunol 2008;180:4090–7.
[229] Warle MC, Farhan A, Metselaar HJ, Hop WC, Perrey C, Zondervan PE, et al. Are [256] Beamer GL, Flaherty DK, Assogba BD, Stromberg P, Gonzalez-Juarrero M, de
cytokine gene polymorphisms related to in vitro cytokine production pro- Waal Malefyt R, et al. Interleukin-10 promotes Mycobacterium tuberculosis
files? Liver Transpl 2003;9:170–81. disease progression in CBA/J mice. J Immunol 2008;181:5545–50.
[230] Eskdale J, Wordsworth P, Bowman S, Field M, Gallagher G. Association [257] Belkaid Y, Hoffmann KF, Mendez S, Kamhawi S, Udey MC, Wynn TA, et al. The
between polymorphisms at the human IL-10 locus and systemic lupus role of interleukin (IL)-10 in the persistence of Leishmania major in the skin
erythematosus. Tissue Antigens 1997;49:635–9. after healing and the therapeutic potential of anti-IL-10 receptor antibody for
[231] Grundtner P, Gruber S, Murray SS, Vermeire S, Rutgeerts P, Decker T, et al. The sterile cure. J Exp Med 2001;194:1497–506.
IL-10R1 S138G loss-of-function allele and ulcerative colitis. Genes Immun [258] Brooks DG, Lee AM, Elsaesser H, McGavern DB, Oldstone MB. IL-10 blockade
2009;10:84–92. facilitates DNA vaccine-induced T cell responses and enhances clearance of
[232] Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J, Ollier WE, et al. persistent virus infection. J Exp Med 2008;205:533–41.
Genetic variation in the interleukin 10 gene promoter and systemic lupus [259] Maroof A, Beattie L, Zubairi S, Svensson M, Stager S, Kaye PM. Posttranscrip-
erythematosus. J Rheumatol 1997;24:2314–7. tional regulation of II10 gene expression allows natural killer cells to express
[233] Oleksyk TK, Shrestha S, Truelove AL, Goedert JJ, Donfield SM, Phair J, et al. immunoregulatory function. Immunity 2008;29:295–305.
Extended IL10 haplotypes and their association with HIV progression to AIDS. [260] McKinstry KK, Strutt TM, Buck A, Curtis JD, Dibble JP, Huston G, et al. IL-10
Genes Immun 2009;10:309–22. deficiency unleashes an influenza-specific Th17 response and enhances
[234] Schoof N, von Bonin F, Konig IR, Mossner R, Kruger U, Reich K, et al. Distal and survival against high-dose challenge. J Immunol 2009;182:7353–63.
proximal interleukin (IL)-10 promoter polymorphisms associated with risk [261] Schreiber T, Ehlers S, Heitmann L, Rausch A, Mages J, Murray PJ, et al.
of cutaneous melanoma development: a case–control study. Genes Immun Autocrine IL-10 induces hallmarks of alternative activation in macrophages
2009;10:586–90. and suppresses antituberculosis effector mechanisms without compromis-
[235] Turner D, Grant SC, Yonan N, Sheldon S, Dyer PA, Sinnott PJ, et al. Cytokine ing T cell immunity. J Immunol 2009;183:1301–12.
gene polymorphism and heart transplant rejection. Transplantation [262] Gottfried E, Kreutz M, Mackensen A. Tumor-induced modulation of dendritic
1997;64:776–9. cell function. Cytokine Growth Factor Rev 2008;19:65–77.
[236] Chong WP, Ip WK, Wong WH, Lau CS, Chan TM, Lau YL. Association of [263] de Lemos Rieper C, Galle P, Hansen MB. Characterization and potential
interleukin-10 promoter polymorphisms with systemic lupus erythemato- clinical applications of autoantibodies against cytokines. Cytokine Growth
sus. Genes Immun 2004;5:484–92. Factor Rev 2009;20:61–75.
[237] Helminen M, Lahdenpohja N, Hurme M. Polymorphism of the interleukin-10 [264] Maeda A, Schwarz A, Bullinger A, Morita A, Peritt D, Schwarz T. Experimental
gene is associated with susceptibility to Epstein–Barr virus infection. J Infect extracorporeal photopheresis inhibits the sensitization and effector phases
Dis 1999;180:496–9. of contact hypersensitivity via two mechanisms: generation of IL-10 and
[238] Sankaran D, Asderakis A, Ashraf S, Roberts IS, Short CD, Dyer PA, et al. induction of regulatory T cells. J Immunol 2008;181:5956–62.
Cytokine gene polymorphisms predict acute graft rejection following renal [265] Yang X, Wang S, Fan Y, Han X. IL-10 deficiency prevents IL-5 overproduction
transplantation. Kidney Int 1999;56:281–8. and eosinophilic inflammation in a murine model of asthma-like reaction.
[239] Groux H, Cottrez F, Rouleau M, Mauze S, Antonenko S, Hurst S, et al. A Eur J Immunol 2000;30:382–91.
