Comprehensive Physiology Wiley Online Library

Role of Endogenous Glucocorticoids in Immune System Function: Regulation and Counterregulation

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 In Vivo Versus in Vitro Glucocorticoids
2 Natural Versus Synthetic Glucocorticoids
2.1 Corticosteroid Receptor Subtypes
2.2 Corticosteroid‐Binding Globulin
3 Physiological Versus Nonphysiological Concentrations of Glucocorticoids
4 Factors Regulating Immune Cell Exposure to Glucocorticoids
4.1 Factors in the Absence of Immune Challenge
4.2 Factors in the Presence of Immune Challenge
5 Direct Effects of Glucocorticoids on Immune Cells
5.1 Molecular Features of Intracellular Glucocorticoid Receptors
5.2 Regulatory Effects of Glucocorticoids on the Expression of Immunologically Important Genes
5.3 Possible Alternative Mechanisms of Glucocorticoid Action
6 Strategies for Assessing the Role of Endogenous Glucocorticoids in Immune System Function
6.1 Circadian Studies
6.2 Stress Studies
6.3 In Vivo Secretagogue Stimulation Studies
6.4 Adrenalectomy and Glucocorticoid Replacement Studies
6.5 Other More Selective Manipulations of Glucocorticoid Action
7 Glucocorticoid Effects on Immune Subsystems
7.1 Immune Cell Maturation, Differentiation, and Turnover
7.2 Immune Cell Trafficking
7.3 Inflammation
7.4 Septic Shock
7.5 T helper 1 and T helper 2 Response
7.6 Antibody Production
7.7 Cytotoxicity and Delayed Type Hypersensitivity
8 General Models of Glucocorticoid Regulation of the Immune System
8.1 Counterregulatory Role of Glucocorticoids
8.2 Regulatory Role of Glucocorticoids
8.3 Regulatory Role of Glucocorticoids During Stress
8.4 Bidirectional Regulatory Effects of Glucocorticoids
Figure 1. Figure 1.

Basic relationship between the hypothalamic‐pituitary‐adrenal (HPA) axis, cortisol, and immune system. The hypothalamic, pituitary, and adrenal components of the HPA axis directly control the secretion of cortisol into the general blood circulation. Cortisol has stimulatory and inhibitory (+/‐) effects on various aspects of immune system function. Cortisol also has a direct negative feedback effect (‐) on the activity of the HPA axis. The HPA axis is stimulated (+) by central nervous system afferents responsive to circadian and stress factors. The HPA axis is also stimulated (+) either directly or indirectly by certain cytokine molecules secreted by activated immune cells.

Figure 2. Figure 2.

Levels of mineralocorticoid and glucocorticoid receptor binding in brain, pituitary, immune tissues, and peripheral blood mononuclear cells (PBMC). Tissue and cells are from rats that were adrenalectomized 24 h prior to death. No mineralocorticoid receptor binding was detected in the thymus and lymph nodes. Mineralocorticoid receptor binding was not determined in PBMC. (Data from .)

Figure 3. Figure 3.

Basic steps in cortisol regulation of gene transcription. Only the cortisol molecules that are not bound to corticosteroid binding globulin (CBG) are free to diffuse into a cell. The two cortisol receptor subtypes, the mineralocorticoid receptor (MR) or the glucocorticoid receptor (GR), are hormone activated transcription factors. The diagram depicts only the glucocorticoid receptor, but the basic sequence of events is believed to apply to both receptor subtypes. In the absence of hormone (unoccupied glucocorticoid receptor) the receptors are located intracellularly in the cell cytoplasm and form a heteromeric complex with other proteins (hsp90 and other accessory proteins). After cortisol binds to a hormone binding region of the receptor protein the receptor becomes activated, which results in (1) dissociation of hsp90 and other accessory proteins, (2) exposure of a DNA binding region of the receptor protein, (3) translocation of the activated receptor into the cell nucleus, (4) dimerization of two activated glucocorticoid receptors, (5) binding of the activated glucocorticoid receptor dimer to a specific sequence of DNA (glucocorticoid response element), and (6) resulting in either an increase or decrease in transcription (mRNA) of the glucocorticoid regulated target gene.

Figure 4. Figure 4.

Cyanoketone treatment (corticosterone synthesis inhibition) of rats virtually eliminates the decrease in white blood cell (WBC) and lymphocyte numbers observed during acute stress, and significantly enhances the increase in neutrophil numbers observed after the cessation of stress. Changes in WBC (A), lymphocyte (B), and neutrophil (C) numbers during 2‐h stress (restraint), and following recovery 3 h after the cessation of stress are shown (n = 5/group). The percentage of change in leukocyte numbers after 2‐h stress relative to baseline (0 h) is indicated. Statistically significant differences are indicated: *p <0.05, significantly different from 0‐h baseline (paired t test); °p <0.05, significantly different from corresponding control value (independent t test).

Reprinted with permission from []
Figure 5. Figure 5.

Acute stress experienced before exposure to antigen enhances a skin delayed‐type hypersensitivity (DTH) reaction to that antigen. A 6‐day time course of changes in the thickness of right pinnae of previously sensitized animals challenged with (2.4‐dinitro‐1‐fluorobenzene DNFB) (0.5% w/v) is shown. Vehicle treated control (left) pinnae showed no change in thickness during the experiment (data not shown). Data are expressed as means ± SEM (n = 6 per treatment group).

Adapted with permission from []


Figure 1.

Basic relationship between the hypothalamic‐pituitary‐adrenal (HPA) axis, cortisol, and immune system. The hypothalamic, pituitary, and adrenal components of the HPA axis directly control the secretion of cortisol into the general blood circulation. Cortisol has stimulatory and inhibitory (+/‐) effects on various aspects of immune system function. Cortisol also has a direct negative feedback effect (‐) on the activity of the HPA axis. The HPA axis is stimulated (+) by central nervous system afferents responsive to circadian and stress factors. The HPA axis is also stimulated (+) either directly or indirectly by certain cytokine molecules secreted by activated immune cells.



Figure 2.

Levels of mineralocorticoid and glucocorticoid receptor binding in brain, pituitary, immune tissues, and peripheral blood mononuclear cells (PBMC). Tissue and cells are from rats that were adrenalectomized 24 h prior to death. No mineralocorticoid receptor binding was detected in the thymus and lymph nodes. Mineralocorticoid receptor binding was not determined in PBMC. (Data from .)



Figure 3.

Basic steps in cortisol regulation of gene transcription. Only the cortisol molecules that are not bound to corticosteroid binding globulin (CBG) are free to diffuse into a cell. The two cortisol receptor subtypes, the mineralocorticoid receptor (MR) or the glucocorticoid receptor (GR), are hormone activated transcription factors. The diagram depicts only the glucocorticoid receptor, but the basic sequence of events is believed to apply to both receptor subtypes. In the absence of hormone (unoccupied glucocorticoid receptor) the receptors are located intracellularly in the cell cytoplasm and form a heteromeric complex with other proteins (hsp90 and other accessory proteins). After cortisol binds to a hormone binding region of the receptor protein the receptor becomes activated, which results in (1) dissociation of hsp90 and other accessory proteins, (2) exposure of a DNA binding region of the receptor protein, (3) translocation of the activated receptor into the cell nucleus, (4) dimerization of two activated glucocorticoid receptors, (5) binding of the activated glucocorticoid receptor dimer to a specific sequence of DNA (glucocorticoid response element), and (6) resulting in either an increase or decrease in transcription (mRNA) of the glucocorticoid regulated target gene.



Figure 4.

Cyanoketone treatment (corticosterone synthesis inhibition) of rats virtually eliminates the decrease in white blood cell (WBC) and lymphocyte numbers observed during acute stress, and significantly enhances the increase in neutrophil numbers observed after the cessation of stress. Changes in WBC (A), lymphocyte (B), and neutrophil (C) numbers during 2‐h stress (restraint), and following recovery 3 h after the cessation of stress are shown (n = 5/group). The percentage of change in leukocyte numbers after 2‐h stress relative to baseline (0 h) is indicated. Statistically significant differences are indicated: *p <0.05, significantly different from 0‐h baseline (paired t test); °p <0.05, significantly different from corresponding control value (independent t test).

Reprinted with permission from []


Figure 5.

Acute stress experienced before exposure to antigen enhances a skin delayed‐type hypersensitivity (DTH) reaction to that antigen. A 6‐day time course of changes in the thickness of right pinnae of previously sensitized animals challenged with (2.4‐dinitro‐1‐fluorobenzene DNFB) (0.5% w/v) is shown. Vehicle treated control (left) pinnae showed no change in thickness during the experiment (data not shown). Data are expressed as means ± SEM (n = 6 per treatment group).

