Stress Hormones, Proinflammatory and

Antiinflammatory Cytokines, and

Autoimmunity
ILIA J. ELENKOVa,b AND GEORGE P. CHROUSOSb
aDivision
of Rheumatology, Immunology and Allergy,
Georgetown University Medical Center, Washington, DC, USA
bPediatric and Reproductive Endocrinology Branch,
National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, Maryland, USA

ABSTRACT: Recent evidence indicates that glucocorticoids and catechola-

mines, the major stress hormones, inhibit the production of proinflammatory
cytokines, such as interleukin (IL)–12, tumor necrosis factor (TNF)-
, and
interferon (IFN)-, whereas they stimulate the production of antiinflammato-
ry cytokines, such as IL-10, IL-4, and transforming growth factor (TGF)- .
Thus, systemically, an excessive immune response, through activation of the
stress system, stimulates an important negative feedback mechanism, which
protects the organism from an “overshoot” of proinflammatory cytokines and
other products of activated macrophages with tissue-damaging potential. Con-
versely, in certain local responses and under certain conditions, stress hor-
mones actually may boost regional immune responses, through induction of
TNF-
, IL-1, and IL-8, and by inhibiting TGF-  production. Therefore, con-
ditions that are associated with significant changes in stress system activity,
such as acute or chronic stress, cessation of chronic stress, severe exercise, and
pregnancy and the postpartum period, through modulation of the systemic or
local pro/antiinflammatory cytokine balance, may suppress or potentiate
autoimmune diseases activity and/or progression.
KEYWORDS: stress; glucocorticoids; catecholamines; autoimmunity; inflam-
mation; interleukin-12; interleukin-10, Th1 cells, Th2 cells, rheumatoid arthri-
tis; multiple sclerosis

INTRODUCTION

The hypothalamic–pituitary–adrenal (HPA) axis and the systemic/adrenomedullary

sympathetic nervous system (SNS) represent the peripheral limbs of the stress system.
Activation of the stress system occurs within the central nervous system (CNS) in
response to distinct blood-borne, neurosensory, and limbic signals. The central
components of the stress system are the corticotropin-releasing hormone (CRH) and
locus ceruleus-norepinephrine (LC-NA)/autonomic (sympathetic) neurons of the

Address for correspondence: Dr. Ilia J. Elenkov, Division of Rheumatology, Immunology

and Allergy, Georgetown University Medical Center, 3800 Reservoir Road, N.W., Washing-
ton, D.C. 20007-2197, USA. Voice: 202-784 4712; fax: 202-784-6423.
ije@georgetown.edu

Ann. N.Y. Acad. Sci. 966: 290–303 (2002). ©2002 New York Academy of Sciences.
ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 291

hypothalamus and brainstem, which, respectively, regulate the peripheral activities of

the HPA axis and the SNS.1,2 The stress-induced release of hypothalamic CRH leads
ultimately to systemic secretion of glucocorticoids and catecholamines, mainly epi-
nephrine and norepinephrine, which, in turn, influence immune responses. An immune
challenge that threatens the stability of the internal milieu can be regarded as a stressor.
Thus, cell products from an activated immune system, predominately the cytokines
tumor necrosis factor (TNF)-α, interleukin (IL)–1, and IL-6, stimulate CRH secretion
and, hence, activate both the HPA axis and the SNS.1–4
The regulation of proinflammatory and antiinflammatory cytokine production
recently has attracted considerable interest.5–7 The equilibrium between proinflam-
matory cytokines, such as IL-12, TNF-α and interferon (IFN)-γ, and antiinflamma-
tory cytokines, such as IL-4 and IL-10, is critically skewed, one way or the other, in
several infectious, autoimmune/inflammatory, allergic (atopic), and neoplastic dis-
eases. Thus, better understanding of the endogenous mechanisms involved in regu-
lation of pro/antiinflammatory cytokine balance may provide critical insights into
mechanisms underlying a variety of common human diseases.
Genetic and immunologic mechanisms undoubtedly play a significant role in the
regulation of pro/antiinflammatory cytokine production. A rapidly increasing body
of evidence suggests that several neuroendocrine factors that are present in the
microenvironment of immunocompetent cells have also important regulatory influ-
ences. Although the list of hormones and neurotransmitters that are able to modulate
the production of pro/antiinflammatory cytokine production is constantly enlarging,
hitherto the best-characterized neuroendocrine factors that regulate the production
of these cytokines include glucocorticoids and catecholamines, the key stress hor-
mones. This review discusses recent evidence of how these hormones affect pro/anti-
inflammatory cytokine balance and how this may shape autoimmune diseases onset,
activity, and progression.