transgenic model to analyze the immunoregulatory role of IL-10 secreted by [266] Sun K, Torres L, Metzger DW. A detrimental effect of interleukin-10 on
antigen-presenting cells. J Immunol 1999;162:1723–9. protective pulmonary humoral immunity during primary influenza A virus
[240] Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient infection. J Virol 2010;84:5007–14.
mice develop chronic enterocolitis. Cell 1993;75:263–74. [267] Oakley OR, Garvy BA, Humphreys S, Qureshi MH, Pomeroy C. Increased
[241] Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, et al. weight loss with reduced viral replication in interleukin-10 knock-out mice
Inflammatory bowel disease and mutations affecting the interleukin-10 infected with murine cytomegalovirus. Clin Exp Immunol 2008;151:155–64.
receptor. N Engl J Med 2009;361:2033–45. [268] Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB.
[242] Berg DJ, Kuhn R, Rajewsky K, Muller W, Menon S, Davidson N, et al. Interleu- Interleukin-10 determines viral clearance or persistence in vivo. Nat Med
kin-10 is a central regulator of the response to LPS in murine models of 2006;12:1301–9.
endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J [269] Penttilä T, Haveri A, Tammiruusu A, Vuola JM, Lahesmaa R, Puolakkainen M.
Clin Invest 1995;96:2339–47. Chlamydia pneumoniae infection in IL-10 knock out mice: accelerated clear-
[243] Pils MC, Pisano F, Fasnacht N, Heinrich JM, Groebe L, Schippers A, et al. ance but severe pulmonary inflammatory response. Microb Pathog
Monocytes/macrophages and/or neutrophils are the target of IL-10 in the LPS 2008;45:25–9.
endotoxemia model. Eur J Immunol 2010;40:443–8. [270] Yang X, Gartner J, Zhu L, Wang S, Brunham RC. IL-10 gene knockout mice
[244] Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK. IL-10 is show enhanced Th1-like protective immunity and absent granuloma forma-
critical in the regulation of autoimmune encephalomyelitis as demonstrated tion following Chlamydia trachomatis lung infection. J Immunol
by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol 1999;162:1010–7.
1998;161:3299–306. [271] Murray PJ, Young RA. Increased antimycobacterial immunity in interleukin-
[245] Elliott DE, Metwali A, Leung J, Setiawan T, Blum AM, Ince MN, et al. Coloni- 10-deficient mice. Infect Immun 1999;67:3087–95.
zation with Heligmosomoides polygyrus suppresses mucosal IL-17 production. [272] Sewnath ME, Olszyna DP, Birjmohun R, ten Kate FJ, Gouma DJ, van Der Poll T.
J Immunol 2008;181:2414–9. IL-10-deficient mice demonstrate multiple organ failure and increased mor-
[246] Guilliams M, Movahedi K, Bosschaerts T, VandenDriessche T, Chuah MK, tality during Escherichia coli peritonitis despite an accelerated bacterial
Herin M, et al. IL-10 dampens TNF/inducible nitric oxide synthase-producing clearance. J Immunol 2001;166:6323–31.
dendritic cell-mediated pathogenicity during parasitic infection. J Immunol [273] Vazquez-Torres A, Jones-Carson J, Wagner RD, Warner T, Balish E. Early
2009;182:1107–18. resistance of interleukin-10 knockout mice to acute systemic candidiasis.
[247] Herbert DR, Orekov T, Perkins C, Finkelman FD. IL-10 and TGF-beta redun- Infect Immun 1999;67:670–4.
dantly protect against severe liver injury and mortality during acute schis- [274] Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R,
tosomiasis. J Immunol 2008;181:7214–20. et al. In the absence of endogenous IL-10, mice acutely infected with
[248] Higgins DM, Sanchez-Campillo J, Rosas-Taraco AG, Lee EJ, Orme IM, Gonza- Toxoplasma gondii succumb to a lethal immune response dependent on
lez-Juarrero M. Lack of IL-10 alters inflammatory and immune responses CD4+ T cells and accompanied by overproduction of IL-12, IFN-gamma
during pulmonary Mycobacterium tuberculosis infection. Tuberculosis (Edinb) and TNF-alpha. J Immunol 1996;157:798–805.
2009;89:149–57. [275] Wilson EH, Wille-Reece U, Dzierszinski F, Hunter CA. A critical role for IL-10
[249] Igyarto BZ, Jenison MC, Dudda JC, Roers A, Muller W, Koni PA, et al. in limiting inflammation during toxoplasmic encephalitis. J Neuroimmunol
Langerhans cells suppress contact hypersensitivity responses via cognate 2005;165:63–74.