Adapted with permission from []
References
 1. Abo, T., T. Kawate, K. Itoh, and K. Kumagai. Studies on the bioperiodicity of the immune response. I. Circadian rhythms of human T, B and K cell traffic in the peripheral blood. J. Immunology 126: 1360–1363, 1981.
 2. Akahoshi, T., J. J. Oppenheim, and K. Matsushima. Induction of high‐affinity interleukin 1 receptor on human peripheral blood lymphocytes by glucocorticoid hormones. J. Exp. Med. 167: 924–936, 1988.
 3. Alkana, S. F., and M. F. Dallman. Feedback and facilitation in the adrenocortical system: unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress. Endocrinology 131: 57–68, 1992.
 4. Akerblom, I. E., E. P. Slater, M. Beato, J. D. Baxter, and P. L. Mellon. Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer. Science 241: 350–353, 1988.
 5. Ali, M., and W. V. Vedeckis. The glucocorticoid receptor protein binds to transfer RNA. Science 235: 467–470, 1987.
 6. Almawi, W. Y., H. N. Beyhum, A. A. Rahme, and M. J. Rieder. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J. Leukoc. Biol. 60: 563–572, 1996.
 7. Almawi, W. Y., D. A. Hess, and M. J. Rieder. Significance of enhanced cytokine receptor expression by glucocorticoids. Blood 92: 3979–3980, 1998.
 8. Altura, B. M., and B. T. Altura. Peripheral vascular actions of glucocorticoids and their relationship to protection in circulatory shock. J. Pharm. Exp. Then 190: 300–315, 1974.
 9. Amano, Y., S. W. Lee, and A. C. Allison. Inhibition by glucocorticoids of the formation of interleukin‐1α, interleukin‐1β, and interleukin‐6: mediation by decreased mRNA stability. Mol. Pharmacol. 43: 176–182, 1993.
 10. Ambrose, C. T. The requirement for hydrocortisone in antibody‐forming tissue cultivated in serum‐free medium. J. Exp. Med. 119: 1027–1049, 1964.
 11. Anderson, G. P. and A.J. Coyle. Th2 and ‘Th2–like’ cells in allergy and asthma: pharmacological perspectives. Trends Pharmacol. Sci. 15: 324–332, 1994.
 12. Ando, T, J. Rivier, H. Yanaihara, and A. Arimura. Peripheral corticotropin‐releasing factor mediates the elevation of plasma IL‐6 by immobilization stress in rats. Am. J. Physiol. 275 (Regulatory Integrative Comp. Physiol. 44): R1461–R1467, 1998
 13. Antonakis, N., E. Markogiannakis, M. Theodoropoulou, V. Georgoulias, C. Stournaras, and A. Gravanis. The antiglucocorticoid RU486 downregulates the expression of interleukin‐2 receptors in normal human lymphocytes. J. Steroid Biochem. Molec. Biol. 39: 929–935, 1991.
 14. Antoni, F. A. Hypothalamic control of adrenocorticotropin secretion: advances since the discovery of 41‐residue corticotropin‐releasing factor. Endocr. Rev. 7: 351–378, 1986.
 15. Armanini, D., S. Endres, U. Kuhnle, and P. C. Weber. Parallel determination of mineralocorticoid and glucocorticoid receptors in T‐ and B‐lymphoctyes of human spleen. Acta Endocrinologica 118: 479–482, 1988.
 16. Armanini, D., T. Strasser, and P. C. Weber. Characterization of aldosterone binding sites in circulating human mononuclear leukocytes. Am. J. Physiol. 248: (Endocrinol. Metab. 11): E388–E390, 1985.
 17. Armanini, D., M. Wehling, and P. C. Weber. Mineralocorticoid effector mechanism in human mononuclear leukocytes. J. Steroid Biochem. 27: 967–970, 1987.
 18. Arriza, J. L., C. Weinberger, G. Cerelli, T. M. Glaser, B. L. Handelin, D. E. Housman, and R. M. Evans. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 237: 268–275, 1987.
 19. Arthur, R. P. and D. Mason. T cells that help B cell responses to soluble antigen are distinguishable from those producing interleukin 2 on mitogenic or allogeneic stimulation. J. Exp. Med. 163: 774–786, 1986.
 20. Arya, S. K., F. Wong‐Staal, and R. C. Gallo. Dexamethasonemediated inhibition of human T cell growth factor and γ‐interferon messenger RNA. J. Immunol. 133: 273–276, 1984.
 21. Arzt, E., J. Sauer, T. Pollmacher, M. Labeur, F. Holsboer, J. M.H. M. Reul, and G. K. Stalla. Glucocorticoids suppress interleukin‐1 receptor antagonist synthesis following induction by endotoxin. Endocrinology 134: 672–677, 1994.
 22. Auphan, N., J. A. DiDonato, C. Rosette, A. Helmberg, and M. Karin. Immunosuppression by glucocorticoids: inhibition of NF‐kB activity through induction of IkB synthesis. Science 270: 286–290, 1995.
 23. Bamberger, C. M., H. M. Schulte, and G. P. Chrousos. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr. Rev. 17: 245–261, 1996.
 24. Bangham, A. D., M. M. Standish, and G. Weissmann. The action of steroids and streptolysin S on the permeability of phospholipid structures to cations. J. Mol. Biol. 13: 253–259, 1965.
 25. Bargatze, R. F., and D. H. Katz. “Allergic breakthrough” after antigen sensitization: height of IgE synthesis is temporally related to diurnal variation in endogenous steroid production. J. Immunol. 125: 2306–2310, 1980.
 26. Bateman, A., A. Singh, T. Kral, and S. Solomon. The immune‐hypothalamic‐pituitary‐adrenal axis. Endocr. Rev. 10: 92–112, 1989.
 27. Baumann, H., G. L Firestone, T. L. Burgess, K. W. Gross, K. R. Yamamoto, and W. A. Held. Dexamethasone regulation of α1‐acid glycoprotein and other acute phase reactants in rat liver and hepatoma cells. J. Biol. Chem. 10: 563–570, 1983.
 28. Baumann, H., and J. Gauldie. The acute phase response. Immunol. Today 15: 74–80, 1994.
 29. Baumann, H., G. P. Jahreis, and K. K. Morella. Interaction of cytokine‐ and glucocorticoid‐response elements of acute‐phase plasma protein genes. J. Biol. Chem. 265: 22275–22281, 1990.
 30. Beck, C. A., P. A. Estes, B. J. Bona, C. A. Muro‐Cacho, S. K. Nordeen, and D. P. Edwards. The steroid antagonist RU486 exerts different effects on the glucocorticoid and progesterone receptors. Endocrinology 133: 728–740, 1993.
 31. Beisel, W. R., and M. I. Rapoport. Inter‐relations between adrenocortical functions and infectious illness (concluded). New Engl. J. Med. 280: 596–604, 1969.
 32. Berkenbosch, F., J. V. Oers, A. Del Rey, F. Tilders, and H. Besedovsky. Corticotropin‐releasing factor‐producing neurons in the rat activated by interleukin‐1. Science 238: 524–526, 1987.
 33. Bernton, E. W., J. E. Beach, J. W. Holaday, R. C. Smallridge, and H. G. Fein. Release of multiple hormones by a direct action of interleukin‐1 on pituitary cells. Science 238: 519–521, 1987.
 34. Bertini, R., M. Bianchi, and P. Ghezzi. Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J. Exp. Med. 167: 1708–1712, 1988.
 35. Besedovsky, H. O., A. E. del Rey, and E. Sorkin. Immune‐neuroendocrine interactions. J. Immunol. 135: 750s–754s, 1985.
 36. Beutler, B., N. Krochin, I. W. Milsark, C. Luedke, and A. Cerami. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science 232: 977–980, 1986.
 37. Blalock, J. E. The syntax of immune‐neuroendocrine communication. Immunol. Today 15: 504–511, 1994.
 38. Blecha, F., R. A. Barry, and K. W. Kelley. Stress‐induced alterations in delayed‐type hypersensitivity to SRBC and contact sensitivity to DNFB in mice. Proc. Soc. Exp. Biol. Med. 169: 239–246, 1982.
 39. Boumpas, D. T., E. D. Anastassiou, S. A. Older, G. C. Tsokos, D. L. Nelson, and J. E. Balow. Dexamethasone inhibits human interleukin 2 but not interleukin 2 receptor gene expression in vitro at the level of nuclear transcription. J. Clin. Invest. 87: 1739–1747, 1991.
 40. Boumpas, D. T., F. Paliogianni, E. D. Anastassiou, and J. E. Balow. Glucocorticosteroid action on the immune system: molecular and cellular aspects. Clin. Exp. Rheum. 9: 413–423, 1991.
 41. Braun, C. M., S‐K. Huang, G. G. Bashian, A. Kagey‐Sobotka, L. M. Lichenstein, and D. M. Essayan. Corticosteroid modulation of human, antigen‐specific Th1 and Th2 responses. J. Allergy Clin. Immunol. 100: 400–407, 1997.
 42. Brien, T. G. Free Cortisol in human plasma. Horm. Metab. Res. 12: 643–650, 1980.
 43. Brown, H. E., and T. F. Dougherty. The diurnal variation of blood leucocytes in normal and adrenalectomized mice. Endocrinology 58: 365–375, 1956.
 44. Brown, M. R., and L. A. Fisher. Corticotropin‐releasing factor: effects on the autonomic nervous system and visceral systems. Federation Proc. 44: 243–248, 1985.
 45. Bryant, H. U., E. W. Bernton, J. R. Kenner, and J. W. Holaday. Role of adrenal cortical activation in the immunosuppressive effects of chronic morphine treatment. Endocrinology 128: 3253–3258, 1991.
 46. Bucala R. Neuroimmunomodulation by macrophage migration inhibitory factor (MIF). Ann. N.Y. Acad. Sci. 840: 74–82, 1998.
 47. Burchfield, S. R., S. C. Woods, and M. S. Elich. Pituitary adrenocortical response to chronic intermittent stress. Physiol. Behav. 24: 297–302, 1980.
 48. Burnstein, K. L., and Cidlowski, J. A. Regulation of gene expression by glucocorticoids. Annu. Rev. Physiol. 51: 683–699, 1989.
 49. Calandra, T., J. Bernhagen, C. N. Metz, L. A. Spiegel, M. Bacher, T. Donnelly, A. Cerami, and R. Bucala. MIF as a glucocorticoid‐induced modulator of cytokine production. Nature 377: 68–71, 1995.
 50. Caldenhoven, E., J. Liden, S. Wissink, A. Van de Stolpe, J. Raaijmakers, L. Koenderman, S. Okret, J.‐A. Gustafsson, and P. T. Van der Saag. Negative cross‐talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. Mol. Endocrinol. 9: 401–412, 1995.
 51. Chung, H.‐T., W. E. Samlowski, and R. A. Daynes. Modification of the murine immune system by glucocorticosteroids: alterations of the tissue localization properties of circulating lymphocytes. Cell. Immunol. 101: 571–585, 1986.
 52. Claman, H. N. Corticosteroids and lymphoid cells. New Eng. J. Med. 287: 388–397, 1972.
 53. Clerici, M., and G. M. Shearer. The Th1‐Th2 hypothesis of HIV infection: new insights. Immunol. Today 15: 578–581, 1994.