TH1/TH2 AND PRO/ANTIINFLAMMATORY CYTOKINES PARADIGM

Immune responses are regulated by antigen-presenting cells (APCs), such as

monocytes/macrophages, dendritic cells, and other phagocytic cells, that are compo-
nents of innate immunity, and by the recently described T helper (Th) lymphocyte
subclasses Th1 and Th2, that are components of acquired (adaptive) immunity. Th1
cells primarily secrete IFN-γ, IL-2, and TNF-β, which promote cellular immunity,
whereas Th2 cells secrete a different set of cytokines, primarily IL-4, IL-10, and
IL-13, which promote humoral immunity5–8 (see FIGURE 1).
Naïve CD4+ (antigen-inexperienced) Th0 cells are clearly bipotential and serve
as precursors of Th1 and Th2 cells. Among the factors currently known to influence
the differentiation of these cells toward Th1 or Th2, cytokines produced by cells of
the innate immune system are the most important. Thus, IL-12, produced by activat-
ed monocytes/macrophages or other APCs, is a major inducer of Th1 differentiation
and hence cellular immunity. This cytokine acts in concert with natural killer (NK)–
derived IFNγ to further promote Th1 responses.8 APC-derived IL-12 and TNF-α,
in concert with NK cell and Th1-derived IFNγ, stimulate the functional activity of
T cytotoxic cells (Tc), NK cells, and activated macrophages, which are the major
292 ANNALS NEW YORK ACADEMY OF SCIENCES

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

Systemic Effects of Stress Hormones

Previous studies have shown that glucocorticoids suppress the production of
TNF-α, IFNγ, and IL-2 in vitro and in vivo in animals and humans.9,10 Recent evi-
dence indicates that glucocorticoids also act through their classic cytoplasmic/nucle-
ar receptors on APCs to suppress the production of the main inducer of Th1
responses of IL-12 in vitro and ex vivo.11,12 Because IL-12 is extremely potent in
enhancing IFNγ and inhibiting IL-4 synthesis by T cells, the inhibition of IL-12 pro-
duction by APCs may represent a major mechanism by which glucocorticoids affect
the Th1/Th2 balance. Thus, glucocorticoid-treated monocytes/macrophages produce
significantly less IL-12, leading to their decreased capacity to induce IFNγ produc-
tion by antigen-primed CD4+ T cells. This also is associated with an increased pro-
duction of IL-4 by T cells, probably resulting from disinhibition from the
suppressive effects of IL-12 on Th2 activity.13 Furthermore, glucocorticoids potently
downregulate the expression of IL-12 receptors on T and NK cells. This explains
why human peripheral blood mononuclear cells stimulated with immobilized anti-
CD3 lose their ability to produce IFNγ in the presence of glucocorticoids.14 Thus,
although glucocorticoids may have a direct suppressive effect on Th1 cells, the over-
all inhibition of IFNγ production by these cells appears to result mainly from the
inhibition of IL-12 production by APCs and from the loss o IL-12 responsiveness of
NK and Th1 cells.
It is particularly noteworthy that glucocorticoids have no effect on the production
of the potent antiinflammatory cytokine IL-10 by monocytes;11,15 yet, lymphocyte-
derived IL-10 production appears to be upregulated by glucocorticoids (see FIGURE 2).
Thus, rat CD4+ T cells pretreated with dexamethasone show increased levels of
mRNA for IL-10.16 Similarly, during experimental endotoxemia or cardiopulmonary
bypass, or in multiple sclerosis patients experiencing acute relapse, treatment with
glucocorticoids is associated with increased plasma IL-10 secretion.15,17,18 This could
be the result of a direct stimulatory effect of glucocorticoids on T-cell IL-10 produc-
tion and/or a block on the restraining inputs of IL-12 and IFNγ on monocyte/lympho-
cyte IL-10 production.
294 ANNALS NEW YORK ACADEMY OF SCIENCES