CD4 interaction and langerhans cell-derived IL-10. J Immunol [276] Anderson CF, Mendez S, Sacks DL. Nonhealing infection despite Th1 polari-
2009;183:5085–93. zation produced by a strain of Leishmania major in C57BL/6 mice. J Immunol
[250] Johansson AC, Hansson AS, Nandakumar KS, Backlund J, Holmdahl R. IL-10- 2005;174:2934–41.
deficient B10.Q mice develop more severe collagen-induced arthritis, but are [277] Li C, Corraliza I, Langhorne J. A defect in interleukin-10 leads to enhanced
protected from arthritis induced with anti-type II collagen antibodies. J malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infect
Immunol 2001;167:3505–12. Immun 1999;67:4435–42.
[251] Londono D, Marques A, Hornung RL, Cadavid D. IL-10 helps control pathogen [278] Li C, Sanni LA, Omer F, Riley E, Langhorne J. Pathology of Plasmodium chabaudi
load during high-level bacteremia. J Immunol 2008;181:2076–83. chabaudi infection and mortality in interleukin-10-deficient mice are ame-
liorated by anti-tumor necrosis factor alpha and exacerbated by anti-trans- Stefan Kirsch studied Biotechnology at the University of
forming growth factor beta antibodies. Infect Immun 2003;71:4850–6. Applied Sciences Berlin. After receiving his diploma in 2004
[279] Sanni LA, Jarra W, Li C, Langhorne J. Cerebral edema and cerebral hemor- he worked for Biosyntan GmbH. Since 2007 he is a PhD
rhages in interleukin-10-deficient mice infected with Plasmodium chabaudi. student in the Interdisciplinary group of Molecular Immu-
Infect Immun 2004;72:3054–8. nopathology at the University Hospital Charité, Berlin.
[280] Holscher C, Mohrs M, Dai WJ, Kohler G, Ryffel B, Schaub GA, et al. Tumor
necrosis factor alpha-mediated toxic shock in Trypanosoma cruzi-infected
interleukin 10-deficient mice. Infect Immun 2000;68:4075–83.
[281] Hunter CA, Ellis-Neyes LA, Slifer T, Kanaly S, Grunig G, Fort M, et al. IL-10 is
required to prevent immune hyperactivity during infection with Trypano-
soma cruzi. J Immunol 1997;158:3311–6.
[282] Wynn TA, Cheever AW, Williams ME, Hieny S, Caspar P, Kuhn R, et al. IL-10
regulates liver pathology in acute murine Schistosomiasis mansoni but is not
required for immune down-modulation of chronic disease. J Immunol
1998;160:4473–80.
[283] Sadler CH, Rutitzky LI, Stadecker MJ, Wilson RA. IL-10 is crucial for the
transition from acute to chronic disease state during infection of mice with Ellen Witte is a research fellow in the Interdisciplinary
Schistosoma mansoni. Eur J Immunol 2003;33:880–8. Department of Molecular Immunopathology directed by
Robert Sabat M.D. (Charité University Hospital). She
received her diploma (5-year degree) in Biology from
Robert Sabat (born in 1969 in Poland) is the director of
the Humboldt University in Berlin, Germany. She just
the Molecular Immunopathology interdisciplinary de-
has completed her Ph.D. work that dealt with the bio-
partment at the University Hospital Charité in Berlin,
logical significance of the cytokine IL-22 and its natural
Germany. In 1995, he graduated from the Humboldt
inhibitor IL-22BP in psoriasis and Crohn’s disease.
University medical school in Berlin, Germany. Subse-
quently, he completed his medical internship and resi-
dency at the Institute for Medical Immunology,
University Hospital Charité, Berlin. His medical doctor-
ate thesis focused on interleukin-10. In 1999, he went to
the Department of Dermatology at Schering Inc. to work
as a research group head for three years. During this
time, he directed two projects: ‘‘Molecular mechanisms
of the immunosuppressive effects of interleukin-10’’ Kerstin Wolk is an immunologist and works as a re-
and ‘‘New members of the cytokine receptor family class 2’’. The Molecular Immu- search team head in the Interdisciplinary Molecular
nopathology department of the Charité Berlin, which he has been charged with since Immunopathology Department at the University Hospi-
2003, links clinical research at the Department of Dermatology with basic science at tal Charité in Berlin, Germany. She obtained both a
the Institute for Medical Immunology. His main research interests lie in: the diploma (5-year degree) in Biopharmacology from the