 54. Cohen, I. R., L. Stavy, and M. Feldman. Glucocorticoids and cellular immunity in vitro. Facilitation of the sensitization phase and inhibition of the effector phase of a lymphocyte anitfirbroblast reaction. J. Exp. Med. 132: 1055–1070, 1970.
 55. Cohen, J., and M. P. Glauser. Septic shock: treatment. Lancet 338: 736–739, 1991.
 56. Cohen, J. J. Thymus‐derived lymphocytes sequestered in the bone marrow of hydrocortisone‐treated mice. J. Immunol. 108: 841–844, 1972.
 57. Cohen, J. J. Lymphocyte death induced by glucocorticoids. In: Anti‐Inflammatory Steroid Action: Basic and Clinical Aspects, edited by R. P. Schleimer, H. N. Claman, and A. Oronsky. San Diego: Academic Press, 1989, p 110–131.
 58. Cohen, J. J., and H. N. Claman. Hydrocortisone resistance of activated initiator cells in graft versus host reactions. Nature 229: 274–275, 1971.
 59. Cohen, J. J., M. Fishback, and H. N. Claman. Hydrocortisone resistance of graft versus host activity in mouse thymus, spleen, and bone marrow. J. Immunol. 105: 1146–1150, 1970.
 60. Cohen, S., and G. M. Williamson. Stress and infectious disease in humans. Psych. Bull. 109: 5–24, 1991.
 61. Constant, S. L., and K. Bottomly. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Ann. Rev. Immunol. 15: 297–322, 1997.
 62. Corrigan, C. J., Q. Hamid, J. North, J. Barkans, R. Moqbel, S. Durham, V. Gemou‐Engesaeth, and A. B. Kay. Peripheral blood CD4 but not CD8 T‐lymphocytes in patients with exacerbation of asthma transcribe and translate messenger RNA encoding cytokines which prolong eosinophil survival in the context of a Th2‐type pattern: effect of glucocorticoid therapy. Am. J. Respir. Cell. Mol. Biol. 12: 567–578, 1995.
 63. Coulpier, M., S. Andreev, C. Lemercier, H. Dauchel, O. Lees, M. Fontaine, and J. Ripoche. Activation of the endothelium by IL‐1α and glucocorticoids results in major increase of complement C3 and factor B production and generation of C3a. Clin. Exp. Immunol. 101: 142–149, 1995.
 64. Cove‐Smith, J. R., P. Kabler, R. Pownall and M. S. Knapp. Orcadian variation in an immune response in man. British Med. J. 2: 253–254, 1978.
 65. Cox, J. H., and W. L. Ford. The migration of lymphocytes across specialized vascular endothelium. IV. Prednisolone acts at several points on the recirculation pathway of lymphocytes. Cell. Immunol. 66: 407–422, 1982.
 66. Craddock, C. G. Corticosteroid‐induced lymphopenia, immunosuppression, and body defense. Ann. Intern. Med. 88: 564–566, 1978.
 67. Cronstein, B. N., S. C. Kimmel, R. I. Levin, F. Martiniuk, and G. Weissmann. A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelialleukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc. Natl. Acad. Sci. U.S.A. 89: 9991–9995, 1992.
 68. Culpepper, J. A., and F. Lee. Regulation of IL 3 expression by glucocorticoids in cloned murine T lymphocytes. J. Immunol. 135: 3191–3197, 1985.
 69. Cunnick, J. E., D. T. Lysle, B. J. Kucinski, and B. S. Rabin. Evidence that shock‐induced immune suppression is mediated by adrenal hormones and peripheral β‐adrenergic receptors. Pharm. Biochem. Behav. 36: 645–651, 1990.
 70. Cupps, T. R., L. C. Edgar, C. A. Thomas, and A. S. Fauci. Multiple mechanisms of B cell immunoregulation in man after administration of in vivo corticosteroids. J. Immunol. 132: 170–175, 1984.
 71. Cupps, T. R., and A. S. Fauci. Corticosteroid‐mediated immunoregulation in man. Immunological Rev. 65: 133–155, 1982.
 72. Da Silva, J.A.P. Sex hormones and glucocorticoids: interactions with the immune system. Ann. N.Y. Acad. Sci. 876: 102–118, 1999.
 73. Dallman, M. F., S. F. Akana, C. S. Cascio, D. N. Darlington, L. Jacobson, and N. Levin. Regulation of ACTH secretion: variations on a theme of B. Recent Prog. Horm. Res. 43: 113–173, 1987.
 74. Dantzer, R., and K. W. Kelley. Stress and immunity: an integrated view of relationships between the brain and the immune system. Life Sci. 44: 1995–2008, 1989.
 75. Davies, A. O., and R. J. Lefkowitz. Regulation of β‐adrenergic receptors by steroid hormones. Ann. Rev. Physiol. 46: 119–130, 1984.
 76. Daynes, R. A., and B. A. Araneo. Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4. Eur. J. Immunol. 19: 2319–2325, 1989.
 77. Daynes, R. A., D. J. Dudley, and B. A. Araneo. Regulation of murine lymphokine production in vivo. II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells. Eur. J. Immunol. 20: 793–802, 1990.
 78. De Carli, M., M. M. D'Elios, G. Zancuoghi, S. Romagnani, and G. Del Prete. Human Th1 and Th2 cells: functional properties, regulation of development and role in autoimmunity. Autoimmunity 18: 301–308, 1994.
 79. De Kloet, E. D., P. Burbach, and G. H. Mulder. Localization and role of transcortin‐like molecules in the anterior pituitary. Mol. Cell. Endocrinol. 7: 261–273, 1977.
 80. De Kloet, E. R., E. Vreugdenhil, M. S. Oitzl, and M. Joels. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19: 269–301, 1998.
 81. Deak, T., J. L. Meriwether, M. Fleshner, R. L. Spencer, A. Abouhamze, L. L. Moldawer, R. E. Grahn, L. R. Watkins, and S. F. Maier. Evidence that brief stress may induce the acute phase response in rats. Am. J. Physiol. 273 (Regulatory Integrative Comp. Physiol. 42): R1998–R2004, 1997.
 82. Deak, T., K. T. Nguyen, C. S. Cotter, M. Fleshner, L. R. Watkins, S. F. Maier, and R. L. Spencer. Long term changes in mineralocorticoid and glucocorticoid receptor occupancy following exposure to an acute stressor. Brain. Res. 847: 211–220, 1999.
 83. Dekruyff, R. H., Y. Fang, and D. T. Umetsu. Corticosteroids enhance the capacity of macrophages to induce Th2 cytokine synthesis in CD4+ lymphocytes by inhibiting IL‐12 production. J. Immunology 160: 2231–2237, 1998.
 84. Del Rey, A., H. Besedovsky, and E. Sorkin. Endogenous blood levels of corticosterone control the immunologic cell mass and B cell activity in mice. J. Immunol. 133: 572–575, 1984.
 85. Devenport, L., T. Thomas, A. Knehans, and A. Sundstrom. Acute, chronic, and interactive effects of type I and II corticosteroid receptor stimulation on feeding and weight gain. Physiol. Behav. 47: 1221–1228, 1990.
 86. Dhabhar, F. D. Stress‐induced enhancement of cell‐mediated immunity. Ann. N.Y. Acad. Sci. 840: 359–372, 1998.
 87. Dhabhar, F. S., and B. S. McEwen. Stress‐induced enhancement of antigen‐specific cell‐mediated immunity. J. Immunol. 156: 2608–2615, 1996.
 88. Dhabhar, F. S., and B. S. McEwen. Acute stress enhances while chronic stress suppresses immune function in vivo: a potential role for leukocyte trafficking. Brain Behav. Immun. 11: 286–306, 1997.
 89. Dhabhar, F. S., and B. S. McEwen. Enhancing versus suppressive effects of stress hormones on skin immune function. PNAS 96: 1059–1064, 1999.
 90. Dhabhar, F. S., B. S. McEwen, and R. L. Spencer. Stress response, adrenal steroid receptor levels and corticosteroid‐binding globulin levels—a comparison between Sprague‐Dawley, Fischer 344 and Lewis rats. Brain Res. 616: 89–98, 1993.
 91. Dhabhar, F. S., A. H. Miller, B. S. McEwen, and R. L. Spencer. Effects of stress on immune cell distribution: dynamics and hormonal mechanisms. J. Immunol. 154: 5511–5527, 1995.
 92. Dhabhar, F. S., A. H. Miller, B. S. McEwen, and R. L. Spencer. Stress‐induced changes in blood leukocyte distribution: role of adrenal steroid hormones. J. Immunol. 157: 1638–1644, 1996.
 93. Dhabhar, F. S., A. H. Miller, M. Stein, B. S. McEwen, and R. L. Spencer. Diurnal and acute stress‐induced changes in distribution of peripheral blood leukocyte subpopulations. Brain, Behavior and Immunity 8: 66–79, 1994.
 94. Diamond, D. M., M. C. Bennett, M. Fleshner, and G. M. Rose. Inverted‐U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2: 421–430, 1992.
 95. Dinarello, C. A., and S. M. Wolff. The role of interleukin‐1 in disease. N. Engl. J. Med. 328: 106–113, 1993.
 96. Dobbs, C. M., N. Feng, F. M. Beck, and J. F. Sheridan. Neuroendocrine regulation of cytokine production during experimental influenza viral infection. J. Immunol. 157: 1870–1877, 1996.
 97. Doenhoff, M. J., and E. Leuchars. Effects of irradiation, anti‐thymocyte serum, and corticosteroids on PHA and LPS responsive cells of the mouse. Int. Arch. Allergy Appl. Immunol. 53: 505–514, 1977.
 98. Dougherty, R. F., and A. White. Functional alterations in lymphoid tissue induced by adrenal cortical secretion. Am. J. Anatomy 77: 81–116, 1945.
 99. Dougherty, T. F. Effect of hormones on lymphatic tissue. Physiol. Rev. 32: 379–401, 1952.
 100. Dunn, A. J. Psychoneuroimmunology for the psychoneuroendocrinologist: a review of animal studies of nervous system‐immune system interactions. Psychoneuroendo 14: 251–274, 1989.
 101. Dunn, A. J. Virus infection as a stressor: influenza virus elevates plasma concentrations of corticosterone, and brain concentrations of MHPG and tryptophan. Physiol. Behav. 45: 591–594, 1989.
 102. Dunsky, E. H., B. Zweiman, E. Fishchler, and D. A. Levy. Early effects of corticosteroids on basophils, lekocyte histamine, and tissue histamine. J. Allergy Clin. Immunol. 64: 426–432, 1979.
 103. Elenkov, I. J., E. L. Webster, D. J. Torpy, and G. P. Chrousos. Stress, corticotropin‐releasing hormone, glucocorticoids, and the immune/inflammatory response: acute and chronic effects. Ann. N.Y. Acad. Sci. 876: 1–13, 1999.
 104. Eskola, J., H. Frey, G. Molnar, and E. Soppi. Biological rhythm of cell‐mediated immunity in man. Clin. exp. Immunol. 26: 253–257, 1976.
 105. Evans‐Storms, R. B., and J. A. Cidlowski. Regulation of apoptosis by steroid hormones. J. Steroid Biochem. Mol. Biol. 53: 1–8, 1995.
