Ann. N.Y. Acad. Sci. 966: 290���303 (2002). ��2002 New York Academy of Sciences. Stress Hormones, Proinflammatory and Antiinflammatory Cytokines, and Autoimmunity ILIA J. ELENKOV a,b AND GEORGE P. CHROUSOS b a Division of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, DC, USA b Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA A BSTRACT : 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. K EYWORDS : 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

291 ELENKOV & CHROUSOS: STRESS HORMONES AND AUTOIMMUNITY 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)- �� , 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- �� and interferon (IFN)- �� , 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- �� , IL-2, and TNF- �� , which promote cellular immunity, whereas Th2 cells secrete a different set of cytokines, primarily IL-4, IL-10, and IL-13, which promote humoral immunity 5���8 (see F IGURE 1). Na��ve 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 IFN �� to further promote Th1 responses. 8 APC-derived IL-12 and TNF- �� , in concert with NK cell and Th1-derived IFN �� , stimulate the functional activity of T cytotoxic cells (Tc), NK cells, and activated macrophages, which are the major