E Lenkov 2002
E Lenkov 2002
E Lenkov 2002
INTRODUCTION
Ann. N.Y. Acad. Sci. 966: 290–303 (2002). ©2002 New York Academy of Sciences.
ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 291
FIGURE 1. Role of APCs, Th1 and Th2 cells, and proinflammatory and antiinflam-
matory cytokines in the regulation of cellular and humoral immunity. Cellular immunity
provides protection against intracellular bacteria, protozoa, fungi, and several viruses,
whereas humoral immunity provides protection against multicellular parasites, extracellu-
lar bacteria, some viruses, soluble toxins, and allergens (see text). Solid lines represent
stimulation; dashed lines represent inhibition. ABBREVIATIONS: Ag, antigen; APC, antigen-
presenting cell; NK, natural killer cell; B, B cell; Th, T helper cell; Tc, T cytotoxic cell;
Eo, eosinophil; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon. (From Elenk-
ov and Chrousos, Ref. 7. Reproduced by permission.)
ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 293
components of cellular immunity. The type 1 cytoknes IL-12, TNF-α, and IFNγ also
stimulate the synthesis of nitric oxide and other inflammatory mediators that drive
chronic delayed type inflammatory responses. Because of these crucial and synergis-
tic roles in inflammation, IL-12, TNF-α, and IFNγ are considered the major proin-
flammatory cytokines.
Th1 and Th2 responses are mutually inhibitory. Thus, IL-12 and IFNγ inhibit Th2
cells activities, whereas IL-4 and IL-10 inhibit Th1 responses. IL-4 and IL-10 pro-
mote humoral immuniy by stimulating the growth and activation of mast cells and
eosinophils, the differentiation of B cells into antibody-secreting B cells, and B-cell
immunoglobulin switching to IgE. Importantly, these cytokines also inhibit mac-
rophage activation, T-cell proliferation, and the production of proinflammatory
cytokines.5,6,8 Therefore, the Th2 (type 2) cytokines IL-4 and IL-10 are the major
antiinflammatory cytokines.
HORMONAL REGULATION OF
PRO/ANTIINFLAMMATORY CYTOKINE BALANCE
Catecholamines drive a Th2 shift at the level of both APCs and Th1 cells (FIG. 2).
Norepinephrine and epinephrine potently inhibit or enhance the production of IL-12
and IL-10, respectively, in human whole blood cultures stimulated with bacterial
lipopolysaccharide (LPS) ex vivo.11 These effects are mediated by stimulation of
β-adrenoreceptors (ARs) because they are completely prevented by propranolol, a
β-AR antagonist. In addition, the nonselective β- and selective β2-AR agonists
inhibit the production of IL-12 in vitro and in vivo.19,20 In conjunction with their
ability to suppress IL-12 production, β2-AR agonists also inhibit the development of
Th1-type cells, while promoting Th2 cell differentiation.19
β2-ARs are expressed on Th1 cells, but not on Th2 cells.21 This might provide an
additional mechanistic basis for the differential effect of catecholamines on Th1/Th2
functions (see FIG. 2). In fact, in both murine and human systems, β2-AR agonists
inhibit IFNγ production by Th1 cells, but do not affect IL-4 production by Th2
cells.21,22 Importantly, the differential effect of catecholamines on type 1/type 2
cytokine production also operates in in vivo conditions. Thus, increasing sympathet-
ic outflow in mice by selective α2-AR antagonists or application of β-AR agonists
results in inhibition of LPS-induced TNF-α and IL-12 production.4,23 In humans, the
administration of the β2-AR agonist salbutamol results in inhibition of IL-12 produc-
tion ex vivo.19 Also, acute brain trauma that is followed by massive release of cate-
cholamines triggers secretion of substantial amounts of systemic IL-10.24
Catecholamines exert tonic inhibition on the production of proinflammatory
cytokines in vivo. Application of propranolol, a β-AR antagonist that blocks their
inhibitory effect on cytokine-producing cells, results in a substantial increase of
LPS-induced secretion of TNF-α and IL-12 in mice.20,25 Thus, systemically, both
glucocorticoids and catecholamines, through inhibition and stimulation of type 1
and type 2 cytokine secretion, respectively, cause selective suppression of cellular
immunity and a shift toward Th2-mediated humoral immunity. This is substantiated
further by studies showing that stress hormones inhibit effector function of cellular
immunity components, that is, the activity of NK, Tc, and activated macrophages.