 106. Fan, J., X.‐q. Gong, J. Wu, Y.‐f. Zhang, and R.‐b. Xu. Effect of glucocorticoid receptor (GR) blockage on endotoxemia in rats. Circ. Shock 42: 76–82, 1994.
 107. Fauci, A. S. Mechanisms of corticosteroid action on lymphocyte subpopulations. I. Redistribution of circulating T and B lymphocytes to the bone marrow. Immunology 28: 669–680, 1975.
 108. Fauci, A. S. Immunosuppressive and anti‐inflammatory effects of glucocorticoids. In: Glucocorticoid Hormone Action, edited by J. D. Baxter and G. G. Rousseau. Berlin: Springer‐Verlag, 1979, p 449–465.
 109. Fauci, A. S., and D. C. Dale. The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J. Clin. Invest. 53: 240–246, 1974.
 110. Fauci, A. S., D. C. Dale, and J. E. Balow. Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann. Intern. Med. 84: 304–315, 1976.
 111. Fauci, A. S., K. R. Pratt, and G. Whalen. Activation of human B lymphocytes. IV. Regulatory effects of corticosteroids on the triggering signal in the plaque‐forming cell response of human peripheral blood B lymphocytes to polyclonal activation. J. Immunol. 119: 598–603, 1977.
 112. Fernandes, G., F. Halberg, E.J. Yunis, and R. A. Good. Orcadian rhythmic plaque‐forming cell response of spleens from mice immunized with SRBC. J Immunol. 117: 962–966, 1976.
 113. Fleshner, M., F. X. Brennan, K. Nguyen, L. R. Watkins, and S. F. Maier. RU‐486 blocks differentially suppressive effect of stress on in vivo anti‐KLH immunoglobulin response. Am. J. Physiol. 271 (Regulatory Integrative Comp. Physiol. 40): R1344–R1352, 1996.
 114. Fleshner, M., T. Deak, R. L. Spencer, M. L. Laudenslager, L. Watkins, and S. Maier. A long term increase in basal levels of corticosterone and a decrease in corticosteroid‐binding globulin after acute stressor exposure. Endocrinology 136: 5336–5342, 1995.
 115. Fleshner, M., K. T. Nguyen, C. S. Cotter, L. R. Watkins, and S. F. Maier. Acute stressor exposre both suppresses acquired immunity and potentiates innate immunity. Am. J. Physiol. 275 (Regulatory Integrative Comp. Physiol. 44): R870–R878, 1998.
 116. Forner, M. A., C. Barriga, A. B. Rodriquez, and E. Ortega. A study of the role of corticosterone as a mediator in exercise‐induced stimulation of murine macrophage phagocytosis. J. Physiol. 488: 789–794, 1995.
 117. Funder, J. W., P. T. Pearce, R. Smith, and A. I. Smith. Miner‐alocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242: 583–585, 1988.
 118. Gagne, E., M. Pons, and D. Philibert. RU38486: a potent antiglucocorticoid in vitro and in vivo. J. Steroid. Biochem. 23: 247–251, 1985.
 119. Gervais, P., A. Reinberg, C. Gervais, M. Smolensky, and O. DeFrance. Twenty‐four hour rhythm in the bronchial hyperreactivity to house dust in asthmatics. J. Allergy Clin. Immunol. 59: 207–213, 1977.
 120. Girard, M. T., S. Hjaltadottir, A. N. Fejes‐Toth, and P. M. Guyre. Glucocorticoids enhance the γ‐interferon augmentation of human monocyte immunoglobulin G Fc receptor expression. J. Immunol. 138: 3235–3241, 1987.
 121. Glaser, R., and J. K. Kiecolt‐Glaser. Stress‐associated immune modulation: relevance to viral infections and chronic fatigue syndrome. Am. J. Med. 105 (3A): 35S–42S, 1998.
 122. Gold, P. W., F. K. Goodwin, and G. P. Chrousos. Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. N. Engl. J. Med. 319: 413–419, 1988.
 123. Gonzalo, J. A., A. Gonzalez‐Garcia, C. Martinez‐A, and G. Kroemer. Glucocorticoid‐mediated control of the activtion and clonal deletion of peripheral T cells in vivo. J. Exp. Med. 177: 1239–1246, 1993.
 124. Goppelt‐Struebe, M., D. Schaefer, and A.J.R. Habenicht. Differential regulation of cyclo‐oxygenase‐2 and 5‐lipoxygenase‐activating protein (FLAP) expression by glucocorticoids in monocytic cells. Brit. J. Pharmacol. 122: 619–624, 1997.
 125. Gottschall, P. E., K. Koves, K. Mizuno, I. Tatsuno, and A. Arimura. Glucocorticoid upregulation of interleukin 1 receptor expression in a glioblastoma cell line. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E362–E368, 1991.
 126. Goulding, N. J., and P. M. Guyre. Glucocorticoids, lipocortins and the immune response. Curr. Opin. Immunol. 5: 108–113, 1993.
 127. Gruol, D. J., and J. Altschmied,. Synergistic induction of apoptosis with glucocorticoids and 3′,5′‐cyclic adenosine monophosphate reveals agonist activity by RU 486. Mol. Endocrinol. 7: 104–113, 1993.
 128. Guillemin, R., T. Vargo, J. Rossier, S. Minick, N. Ling, C. Rivier, W. Vale, and F. Bloom. β‐endorphin and adrenocorticotropin are secreted concomitantly by the pituitary gland. Science 197: 1367–1369, 1977.
 129. Halliday, W. J., and J. S. Garvey. Some factors affecting the secondary immune response in tissue cultures containing hydrocortisone. J. Immunol. 93: 757–762, 1964.
 130. Hammond, G. L. Molecular properties of corticosteroid binding globulin and the sex‐steroid binding proteins. Endocr. Rev. 11: 65–79, 1990.
 131. Hammond, G. L., and P.L.A. Lahteenmaki. A versatile method for the determination of serum Cortisol binding globulin and sex hormone binding globulin binding capacities. Clin. Chim. Acta. 132: 101–110, 1983.
 132. Hammond, G. L., C. L. Smith, N.A.M. Paterson, and W. J. Sibbald. A role for corticosteroid‐binding globulin in delivery of Cortisol to activated neutrophils. J. Clin. Endocrinol. Metab. 71: 34–39, 1990.
 133. Hammond, G. L., C. L. Smith, and D. A. Underhill. Molecular studies of corticosteroid binding globulin structure, biosynthesis and function. J. Steroid. Biochem. Molec. Biol. 40: 755–762, 1991.
 134. Hart, B. L. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12: 123–137, 1988.
 135. Hawrylowicz, C. M., L. Guida, and E. Paleolog. Dexamethasone up‐regulates granulocyte‐macrophage colony‐stimulating factor receptor expression on human monocytes. Immunology 83: 274–280, 1994.
 136. Hedman, L. A., and P. M. Lundin. The effect of steroids on the circulating lymphocyte population. II. Studies of the thoracic duct lymphocyte population of the guinea pig after neonatal thymectomy and prednisolone treatment. Lymphology 10: 192–198, 1977.
 137. Herman, J. P. Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system. Cell. Mol. Neurobiol. 13: 349–372, 1993.
 138. Herman, J. P., and W. E. Cullinan. Neurocircuitry of stress: central control of the hypothalamo‐pituitary‐adrenocortical axis. Trends Neurosci. 20: 78–84, 1997.
 139. Hiemke, C., R. Brunner, E. Hammes, H. Muller, K.‐H. Meyer Zum Buschenfelde, and A. W. Lohse. Orcadian variations in antigen‐specific proliferation of human T lymphocytes and correlation to Cortisol production. Psychoneuroendo 20: 335–342, 1995.
 140. Holder, M. J., K. Knox, and J. Gordon. Factors modifying survival pathways of germinal center B cells. Glucocorticoids and transforming growth factor‐B, but not cyclosporin A or anti‐CD19, block surface immunoglobulin‐mediated rescue from apoptosis. Eur. J. Immunology 22: 2725–2728, 1992.
 141. Holsboer, F., and N. Barden. Antidepressants and hypothalamic‐pituitary‐adrenocortical regulation. Endocr. Rev. 17: 187–205, 1996.
 142. Hrushesky, W.J.M., T. Langevin, Y. J. Kim, and P. A. Wood. Orcadian dynamics of tumor necrosis factor α (cachectin) lethality. J. Exp. Med. 180: 1059–1065, 1994.
 143. Ibarrola, I., K. Ogiza, A. Marino, J. M. Macarulla, and M. Trueba. Steroid hormone specifically binds to rat kidney plasma membrane. J. Bioenerg. Biomem. 23: 919–926, 1991.
 144. Ing, N. H., and B. W. O'Malley. The steroid hormone receptor superfamily: molecular mechanisms of action. In: Molecular Endocrinology: Basic Concepts and Clinical Correlations, edited by B. D. Weintraub. Raven Press: New York, 1995.
 145. Ingle, D. J. Permissibility of hormone action. A review. Acta. Endocrinologica. 17: 172–186, 1954.
 146. Ishida, T., K. Matsuura, M. Setoguchi, Y. Higuchi, and S. Yamamoto. Enhancement of murine serum amyloid A3 mRNA expression by glucocorticoids and its regulation by cytokines. J. Leukoc. Biol. 56: 797–806, 1994.
 147. Irwin, M., M. Daniels, E. Bloom, T. L. Smith, and H. Weiner. Life events, depressive symptoms, and immune function. Am. J. Psychiatry 144: 437–441, 1987.
 148. Jabara, H. H., D. J. Ahern, D. Vercelli, and R. S. Geha. Hydrocortisone and IL‐4 induce IgE isotype switching in human B cells. J. Immunology 147: 1557–1560, 1991.
 149. Jacobson, L., S. F. Akana, C. S. Cascio, J. Shinsako, and M. F. Dallman. Circadian variations in plasma corticosterone permit normal termination of adrenocorticotropin responses to stress. Endocrinology 122: 1343–1348, 1988.
 150. Jacobson, L., and R. M. Sapolsky. The role of the hippocampus in feedback regulation of the hypothalamic‐pituitary‐adrenocortical axis. Endocrinol. Rev. 12: 118–133, 1991.
 151. Jensen, L. E., and A. S. Whitehead. Regulation of serum amyloid A protein expression during the acute‐phase response. Biochem. J. 334: 489–503, 1998.
 152. Joels, M., and E. R. de Kloet. Control of neuronal excitability by corticosteroid hormones. Trends Neurosci. 15: 25–30, 1992.
 153. Jondal, M., S. Okret, and D. McConkey. Killing of immature CD4+CD8+ thymocytes in vivo by anti‐CD3 or 5′‐(N‐ethyl)‐carboxamido‐adenosine is blocked by glucocorticoid receptor antagonist RU‐486. Eur. J. Immunol. 23: 1246–1250, 1993.
 154. Kam, J. C., S. J. Szefler, W. Surs, E. R. Sher, and D.Y.M. Leung. Combination IL‐2 and IL‐4 reduces glucocorticoid receptor‐binding affinity and T cell response to glucocorticoids. J. Immunol. 151: 3460–3466, 1993.