function of novel interleukin-10 related cytokines and the pathogenesis of chronic University of Greifswald, Germany, and a diploma in
inflammatory diseases. Environmental Toxicology from the University of Metz,
France. She later graduated with a Ph.D. from the Uni-
Gerald Grütz studied Biochemistry/Molecular Biology versity of Greifswald (supervisors: Reinhard Walter,
at the Humboldt University in Berlin. He obtained his M.D., Ph.D., Institute of Biochemistry of the University
PhD in 1994 after working at the Institute of Medical Hospital Greifswald and Hans-Dieter Volk, M.D., Ph.D.,
Immunology of the University Hospital Charité in Berlin Institute of Medical Immunology of the University Hos-
under supervision of Prof. von Baehr and Prof. Volk in pital Charité, Berlin, Germany). For her thesis she
the area of antibody engineering against pro-inflamma- worked on endotoxin tolerance as a model of post-inflammatory immunodepres-
tory cytokines for therapeutic approaches in septic sion in critically ill patients. Afterwards, she accepted a postdoctoral position at
shock. He moved then to work as a postdoc with Dr. Schering, Inc., Berlin, in the Department of Dermatology. With her research team in
Rabbitts at the PNAC department of the MRC-LMB in the Molecular Immunopathology Department (director: Robert Sabat) at the Charité
Cambridge (UK) for 5 years. His focus there was the in Berlin, she currently investigates the role of interleukin (IL)-10 family cytokines,
molecular basis of acute T cell leukaemia caused by the such as IL-22 and IL-28IL-29.
transcription factor LMO2. His research interest
returned back to Immunology when he started his
own group at the Institute of Medical Immunology at Charité from 1998. There Jens Geginat (born 1968 in Berlin, Germany) is heading
he was working on gaining insight into the cellular and molecular mechanism of the Autoimmunity Program at the Istituto Nazionale di
inflammation and cytokine regulation by the anti-inflammatory cytokines IL-10 Genetica Molecolare (INGM) in Milan, Italy. He gradu-
and TGF-b. Since the beginning of 2010 he is heading the Department of Biocom- ated in Biochemistry at the Free University of Berlin in
patibility at the Biomaterial Research Centre of the GKSS in Teltow. There he is 1994 and did the experimental work of his PhD at the
studying the impact of biomaterials designed for regenerative therapeutic Scientific Institute S. Raffaele DiBit in Milan with Rug-
approaches on the immune system. gero Pardi. In 1999 he joined the group of Antonio
Lanzavecchia at the Basel Institute for Immunology
Katarzyna Warszawska obtained her BSc and MSc in and in 2000 he moved to the Research Institute for
Biology from the University of Warsaw, Poland. For the Biomedicine (IRB) in Bellinzona, Switzerland. In 2006
last 4 years she has been working on her Ph.D. thesis in he became a Junior Group Leader in Berlin of the Uni-
the Interdisciplinary Department of Molecular Immuno- versity Hospital Charité at the German Rheumatology
pathology at the Charité University Hospital, Berlin. Her Research Centre (DRFZ) headed by Andreas Radbruch. In
work is concerned with the research on the determina- 2009 he was appointed as a Program Leader at INGM, whose mission is to perform
tion of the role of IL-22 in inflammatory conditions, like translational research in Biomedicine. In 2010 he obtained his Habilitation in
skin diseases and various infection models. Immunology at the Charitè. His main research interest is human T cell biology,
in particular the generation and maintenance of memory T cells and more recently
the characterization of regulatory T cell subsets.

Biology of Interleukin-10

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Cytokine & Growth Factor Reviews 21 (2010) 331–344

Contents lists available at ScienceDirect

Cytokine & Growth Factor Reviews

1. Introduction isms are associated with differential expression of IL-10 in vitro,

Fig. 1. CD4+ T cells as IL-10 sources.

Model Phenotype IL-10 knockout (mouse) References

Inﬂammatory bowel disease Spontaneous inﬂammatory bowel disease [16,240]

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