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

FIGURE 2. Systemic effects of stress hormones on proinflammatory and antiinflam-

matory cytokine production. Note that glucocorticoids do not affect the production of IL-
10 by monocytes/macrophages but upregulate the production of IL-10 and IL-4 by Th2
cells. Catecholamines upregulate IL-10 production by monocytes/macrophages; however,
they do not affect Th2 cells directly (Th2 cells have very few or no β-adrenergic receptors).
* Indirectly, however, catecholamines may potentiate the cytokine production by Th2 cells,
because they remove the inhibitory restrains on these cells exerted by IL-12. Solid lines
represent stimulation; dashed lines represent inhibition. ABBREVIATIONS: APC, antigen-
presenting cell; β, β-adrenergic receptor; GR, glucocorticoid receptor; IL, interleukin; IFN,
interferon; Th, T helper lymphocyte; TNF, tumor necrosis factor.
ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 295

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

Local Effects of Stress Hormones

The above general conclusion on the effects of stress hormones on Th1/Th2 bal-
ance may not pertain to certain conditions or local responses in specific compart-
ments of the body. Thus, the synthesis of TGF-β, another type 2 cytokine with potent
antiinflammatory activities, is differentially regulated by glucocorticoids: it is
enhanced in human T cells but suppressed in glial cells.28 In addition, norepineph-
rine, via stimulation of α2-ARs can augment LPS-stimulated production of TNF-α
from mouse peritoneal macrophages,29 whereas hemorrhage, a condition associated
with elevations of systemic catecholamine concentrations, increases the expression
of TNF-α and IL-1 by lung mononuclear cells via stimulation of α-ARs.30 Because
the response to β-AR agonist stimulation wanes during maturation of human mono-
cytes into macrophages,31 it is possible that in certain compartments of the body, the
α-AR–mediated effect of catecholamines becomes transiently dominant.
Interestingly, in vitro, long-term incubation with low concentrations of the syn-
thetic glucocorticoid dexamethasone indeed can activate alveolar macrophages,
leading to increased LPS-induced IL-1β production.32 Exposure of rats to mild ines-
capable electrical foot shock stress also results in increased IL-1β and TNF-α pro-
duction by alveolar macrophages.33 The upregulation of proinflammatory cytokine
production in vivo conditions appears to be dependent of intact sympathetic inner-
vation and β-ARs. However, the effect is most likely indirect, because in vitro a
296 ANNALS NEW YORK ACADEMY OF SCIENCES

direct modulatory effect of catecholamines on LPS-induced IL-1β production by

alveolar macrophages has not been shown. It can be envisaged that the stress-
induced changes in alveolar macrophage activity result from β-ARs–mediated alve-
olar type II epithelial cell activation, leading to release of surfactant and/or other
factors.33 Through the above mechanisms, catecholamines actually may boost local
cellular immune responses in a transitory fashion. This is substantiated further by the
finding that catecholamines potentiate the production of IL-8 by monocytes and epi-
thelial cells of the lung,34,35 thus probably promoting recruitment of polymorphonu-
clear leukocytes in local inflammation.