 155. Kant, G. J., R. H. Lenox, B. N. Bunnell, E. H. Mougey, L. L. Pennington, and J. L. Meyerhoff. Comparison of stress response in male and female rats: pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone. Psychoneuroendo. 8: 421–428, 1983.
 156. Kaplan, G., W.J. Britton, G. E. Hancock, W.J. Theuvenet, K. A. Smith, C. K. Job, P. W. Roche, A. Molloy, R. Burkhardt, J. Barker, H. M. Pradhan, and Z. A. Cohn. The systemic influence of recombinant interleukin 2 on the manifestations of lepromatous leprosy. J. Exp. Med. 173: 993–1006, 1991.
 157. Katz, P., A. M. Zaytoun, and J. H. Lee. Characterization of corticosteroid receptors in natural killer cells: comparison with circulating lymphoid and myeloid cells. Cell. Immun. 94: 347–352, 1985.
 158. Kawate, T., T. Abo, S. Hinuma, and K. Kumagai. Studies on the bioperiodicity of the immune response. II. Co‐variations of murine T and B cells and a role of corticosteroid. J. Immunology. 126: 1364–1367, 1981.
 159. Keller, S. E., S. J. Schleifer, and M. K. Demetrikopoulos. Stress‐induced changes in immune function in animals: hypothalamic‐pituitary‐adrenal influences. In: Psychoneuroimmology, 2nd edition, edited by R. Ader, D. L. Reiten, and N. Cohen. Academic Press: New York, 1991.
 160. Keller, S. E., J. M. Weiss, S.J. Schleifer, N. E. Miller, and M. Stein. Suppression of immunity by stress: Effect of a graded series of stressors on lymphocyte stimulation in the rat. Science 213: 1397–1400, 1981.
 161. Keller, S. E., J. M. Weiss, S.J. Schleifer, N. E. Miller, and M. Stein. Stress‐induced suppression of immunity in adrenalectomized rats. Science 221: 1301–1304, 1983.
 162. Keller‐Wood, M. E., and M. F. Corticosteroid inhibition of ACTH secretion. Endocr. Rev. 5: 1–24, 1984.
 163. Kelso, A. Th1 and Th2 subsets: paradigms lost? Immunol. Today 16: 374–379, 1995.
 164. Kim, P. J., M. A. Cole, B. A. Kalman, and R. L. Spencer. Evaluation of RU28318 and RU40555 as selective mineralocorticoid receptor and glucocorticoid receptor antagonists, respectively: receptor measures and functional studies. J. Steroid Biochem. Mol. Biol. 67: 213–222, 1998.
 165. Kirkham, B. W., and G. S. Panayi. Dirunal periodicity of Cortisol secretion, immune reactivity and disease activity in rheumatoid arthritis: implications for steroid treatment. Br. J. Rheumatology 28: 154–157, 1989.
 166. Kizaki, T., S. Oh‐Ishi, T. Ookawara, M. Yamamoto, T. Izawa, and H. Ohno. Glucocorticoid‐mediated generation of suppressor macrophages with high density FcyRII during acute cold stress. Endocrinology 137: 4260–4267, 1996.
 167. Kleinert, H., C. Euchenhofer, I. Ihrig‐biedert, and U. Forstermann. Glucocorticoids inhibit the induction of nitric oxide synthase II by down‐regulating cytokine‐induced activity of transcription factor nuclear factor‐kB. Mol. Pharmacol. 49: 15–21, 1996.
 168. Knapp, M. S., J. R. Cove‐Smith, R. Dugdale, N. Mackenzie, and R. Pownall. Possible effect of time on renal allograft rejection. Br. J. Med. 1: 75–77, 1979.
 169. Krymskaya, L. G., N. Y. Gromykhina, A. A. Tinnikov, and V. A. Kozlov. The interaction between inrerleukin‐1 and glucocorticoids in the in vivo antibody response of mice to three concentrations of antigen. Brain Behav. Immun. 8: 327–340, 1994.
 170. Kulkarni, A. B., R. Reinke, and P. Feigelson. Acute phase mediators and glucocorticoids elevate α1‐acid glycoprotein gene transcription. J. Biol. Chem. 260: 15386–15389, 1985.
 171. Labeur, M.S., E. Arzt, G.J. Wiegers, F. Holsboer, and J.M.H.M. Reul. Long‐term intracerebroventricular corti‐cotropin‐releasing hormone administration induced distinct changes in rat splenocyte activation and cytokine expression. Endocrinology 136: 2678–2688, 1995.
 172. Lamas, M., E. Sanz, L. Martin‐Parras, E. Espel, P. Sperisen, M. Collins, and A. G. Silva. Glucocorticoid hormones upregulate interleukin 2 receptor α gene expression. Cell Immunol. 151: 437–450, 1993.
 173. Lappin, D. F. and K. Whaley. Modulation of complement gene expression by glucocorticoids. Biochem. J. 280: 117–123, 1991.
 174. Laue, L., G. P. Chrousos, D. L. Loriaux, K. Barnes, P. Munson, L. Nieman, and G. Schaison. The antiglucocorticoid and anti‐progestin steroid RU486 suppresses the adrenocorticotropin response to ovine corticotropin releasing hormone in man. J. Clin. Endocrinol. Metab. 66: 290–293, 1988.
 175. Laue, L., S. Kawai, D. D. Brandon, D. Brightwell, K. Barnes, R. A. Knazek, D. L. Loriaux, and G. P. Chrousos. Receptormediated effects of glucocorticoids on inflammation: enhancement of the inflammatory response with a glucocorticoid antagonist. J. Steroid Biochem. Mel. Biol. 29: 591–598, 1988.
 176. Laue, L., M. T. Lotze, G. P. Chrousos, K. Barnes, D. L. Loriaux, and T. A. Fleisher. Effect of chronic treatment with the glucocorticoid antagonist RU486 in man: toxicity, immunological and hormonal aspects. J. Clin. Endocrinol. Metab. 71: 1474–1480, 1990.
 177. Lazar Jr., G., E. Duda, and G. Lazar. Effect of RU38486 on TNF production and toxicity. FEBS 308: 137–140, 1992.
 178. Lee, S. W., A.‐P. Tsou, H. Chan, J. Thomas, K. Petrie, E. M. Eugui, and A. C. Allison. Glucocorticoids selectively inhibit the transcription of the interleukin 1β gene and decrease the stability of interleukin 1β mRNA. Proc. Natl. Acad. Sci. U.S.A. 5: 1204–1208, 1988.
 179. Leech, M., P. Hutchinson, S. R. Holdsworth, and E. F. Morand. Endogenous glucocorticoids modulate neutrophil migration and synovial P‐selectin but not neutrophil phagocytic or oxidative function in experimental arthritis. Clin. Exp. Immunol. 112: 383–388, 1998.
 180. Leung, D.Y.M., Q. Hamid, A. Vottero, S. J. Szefler, W. Surs, E. Minshall, G. P. Chrousos, and D. J. Klemm. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor B. J. Exp. Med. 186: 1567–1574, 1997.
 181. Lippman, M., and R. Barr. Glucocorticoid receptors in purified subpopulations of human peripheral blood lymphocytes. J. Immunology 118: 1977–1981, 1977.
 182. Livett, B. G. Adrenal medullary chromaffin cells in vitro. Physiol. Rev. 64: 1103–1161, 1984.
 183. Lowy, M. T. Quantification of type I and II adrenal steroid receptors in neuronal, lymphoid and pituitary tissues. Brain Res. 503: 191–197, 1989.
 184. Lysle, D. T., J. E. Cunnick, and B. S. Rabin. Stressor‐induced alteration of lymphocyte proliferation in mice: evidence for enhancement of mitogenic responsiveness. Brain Behav. Immun. 4: 269–277, 1990.
 185. MacPhee, I.A.M., F. A. Antoni, and D. W. Mason. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J. Exp. Med. 169: 431–445, 1989.
 186. Maes, M. A review on the acute phase response in major depression. Rev. Neurosci. 4: 407–416, 1993.
 187. Maes, M., S. Scharpe, H. Y. Meltzer, E. Bosmans, E. Suy, J. Calabrese, and P. Cosyns. Relationships between interleukin‐6 activity, acute phase proteins, and function of the hypothalamic‐pituitary‐adrenal axis in severe depression. Psychiatry Res. 49: 11–27, 1993.
 188. Maes, M., A. Wauters, H. Neels, S. Scharpe, A. Van Gastel, P. D'Hondt, D. Peeters, P. Cosyns, and R. Desnyder. Total serum protein and serum protein fractions in depression: relationships to depressive symptoms and glucocorticoid activity. J. Affect. Disord. 34: 61–69, 1995.
 189. Maier, S. F., L. E. Goehler, M. Fleshner, and L. R. Watkins. The role of the vagus nerve in cytokine‐to‐brain communication. Ann. N. Y. Acad. Sci. 840: 289–299, 1998.
 190. Maier, S. F., L. R. Watkins, and M. Fleshner. Psychoneuroimmunology: the interface between behavior, brain and immunity. Am. Psychol. 49: 1004–1017, 1994.
 191. Martins, V. R., M.I.A. Birolli, A.J.S. Duarte, and M. M. Brentani. Glucocorticoid receptors in subpopulations of human lymphocytes defined by monoclonal antibodies. Cellular Immun. 105: 443–446, 1987.
 192. Masferrer, J. L., S. T. Reddy, B. S. Zweifel, K. Seibert, P. Needleman, R. S. Gilbert, and H. R. Herschman. In vivo glucocorticoids regulate cyclooygenase‐2 but not cyclooygenase‐1 in peritoneal macrophages. J. Pharm. Exp. Ther. 270: 1340–1344, 1994.
 193. Mason, D. Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today 12: 57–60, 1991.
 194. McEwen, B. S. Nongenomic and genomic effects of steroids on neural activity. Trends Pharmacol. Sci. 12: 141–147, 1991.
 195. McEwen, B. S., C. A. Biron, K. W. Brunson, K. Bulloch, W. H. Chambers, F. S. Dhabhar, R. H. Goldfarb, R. P. Kitson, A. H. Miller, R. L. Spencer, and J. M. Weiss. Neural‐endocrine‐immune interactions: the role of adrenocorticosteroids as modulators of immune function in health and disease. Brain Res. Rev. 23: 79–133, 1997.
 196. McKay, L. I., and J. A. Cidlowski. Molecular control of immune/inflammatory responses: interactions between nuclear factor‐kB and steroid receptor‐signalling pathways. Endocr. Rev. 20: 435–459, 1999.
 197. McNulty, J. A., M. Relfson, L. M. Fox, L. M. Fox, L. Kus, R. J. Handa, and G. B. Schneider. Circadian analysis of mononuclear cells in the rat following pinealectomy and superior cervical ganglionectomy. Brain Behav. Immun. 4: 292–307, 1990.
 198. Melby, J. C. Clinical pharmacology of systemic corticosteroids. Ann. Rev. Pharmacol. Toxicol. 17: 511–527, 1977.
 199. Mendel, C. M. The free hormone hypothesis: a physiologically based mathematical model. Endocr. Rev. 10: 232–274, 1989.
 200. Mendelson, S. C., and B. S. McEwen. Autoradiographic analyses of the effects of adrenalectomy and corticosterone on 5‐HT1A and 5‐HT1B receptors in the dorsal hippocampus and cortex of the rat. Neuroendocrinal. 55: 444–450, 1992.