For example, catecholamines are potent inhibitors of NK-cell activity, both directly,
acting on β2-ARs expressed on these cells, or indirectly, through suppression of the
production of IL-12 and INFγ, which are essential for NK-cell activity.11,26 It
appears that NK cells are the cells most “sensitive” to the suppressive effect of stress;
indeed, NK-cell activity has been used as an index of stress-induced immunosup-
pression in other studies.2,27
state, supporting the disease process of RA. In addition, Lombardi et al.62 showed a
decrease in G-protein–coupled receptor kinase (GRK) activity in lymphocytes of RA
patients, particularly GRK2 and GRK6 subtypes. The GRKs are responsible for the
rapid loss of receptor responsiveness despite continuous presence of the agonist, a
process known as homologous desensitization. The decrease in GRK2 activity in RA
appears to be mediated by cytokines such as IL-6 and IFNγ. Local proinflammatory
cytokines or a hypoactive SNS may, therefore, mediate the changes in coupling of
β-ARs to G-proteins observed in RA patients.
the hormonal state abruptly shifts. The deficit in hormones that inhibit Th1-
type/proinflammatory cytokines and cell-mediated immunity might permit autoim-
mune diseases, such as RA and MS, to develop first or established disease to flare
up.48,73,74
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Discussion
Cutolo: Thank you very much for your presentation, Dr. Elenkov. You put focus
on the relevant role of IL-12 in influencing the Th1/Th2 shift. Do you think that
locally produced CRH can have a direct effect on this IL-12 production?
Elenkov: I do not know.
Question: Did you see any effect of gonadal hormones on the IL-12 genes?
Elenkov: Indeed, we checked the p40.
Cutolo: What is the effect of estradiol on IL-12?
ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 303
Elenkov: We checked not only estradiol, but also the other estrogens and andro-
gens in our system and none of these hormones had any direct effect on IL-12.
Masi: Did you look for the effect on IL-18?
Elenkov: This is a good question since quite often IL-12 goes together with
IL-18. We did not look at this.
Huisman: What do you think of the role of 1.25 vitamin D as an immunomodulator?
Elenkov: This will be clinically relevant; different groups are looking into this
now.
Straub: It is very important to describe the concentration of the different neu-
rotransmitters used. The effect of these neurotransmitters can completely differ
when used in a low dosage or used in a high dosage.
Elenkov: This is indeed the case, especially in the microenvironment. It also
depends on the differentiation of the cells. I assume that especially in lymphoid organs
the concentration of norepinephrine can be very high, but it is very complicated.
Derksen: What is the value of these measurements when you have to use LPS,
which is not a physiological thing to do? In addition what do measurements in
peripheral blood mean for the local process, for example, in the joint?
Elenkov: It is indeed a specific model, not directly related to disease. However,
you should not confuse hormones and cytokines. Cytokines are not acting like a hor-
mone; only local concentrations are of relevance. Only a few cytokines, however,
may have a more systemic effect, such as IL-6. In our interpretation we should
always be aware what system is used; however, it is sometimes the only possibility
to evaluate these complex interactions.
Cutolo: You have shown that glucocorticoids induce a shift to Th2; how does this
relate to the use of glucocorticoids in a Th2-driven disease such as allergy.
Elenkov: In the long-term glucocortcoids will not be good for this kind of dis-
eases; other medication, such as histamine receptors, should be used preferentially.