Anatomically, a close spatial relationship between sympathetic and peptidergic

nerve fibers on one hand, and macrophages and mast cells on the other, frequently is
observed (cf. Ref. 2). Neuro–macrophage and neuro–mast cell connections are not
restricted to the preformed lymphoid organs and tissues but are also regularly
encountered in virtually all somatic and visceral tissues. Substance P and peripheral
CRH, which are released from sensory peptidergic neurons, are two of the most
potent mast cell secretagogues.36–39 Peripheral CRH has proinflammatory, vascular
permeability-enhancing and vasodilatory actions,40 whereas histamine, a major
product of mast cell degranulation, is a well-recognized mediator of acute inflamma-
tion and allergic reactions. Furthermore, recent evidence indicates that CRH directly
stimulate IL-1 and IL-6, and substance P upregulates TNF-α and IL-12 production
by peripheral blood mononuclear cells and monocytes/macrophages.41–45 This adds
further complexity to the local effects of stress hormones, in conjunction with other
neurotransmitters and/or mediators (for more details, see Refs. 2 and 46). Thus, in
summary, whereas stress hormones suppress Th1 responses and proinflammatory
cytokine secretion and boost Th2 responses systemically, they may affect certain
local responses differently. Further studies are needed to address this question.

STRESS HORMONES AND AUTOIMMUNITY

Several autoimmune diseases are characterized by common alterations of the Th1

versus Th2 and IL-12/TNF-α versus IL-10 balance. In rheumatoid arthritis (RA),
multiple sclerosis (MS), type 1 diabetes mellitus, autoimmune thyroid disease, and
Crohn’s disease, the balance is skewed toward Th1 and an excess of IL-12 and
TNF-α production, whereas Th2 activity and the production of IL-10 are deficient.
This appears to be a critical factor that determines the proliferation and differentia-
tion of Th1-related autoreactive cellular immune responses in these disorders.47
Conversely, systemic lupus erythematosus (SLE) is associated with a Th2 shift and
an excessive production of IL-10, whereas IL-12 and TNF-α production appear to
be deficient. Taking into consideration the Th2-driving effects of stress hormones
systemically, one could postulate that a hypoactive stress system may facilitate or
sustain the Th1 shift in RA or MS, and vice versa stress system hyperactivity may
intensify the Th2 shift and induce or facilitate flares of SLE. Animal studies and cer-
tain clinical observations support this hypothesis.
ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 297

Activity of the HPA Axis and the SNS in RA and MS

Recent studies suggest that suboptimal production of cortisol is involved in the
onset and/or progression of RA.46,48,49 Most patients with RA have relatively “inap-
propriately normal” plasma cortisol levels in the setting of severe, chronic inflam-
mation characterized by increased production of TNF-α, IL-1, and IL-6. Because
these cytokines are powerful stimulants to the HPA axis and cortisol production, we
would have expected significantly elevated plasma cortisol levels in RA patients.
The available data suggest that the HPA axis response is blunted in these patients.
Whether this abnormality is primary or secondary has not been established.49
Several lines of evidence indicate that the sympathetic immune interface is defec-
tive in MS and its experimental model, the experimental allergic encephalomyelitis.
Thus, sympathetic skin responses are decreased and lymphocyte β-ARs are
increased in progressive MS.50 The density of β-ARs on CD8+ T cells are increased
between two- and threefold, compared with age-matched controls.51,52 Similarly, in
the preclinical stage of experimental allergic encephalomyelitis the norepinephrine
content in spleen is reduced, accompanied by an increase of splenocyte β-ARs
density.53 A defective or hypoactive SNS is most likely to be a “causative” factor for
the upregulation of β-ARs observed in MS.54 Furthermore, isoproterenol and terb-
utaline, β-AR and β2-AR agonists, respectively, were reported to suppress chron-
ic/relapsing experimental allergic encephalomyelitis in Lewis rats.55,56 The latter
observation might have resulted from the above-discussed effects of catecholamines
and β-AR agonists on the production of type 1 cytokines.
Several recent data suggest a “protective” role of the SNS in RA or its experimen-
tal models in animals. Thus, in the arthritis-prone Lewis rats sympathectomy with
6-OHDA enhanced the severity of adjuvant-induced arthritis.57,58 In this animal
model of arthritis, selective sympathetic denervation of the reactive secondary lym-
phoid organs (the popliteal and inguinal lymph nodes), was achieved with local
injection into the fat pads surrounding these lymph nodes.57,58 This denervation
resulted in earlier onset and enhanced severity of inflammation and bone erosions
compared with nondenervated rats. The “protective” role of SNS is substantiated
further by the recent study of Malfait et al.59 showing that the β2-AR agonist salb-
utamol is a potent suppressor of established collagen-induced arthritis in mice. This
drug had a profound protective effect as assessed by clinical score, paw thickness,
and joint histology. In addition, in in vitro experiments salbutamol reduced IL-12
and TNF-α release by peritoneal macrophages and blocked mast cell degranulation
in joint tissues.
Recent studies in humans also suggest a defective SNS in RA. In patients with
RA, diminished autonomic responses were observed after cognitive discrimination
and the Stroop color-word interference tests.60 Miller et al. showed that patients with
long-term RA had a highly significant reduction of sympathetic nerve fibers in syn-
ovial tissues, which was dependent on the degree of inflammation. Thus, the reduc-
tion of sympathetic nerve fibers in the chronic disease may lead to uncoupling of the
local inflammation from the antiinflammatory input of SNS. Interestingly, in RA
synovial tissues it appears there is preponderance of approximately 10: 1 for primary
sensory, substance P–positive fibers as compared with sympathetic fibers.61 Because
substance P is a powerful proinflammatory agent, via release of histamine and
TNF-α and IL-12, such preponderance may lead to an unfavorable proinflammatory
298 ANNALS NEW YORK ACADEMY OF SCIENCES