 201. Meyerhoff, J. L., M. A. Oleshansky, and E. H. Mougey. Psychologic stress increases plasma levels of prolactin, Cortisol, and POMC‐derived peptides in man. Psychosomatic Medicine 50: 295–303, 1988.
 202. Miller, A. H., R. L. Spencer, J. Hassett, C. Kim, R. Rhee, D. Ciurea, F. Dhabhar, B. S. McEwen, and M. Stein. Effects of selective type I and II adrenal steroid agonists on immune cell distribution. Endocrinology 135: 1934–1944, 1994.
 203. Miller, A. H., R. L. Spencer, A. Husain, R. Rhee, B. S. McEwen, and M. Stein. Differential expression of type I adrenal steroid receptors in immune tissues is associated with tissue‐specific regulation of type II receptors by aldosterone. Endocrinology 133: 2133–2140, 1993.
 204. Miller, A. H., R. L. Spencer, B. D. Pearce, T. L. Pisell, Y. Azrieli, P. Tanapat, M. Moday, R. Rhee, and B. S. McEwen. Glucocorticoid receptors are differentially expressed in the cells and tissues of the immune system. Cell. Immunol. 186: 45–54, 1998.
 205. Miller, A. H., R. L. Spencer, M. Stein, and B. S. McEwen. Adrenal steroid receptor binding in spleen and thymus after stress or dexamethasone. Am. J. Physiol. 259 (Endocrinol. Metab. 22): E405–E412, 1990.
 206. Miner, J. N., and Yamamoto, K. R. Regulatory crosstalk at composite response elements. Trends Biol. Sci. 16: 423–426, 1991.
 207. Monjan, A. A. and M. I. Collector. Stress‐induced modulation of the immune response. Science 196: 307–308, 1977.
 208. Moorhead, J. W., and H. N. Claman. Thymus‐derived lymphocytes and hydrocortisone: identification of subsets of theta‐bearing cells and redistribution to bone marrow. Cell. Immunol. 5: 74–86, 1972.
 209. Morale, M. C., N. Batticane, F. Gallo, N. Barden, and B. Marchetti. Disruption of hypothalamic‐pituitary‐adrenocortical system in transgenic mice expressing type II glucocorticoid receptor antisense ribonucleic acid permanently impairs T cell function: effects on T cell trafficking and T cell responsiveness during postnatal development. Endocrinology 136: 3949–3960, 1995.
 210. Morrow‐Tesch, J. L., J. J. McGlone, and R. L. Norman. Consequences of restraint stress on natural killer cell activity, behavior, and hormone levels in Rhesus Macaques (Macaca mulatta). Psychoneuroendocrinol. 18: 383–395, 1993.
 211. Mosmann, T. R., H. Cherwinski, M. W. Bond, M. A. Giedlin, and R. L. Coffman. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136: 2348–2357, 1986.
 212. Mosmann, T. R., and S. Sad. The expanding universe of T‐cell subsets: Th1, Th2 and more. Immunol. Today 17: 138–146, 1996.
 213. Moyniham, J. A., J. D. Karp, N. Cohen, and R. Cocke. Alterations in interleukin‐4 and antibody production following pheromone exposure: role of glucocorticoids. J. Neuroimmunol. 54: 51–58, 1994.
 214. Muir, J. L., and H. P. Pfister. Time course of the corticosterone and prolactin response following predictable and unpredictable novelty stress in rattus norvegicus. Physiol. Behav. 40: 103–107, 1987.
 215. Mukaida, N., M. Morita, Y. Ishikawa, N. Rice, S. Okamoto, T. Kasahara, and K. Matsushima. Novel mechanism of glucocorticoid‐mediated gene repression. J. Biol. Chem. 269: 13289–13295, 1994.
 216. Munck, A., P.M. Guyre, and N.J. Holbrook. Physiological functions of glucocorticoids in stress and their relationship to pharmacological actions. Endocr. Rev. 5: 25–44, 1984.
 217. Munck, A., and A. Naray‐Fejes‐Toth. The ups and downs of glucocorticoid physiology. Permissive and suppressive effects revisited. Mol. Cell. Endocrinol. 90: C1–C4, 1992.
 218. Murakami, T. Positive cooperativity of [3H]dexamethasone binding to chick corticosteroid‐binding globulin. Comp. Biochem. Physiol. 100A: 361–364, 1991.
 219. Murakami, T., D. Brandon, D. Rodbard, D. L. Loriaux, and M. B. Lipsett. Glucocorticoid receptor in polymorphonuclear leukocytes: a simple method for leukocyte glucocorticoid receptor characterization. J. Steroid. Biochem. 10: 475–481, 1979.
 220. Murphy, D., B. Costall, and J. W. Smythe. Regulation of hippocampal theta activity by corticosterone: opposing functions of mineralocorticoid and glucocorticoid receptors. Brain. Res. Bull. 45: 631–635, 1998.
 221. Nakajima, H., T. Fukuda, N. Ando, and S. Makino. Inhibitory effects of oral glucocorticoid therapy on T lymphocyte infiltration in the bronchial mucosa of asthamatic subjects. Jpn. J. Allergology 42: 505–513, 1993.
 222. Nakano, K., S. Suzuki, and C. Oh. Significance of increased secretion of glucocorticoids in mice and rats injected with bacterial endotoxin. Brain. Behav. Immun. 1: 159–172, 1987.
 223. Nakano, K., S. Suzuki, C. Oh, and K. Yamashita. Possible role of glucocorticoids in a complement‐activated state induced by cobra venom factor in rats. Acta Endocrinol 112: 122–129, 1986.
 224. Naliboff, B. D., D. Benton, G. F. Solomon, J. E. Morley, J. L. Fahey, E. T. Bloom, T. Makinodan, and S. L. Gilmore. Immunological changes in young and old adults during brief laboratory stress. Psychosom. Med. 53: 121–132, 1991.
 225. Natelson, B. H., J. E. Ottenweller, J. A. Cook, D. Pitman, R. McCarty, and W. N. Tapp. Effect of stressor intensity on habituation of the adrenocortical stress response. Physiol. Behav. 43: 41–46, 1988.
 226. Neifeld, J. P., M. E. Lippman, and D. C. Tormey. Steroid hormone receptors in normal human lymphocytes: induction of glucocorticoid receptor activity by phytohemagglutinin stimulation. J. Biol. Chem. 252: 2972–2977, 1977.
 227. Norbiato, G., M. Bevilacqua, T. Vago, and M. Clerici. Glucocorticoids and Th‐1, Th‐2 type cytokines in rheumatoid arthritis, osteoarthritis, asthma, atopic dermatitis and AIDS. Clin. Exp. Rheumatol. 15: 315–323, 1997.
 228. Norris, D. A., L. Capin, and W. Weston. The effect of epicutaneous glucocorticosteroids on human monocyte and neutrophil migration in vivo. J. Invest. Dermatol. 78: 78–83, 1982.
 229. Oakley, R. H., and J. A. Cidlowski. Homologous down regulation of the glucocorticoid receptor: the molecular machinery. Crit. Rev. Eukaryotic Gene Exp. 3: 63–88, 1993.
 230. Okayama, H., T. Fushimi, S. Shimura, H. Sasaki, and K. Shirato. Glucocorticoids suppressed production and gene expression of interleukin‐5 by peripheral blood mononuclear cells in atopic patients and normal subjects. J. Allergy Clin. Immunol. 93: 1006–1012, 1994.
 231. Olsen, N. J., W. E. Nicholson, C. R. DeBold, and D. N. Orth. Lymphocyte‐derived adrenocorticotropin is insufficient to stimulate adrenal steroidogenesis in hypophysectomized rats. Endocrinology 130: 2113–2119, 1992.
 232. O'Neill, L.A.J., and C. Kaltschmidt. NF‐κB: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci. 20: 252–258, 1997.
 233. Orchinik, M., T. F. Murray, and F. L. Moore. A corticosteroid receptor in neuronal membranes. Science 251: 1848–1851, 1991.
 234. Orson, F. M., J. Grayson, S. Pike, V. de Seau, and R. M. Blaese. T cell‐replacing factor for glucocorticosteroid‐induded immunoglobulin production. A unique steroid‐dependent cytokine. J. Exp. Med. 158: 1473–1482, 1983.
 235. Orti, E., J. E. Bodwell, and A. Munck. Phosphorylation of steroid hormone receptors. Endocr. Rev. 13: 105–128, 1992.
 236. Osmond, D. G. The ontogeny and organization of the lymphoid system. J. Investigative Dermatology 85: 2s–9s, 1985.
 237. Ottenweller, J. E., R. J. Servatius, W. N. Tapp, S. D. Drastal, M. T. Bergen, and B. H. Natelson. A chronic stress state in rats: effects of repeated stress on basal corticosterone and behavior. Physiol. Behav. 51: 689–698, 1992.
 238. Ozaki, T, S. Yasuoka, T. Nakayama, and E. Tsubura. Glucocorticoid receptors in human alveolar macrophages and peripheral blood cells. Clin. Exp. Immunol. 47: 505–511, 1982.
 239. Padawer, J., and A. S. Gordon. A mechanism for the eosinopenia induced by cortisone and epinephrine. Endocrinology 51: 52–88, 1952.
 240. Pardridge, W. M. Transport of protein‐bound hormones into tissues in vivo. Endocr. Rev. 2: 103–123, 1981.
 241. Pariante, C. M., B. D. Pearce, T. L. Pisell, C. I. Sanchez, C. Po, C. Su, and A. H. Miller. The proinflammatory cytokine, interleukin‐1, reduces glucocorticoid receptor translocation and function. Endocrinology, (in press).
 242. Parker, C. W., M. G. Huber, and M. L. Baumann. Alterations in cyclic AMP metabolism in human bronchial asthma. III. leukocyte and lymphocyte responses to steroids. J. Clin. Invest. 52: 1342–1348, 1973.
 243. Parrillo, J. E., and A. S. Fauci. Mechanisms of glucocorticoid action on immune processes. Annu. Rev. Pharmacol. Toxicol. 19: 179–201, 1979.
 244. Pavlides, C., Y. Watanabe, A. M. Magarinos, and B. S. McEwen. Opposing roles of type I and type II adrenal steroid receptors in hippocampal long‐term potentiation. Neuroscience 68: 387–394, 1995.
 245. Pazirandeh, A., Y. Xue, I. Rafter, J. Sjovall, M. Jondal, and S. Okret. Paracrine glucocorticoid activity produced by mouse thymic epithelial cells. FASEB J. 13: 893–901, 1999.
 246. Pickford, G. E., A. K. Srivastava, A. M. Slicher, and P.K.T. Pang. The stress response in the abundance of circulating leukocytes in the Killifish, Fundulus heteroclitus. I The cold‐shock sequence and the effects of hypophysectomy. J. Exp. Zool. 177: 89–96, 1971.
 247. Plaut, M. Lymphocyte hormone receptors. Annu. Rev. Immunol. 5: 621–669, 1987.
 248. Pos, O., W. Van Dijk, N. Ladiges, C. Linthorst, M. Sala, D. Van Tiel, and W. Boers. Glycosylation of four acute‐phase glycoproteins secreted by rat liver cells in vivo and in vitro. Effects of inflammation and dexamethasone. Eur. J. Cell. Biol. 46: 121–128, 1988.
 249. Pugeat, M. M., J. F. Dunn, and B. C. Nisula. Transport of steroid hormones: interactions of 70 drugs with testosterone‐binding globulin and corticosteroid‐binding globulin in human plasma. J. Clin. Endocrinol. Metab. 53: 69–75, 1981.
 250. Rabin, B. S., J. E. Cunnick, and D. T. Lysle. Stress‐induced alteration of immune function. Prog. Neuroendocrinimmunology 3: 116–124, 1990.
 251. Radomski, M. W., R.M.J. Palmer, and S. Moncada. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc. Natl. Acad. Sci. U.S.A. 87: 10043–10047, 1990.
 252. Ramirez, F., and A. Silva. Glucocorticoids enhance concanavalin A‐induced mitogenic response through the inhibition of nitric oxide production. Immunology 90: 66–73, 1997.
 253. Ranelletti, F. O., N. Maggiano, F. B. Aiello, A. Carbone, L. M. Larocca, P. Musiani, and M. Piantelli. Glucocorticoid receptors and corticosensitivity of human thymocytes at discrete stages of intrathymic differentiation. J. Immunol. 138: 440–445, 1987.
 254. Ray, A., K. S. LaForge, and P. B. Sehgal. On the mechanism for efficient repression of the interleukin‐6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. Mol. Cell. Bio. 10: 5736–5746, 1990.
 255. Raymoure, W. J., and R. W. Kuhn. Homologous radioimmunoassay for rat corticosteroid‐binding globulin. Endocrinology 112: 1091–1097, 1983.
 256. Reed, J., A. Abidi, J. Alpers, R. Hoover, R. Robb and P. Nowell. Effect of cyclosporin A and dexamethasone on interleukin 2 receptor gene expression. J. Immunol. 137: 150–154, 1986.
 257. Reul, J.M.H.M., and E. R. de Kloet. Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117: 2505–2511, 1985.
 258. Reul, J.M.H.M., P. T. Pearce, J. W. Funder, and Z. S. Krozowski. Type I and type II corticosteroid receptor gene expression in the rat: effect of adrenalectomy and dexamethasone administration. Mol. Endocrinol. 3: 1674–1680, 1989.
 259. Rhinehart, J. J., A. L. Sagone, S. P. Balcerzak, G. A. Ackerman, and A. F. LoBuglio. Effects of corticosteroid therapy on human monocyte function. New Engl. J. Med. 292: 236–241, 1975.
 260. Riley, V. Psychoneuroendocrine influences on immunocompetence and neoplasia. Science 212: 1100–1109, 1981.
 261. Rinner, I., K. Schauenstein, H. Mangge, S. Porta, and R. Kvetnansky. Opposite effects of mild and severe stress on in vitro activation of rat peripheral blood lymphocytes. Brain Behav. Immun. 6: 130–140, 1992.
 262. Robinson, D., Q. Hamid, S. Ying, A. Bentley, B. Assoufi, S. Durham, and A. B. Kay. Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin‐4, interleukin‐5, and interferon‐γ cytokine gene expression. Am. Rev. Respir. Dis. 148: 401–406, 1993.
 263. Roess, D. A., C. J. Bellone, M. F. Ruh, E. M. Nadel, and T. S. Ruh. The effect of glucocorticoids on mitogen‐stimulated B‐lymphocytes: thymidine incorporation and antibody secretion. Endocrinology 110: 169–175, 1982.
 264. Rosner, W. The functions of corticosteroid‐binding globulin and sex hormone‐binding globulin: recent advances. Endocr. Rev. 11: 80–91, 1990.
 265. Roux, S., B. Terouanne, H. Defacque, I. Vachier, J. Loubatiere, and J. C. Nicolas. Nonradioactive quantification of glucocorticoid receptor expression during differentiation of human monocytic cells (U937). Anal. Biochem. 227: 235–241, 1995.
 266. Rupprecht, R., J.M.H.M. Reul, B. van Steensel, D. Spengler, M. Soder, B. Berning, F. Holsboer, and K. Damm. Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands. Eur. J. Pharmacol. 247: 145–154, 1993.
 267. Rusu, V. M., and M. D. Cooper. In vivo effects of cortisone on the B cell line in chickens. J. Immunol. 115: 1370–1374, 1975.
 268. Ruzek, M. C., A. H. Miller, S. M. Opal, B. D. Pearce, and C. A. Biron. Characterization of early cytokine responses and an interleukin (IL)‐6‐dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection. J. Exp. Med. 185: 1185–1192, 1997.
 269. Ruzek, M. C., B. D. Pearce, A. H. Miller, and C. A. Biron. Endogenous glucocorticoids protect against cytokine‐mediated lethality during viral infection. J. Immunology 162: 3527–3533, 1999.
 270. Sadeghi, R., C. M. Hawrylowicz, Y. Chernajovsky, and M. Feldmann. Synergism of glucocorticoids with granulocyte macrophage colony stimulating factor (GM‐CSF) but not interferon gamma (IFN‐γ) or interleukin‐4 (IL‐4) on induction of HLA class II expression on human monocytes. Cytokine 4: 287–297, 1992.
 271. Saldanha, C., G. Tougas, and E. Grace. Evidence for anti‐inflammatory effect of normal circulating plasma Cortisol. Clin. Exp. Rheumatol. 4: 365–366, 1986.
 272. Salkowski, C. A., and S. N. Vogel. IFN‐γ mediates increased glucocorticoid receptor expression in murine macrophages. J. Immunol. 148: 2770–2777, 1992.
 273. Sanchez, E. R. Heat shock induces translocation to the nucleus of the unliganded glucocorticoid receptor. J. Biol. Chem. 267: 17–20, 1992.
 274. Sanchez, E. R., J.‐L. Hu, S. Zhong, P. Shen, M. J. Greene, and P. R. Housley. Potentiation of glucocorticoid receptor‐mediated gene expression by heat and chemical shock. Mol. Endocrinol. 8: 408–421, 1994.
 275. Sapolsky, R. M. Glucocorticoids and hippocampal damage. Trends Neurosci. 10: 346–349, 1987.
 276. Sapolsky, R. M. Neuroendocrinology of the stress‐response. In: Behavioral Endocrinology, edited by J. B. Becker, S. M. Breed‐love, and D. Crews. Cambridge, MA: The MIT Press, pp 287–324, 1992.
 277. Sapolsky, R. M., and T. M. Donnelly. Vulnerability to stress‐induced tumor growth increases with age in rats: role of glucocorticoids. Endocrinology 117: 662–666, 1985.
 278. Sapolsky, R. M., L. C. Krey, and B. S. McEwen. Stress down‐regulates corticosterone receptors in a site‐specific manner in the brain. Endocrinology 114: 287–292, 1984.
 279. Sapolsky, R. M., C. Rivier, G. Yamamoto, P. Plotsky, and W. Vale. Interleukin‐1 stimulates the secretion of hypothalamic corticotropin‐releasing factor. Science 238: 522–524, 1987.
 280. Sauer, J., G. K. Stalla, O‐A. Muller, and A. Eduardo. Inhibition of interleukin‐2‐mediated lymphocyte activation in patients with Cushing's syndrome: a comparison with hypocortisolemic patients. Neuroendocrinology 59: 144–151, 1994.
 281. Savoldi, G., A. Fenaroli, F. Ferrari, G. Rigaud, A. Albertini, and D. Di Lorenzo. The glucocorticoid receptor regulates the binding of C/EPBβ on the alpha‐1‐acid glycoprotein promoter in vivo. DNA Cell Biol. 16: 1467–1476, 1997.
 282. Savu, L., C. Lombart, and E. A. Nunez. Corticosterone binding globulin: an acute phase “negative” protein in the rat. FEBS Letters 113: 102–106, 1980.
 283. Savu, L., H. Zouaghi, A. Carli, and E. A. Nunez. Serum depletion of corticosteroid binding activities, an early marker of human septic shock. Biochem. Biophys. Res. Comm. 102: 411–419, 1981.
 284. Schalkwijk, C., M. Vervoordeldonk, J. Pfeilschifter, F. Marki, and H. van den Bosch. Cytokine‐ and forskolin‐induced synthesis of group II phopholipase A2 and prostaglandin E2 in rat mesangial cells is prevented by dexamethasone. Biochem. Biophys. Res. Comm. 180: 46–52, 1991.
 285. Schapiro, S., C. J. Pericin, and F. J. Kotichas. Half‐life of plasma corticosterone during development. Endocrinology 89: 284–286, 1971.
 286. Scheinman, R. I., P. C. Cogswell, A. K. Lofquist, and A. S. Baldwin Jr. Role of transcriptional activation of IkBo in mediation of immunosuppression of glucocorticoids. Science 270: 283–286, 1995.
 287. Schimmer, B. P., and K. L. Parker. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In The Pharmacological Basis of Therapeutics, 9th ed., edited by J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon and A. G. Gilman. McGraw‐Hill: New York, 1996.
 288. Schleimer, R. P. The mechanisms of antiinflammatory steroid action in allergic diseases. Annu. Rev. Pharmacol. Toxicol. 25: 381–412, 1985.
 289. Schobitz, B., J.H.M. Reul, and F. Holsboer. The role of the hypothalamic‐pituitary‐adrenocortical system during inflammatory conditions. Crit. Rev. Neurobiol. 8: 263–291, 1994.
 290. Schroeder, J. T, D. W. MacGIashan, S. M. MacDonald, A. Kagey‐Sobotka, and L. M. Lichenstein. Regulation of IgE‐dependent IL‐4 generation by human basophils treated with glucocorticoids. J. Immunol. 158: 5448–5454, 1997.
 291. Schule, R., and R. M. Evans. Cross‐coupling of signal transduction pathways: zinc finger meets leucine zipper. Trends Genet. 7: 377–381, 1991.
 292. Schwartzman, R. A., and J. A. Cidlowski. Apoptosis: the biochemistry and molecular biology of programmed cell death. Endocr. Rev. 14: 133–151, 1993.
 293. Selye, H. The general adaptation syndrome and diseases of adaptation. J. Clin. Endocrinol. Metab. 6: 117–230, 1946.
 294. Shapiro, S. D., E. J. Campbell, D. K. Kobayashi, and H. G. Welgus. Dexamethasone selectively modulates basal and lipopolysaccharide‐induced metalloproteinase and tissue inhibitor of metalloproteinase production by human alveolar macrophages. J. Immunol. 146: 2724–2729, 1991.
 295. Sheridan, J. F., N. Feng, R. H. Bonneau, C. M. Allen, B. S. Huneycutt, and R. Glaser. Restraint stress differentially affects anti‐viral cellular and humoral immune responses in mice. J. Neuroimmunol. 31: 245–255, 1991.
 296. Shortman, K., and H. Jackson. The differentiation of T lymphocytes. I. Proliferation kinetics and the interrelationships of subpopulations of mouse thymus cells. Cell. Immunol. 12: 230–246, 1974.
 297. Siiteri, P., J. T. Murai, G. L. Hammond, J. A. Nisker, W. J. Raymoure, and R. W. Kuhn. The serum transport of steroid hormones. Recent Prog. Hormone Res. 38: 457–510, 1982.
 298. Silveira, V. L., and E. V. Limaos. Effect of bacterial endotoxin on plasma concentration of haptoglobin and fibrinogen in rats treated with metyropone. Agents Actions 31: 143–147, 1990.