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.

Pregnancy/Postpartum and Autoimmune Diseases Activity

Some autoimmune diseases such as RA and MS often remit during pregnancy,
particularly in the third trimester, but have an exacerbation or their initial onset dur-
ing the postpartum period.48,63–66 The risk of developing new onset RA during preg-
nancy, compared with nonpregnancy, is decreased by approximately 70%. In
contrast, the risk of developing RA is markedly increased in the postpartum period,
particularly the first three months (odds ratio of 5.6 overall and 10.8 after first preg-
nancy). In women with MS, the rate of relapses declines during pregnancy, especial-
ly in the third trimester, increases during the first three months of the postpartum,
and then returns to the prepregnancy rate.65 In apparent contrast, autoimmune dis-
eases that present with symptoms associated predominantly with antibody-mediated
damage, such as SLE and specifically the immune complex-mediated glomerulone-
phritis, tend to develop or flare during pregnancy.63,67–69
A decrease in the production of IL-2 and IFNγ by antigen and mitogen stimulated
peripheral blood mononuclear cells, accompanied by an increase in the production
of IL-4 and IL-10, is observed in normal pregnancy. The lowest quantities of IL-2
and IFNγ and the highest quantities of IL-4 and IL-10 are present in the third trimes-
ter of pregnancy.70 Placental tissues from mothers at term express high levels of
IL-10,71 whereas IL-10 is present in the amniotic fluid of most pregnancies, with
higher concentrations found at term compared with the second trimester.72 We
recently have found that during the third trimester of pregnancy, ex vivo monocytic
IL-12 production was approximately threefold and TNF-α production was approxi-
mately 40% lower than postpartum values.73 These studies suggest that type 1/proin-
flammatory cytokine production and cellular immunity are suppressed, and there is
a Th2 shift during normal pregnancy, particularly in the third trimester.
The third trimester of pregnancy and the early postpartum period are also known
to be associated with abrupt changes of several hormones. Thus, during the third tri-
mester of pregnancy urinary cortisol and norepinephrine excretion and serum levels
of 1,25-dihydroxyvitamin D3 are approximately two- to threefold higher than post-
partum values.73 This is accompanied by the well-known marked elevations of estra-
diol and progesterone serum concentrations. The data reviewed here are consistent
with the view that the increased levels of cortisol, norepinephrine, 1,25-dihydroxy-
vitamin D3, estrogens, and progesterone in the third trimester of pregnancy might
orchestrate the improvement in autoimmune diseases, such as RA and MS via sup-
pression of type 1/proinflammatory (IL-12, IFNγ, and TNF-α) and potentiation of
type2/antiinflammatory (IL-4 and IL-10) cytokine production. Conversely, this par-
ticular type of hormonal control of proinflammatory/antiinflammatory cytokine bal-
ance might contribute to the flare-ups of SLE observed during pregnancy. Postpartum,
ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 299

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.