 299. Singer, C. J., M. S. Khan, and W. Rosner. Characteristics of the binding of corticosteroid‐binding globulin to rat cell membranes. Endocrinology 122: 89–96, 1988.
 300. Sklar, L. S., and H. Anisman. Stress and coping factors influence tumor growth. Science 205: 513–515, 1979.
 301. Sloviter, R. S., G. Valiquette, G. M. Abrams, E. C. Ronk, A. I. Sollas, L. A. Paul, and S. L. Nuebort. Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy. Science 243: 535–538, 1989.
 302. Smith, C. L., and G. L. Hammond. Hormonal regulation of corticosteroid‐binding globulin biosynthesis in the male rat. Endocrinology 130: 2245–2251, 1992.
 303. Smith, K. A., G. R. Crabtree, S. J. Kennedy, and A. U. Munck. Glucocorticoid receptors and glucocorticoid sensitivity of mitogen stimulated and unstimulated human lymphocytes. Nature 267: 523–526, 1977.
 304. Snijdewint, F. G., M. L. Kapsenberg, P.J.J. Wauben‐Penris, and J. D. Bos. Corticosteroids class‐dependently inhibit in vitro Th1‐ and Th2‐type cytokine production. Immunopharmacol. 29: 93–101, 1995.
 305. Snyers, L., L. De Wit, and J. Content. Glucocorticoid upregulation of high‐affinity interleukin 6 receptors on human epithelial cells. Proc. Natl. Acad. Sci. U.S.A. 87: 2838–2842, 1990.
 306. Solito, E., G. Raugei, M. Melli, and L. Parente. Dexamethasone induces the expression of the mRNA of lipocortin 1 and 2 and the release of lipocortin 1 and 5 in differentiated, but not undifferentiated U‐937 cells. FEBS 291: 238–244, 1991.
 307. Spahn, J. D., S. J. Szefler, W. Surs, D. E. Doherty, S. R. Nimmagadda, and D.Y.M. Leung. A novel action of IL‐13. Induction of diminished monocyte glucocorticoid receptor‐binding affinity. J. Immunol. 157: 2654–2659, 1996.
 308. Spain, D. M., and W. Thalhimer. Temporary accumulation of eosinophilic leucocytes in spleen on mice following administration of cortisone. Proc. Soc. Exp. Biol. Med. 76: 320–322, 1951.
 309. Spencer, R. L., A. H. Miller, H. Moday, B. S. McEwen, R. J. Blanchard, D. C. Blanchard, and R. R. Sakai. Chronic social stress produces reductions in available splenic type II corticosteroid receptor binding and plasma corticosteroid binding globulin levels. Psychoneuroendocrinology 21: 95–109, 1996.
 310. Spencer, R. L., A. H. Miller, H. Moday, M. Stein, and B. S. McEwen. Diurnal differences in basal, and acute stress levels of type I and type II adrenal steroid receptor activation in neural and immune tissues. Endocrinology 133: 1941–1950, 1993.
 311. Spencer, R. L., A. H. Miller, M. Stein, and B. S. McEwen. Corticosterone regulation of type I and type II adrenal steroid receptors in brain, pituitary, and immune tissue. Brain Res. 549: 236–246, 1991.
 312. Spencer, R. L., E. A. Young, P. H. Choo, and B. S. McEwen. Adrenal steroid type I and type II receptor binding: estimates of in vivo receptor number, occupancy, and activation with varying levels of steroid. Brain Res. 514: 37–48, 1990.
 313. Spry, C.J.F. Inhibition of lymphocyte recirculation by stress and corticotropin. Cell. Immunol. 4: 86–92, 1972.
 314. Stam, W. B., A.J.M. Van Oosterhout, and F. P. Nijkamp. Pharmacologic modulation of Th1‐and Th2‐associated lymphokine production. Life Sci. 53: 1921–1934, 1993.
 315. Stein, M., E. Ronzoni, and E. F. Gildea. Physiological responses to heat stress and ACTH of normal and schizophrenic subjects. Am. J. Psychiatry 6: 450–455, 1951.
 316. Steiner, A. E. and J. L. Wittliff. Concentration of glucocorticoid receptor sites in normal human lymphocytes. Clin. Chem. 32: 80–83, 1986.
 317. Sternberg, E. M., J. M. Hill, G. P. Chrousos, T. Kamilaris, S. J. Listwack, P. W. Gold, and R. L. Wilder. Inflammatory mediator‐induced hypothalamic‐pituitary‐adrenal axis activation is defective in streptococcal cell wall arthritis‐susceptible Lewis rats. Proc. Natl. Acad. Sci. 86: 2374–2378, 1989.
 318. Stith, R. D., R. E. McCallum, and M. R. Hill. Effect of interleukin‐6/interferon‐β2 on glucocorticoid action in rat hepatoma cells. J. Steroid. Biochem. 34: 479–481, 1989.
 319. Stocklin, E., M. Wissler, F. Gouilleux, and B. Groner. Functional interactions between Stat5 and the glucocorticoid receptor. Nature 383: 726–728, 1996.
 320. Strickland, R. W., L. M. Wahl, and D. S. Finbloom. Corticosteroids enhance the binding of recombinant interferon‐γ to cultured human monocytes. J. Immunol. 137: 1577–1580, 1986.
 321. Sundar, S. K., M. A. Cierpial, C. Kilts, J. C. Ritchie, and J. M. Weiss. Brain IL‐1‐induced immunosuppression occurs through activation of both pituitary‐adrenal axis and sympathetic nervous system by corticotropin‐releasing factor. J. Neurosci. 10: 3701–3706, 1990.
 322. Sutanto, W., and E. R. de Kloet. Species‐specificity of corticosteroid receptors in hamster and rat brains. Endocrinology 121: 1405–1411, 1987.
 323. Suyemitsu, T., and H. Terayama. Specific binding sites for natural glucocorticoids in plasma membranes of rat liver. Endocrinology 96: 1499–1508, 1975.
 324. Swain, M. G., and M. Marie. Prevention of immune‐mediated arthritis in cholestatic rats: involvement of endogenous glucocorticoids. Gastroenterology 107: 1469–1474, 1994.
 325. Swingle, W. W., and J. W. Remington. The role of the adrenal cortex in physiological processes. Physiol. Rev. 24: 89–127, 1944.
 326. Szabo, C., C. Thiemermann, C‐C. Wu, M. Perretti, and J. R. Vane. Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo. Proc. Natl. Acad. Sci. U.S.A. 91: 271–275, 1994.
 327. Tacker, M. M., C. S. Leach, C. A. Owen, and J. A. Rummel. Levels of Cortisol, corticosterone, cortisone and 11‐deoxycortisol in the plasma of stressed and unstressed subjects. J. Endocr. 76: 165–166, 1978.
 328. Tavadia, H. B., K. A. Fleming, P. D. Hume, and H. W. Simpson. Orcadian rhythmicity of human plasma Cortisol and PHA‐induced lymphocyte transformation. Clin. Exp. Immunol. 22: 190–193, 1975.
 329. Thompson, J., and R. Van Furth. The effect of glucocorticosteroids on the kinetics of mononuclear phagocytes. J. Exp. Med. 131: 429–442, 1970.
 330. Thompson, J., and R. Van Furth. The effect of glucocorticoids on the kinetics of promonocytes and monocytes of the bone marrow. J. Exp. Med. 137: 10–21, 1973.
 331. Thompson, W. L., F. B. Abeles, F. A. Beall, R. E. Dinterman, and R. W. Wannemacher Jr. Influence of the adrenal glucocorticoids on the stimulation of synthesis of hepatic ribonucleic acid and plasma acute‐phase globulins by leucocytic endogenous mediator. Biochem. J. 156: 25–32, 1976.
 332. Thomson, S. P., L. J. McMahon, and C. A. Nugent. Endogenous Cortisol: a regulator of the number of lymphocytes in peripheral blood. Clin. Immunol. Immunopath. 17: 506–514, 1980.
 333. Townley, R. G., and F. Suliaman. The mechanism of corticosteroids in treating asthma. Ann. Allergy 58: 1–6, 1987.
 334. Truss, M., and Beato, M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr. Rev. 14: 459–479, 1993.
 335. Tuchinda, M., R. W. Newcomb, and B. L. DeVald. Effect of prednisone treatment on the human immune response to keyhole limpet hemocyanin. Int. Arch. Allergy 42: 533–544, 1972.
 336. Turnbull, A. V., and C. Rivier. Regulation of the HPA axis by cytokines. Brain Behav. Immun. 9: 253–275, 1995.
 337. Vacchio, M. S., and J. D. Ashwell. Thymus‐derived glucocorticoids regulate antigen‐specific positive selection. J. Exp. Med. 185: 2033–2038, 1997.
 338. Vacchio, M. S., V. Papdopoulos, and J. D. Ashwell. Steroid production in the thymus: implications for thymocyte selection. J. Exp. Med. 179: 1835–1846, 1994.
 339. van den Berg, T. K., I. van Die, C. R. de Lavalette, E. A. Dopp, L. D. Smit, P. H. van der Meide, F.J.H. Tilders, P. R. Crocker, and C. D. Dijkstra. Regulation of sialoadhesin expression on rat macrophages. Induction by glucocorticoids and enhancement by IFN‐β, IFN‐γ, IL‐4, and lipopolysaccharide. J. Immunol. 157: 3130–3138, 1996.
 340. van Gool, J., W. Boers, M. Sala, and N.C.J.J. Ladiges. Glucocorticoids and catecholamines as mediators of acute‐phase proteins, especially rat α‐macrofoetoprotein. Biochem. J. 220: 125–132, 1984.
 341. Vishwanath, B. S., F. J. Frey, M. Bradbury, M. F. Dallman, and B. M. Frey. Adrenalectomy decreases lipocortin‐I messenger ribonucleic acid and tissue protein content in rats. Endocrinology 130: 585–591, 1992.
 342. Visintainer, M. A., J. R. Volpicelli, and M.E.P. Seligman. Tumor rejection in rats after inescapable or escapable shock. Science 216: 437–439, 1982.
 343. Visser, J., A. van Boxel‐Dezaire, D. Methorst, T. Brunt, E. R. de Kloet, and L. Nagelkerken. Differential regulation of interleukin‐10 (IL‐10) and IL‐12 by glucocorticoids in vitro. Blood 91: 4255–4264, 1998.
 344. Warren, M. K., and S. N. Vogel. Opposing effects of glucocorticoids on interferon‐γ‐induced murine macrophage Fc receptor and Ia antigen expression. J. Immunol. 134: 2462–2469, 1985.
 345. Watkins, L. R., S. F. Maier, and L. E. Goehler. Cytokine‐to‐brain communication: a review and analysis of alternative mechanisms. Life Sci. 57: 1011–1026, 1995.
 346. Watson, C. S., and B. Gametchu. Membrane‐initiated steroid actions and the proteins that mediate them. Proc. Soc. Exp. Biol. Med. 220: 9–19, 1999.
 347. Wehling, M., M. Christ, and K. Theisen. Membrane receptors for aldosterone: a novel pathway for mineralocorticoid action. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E974–E979, 1992.
 348. Whelan, C. J., S. C. Hughes, and G.P.A. Wren. Inhibition of some aspects of acute inflammation of guinea‐pig lung by intraperitoneal dexamethasone and mifepristone: demonstration of agonist activity of mifepristone in the guinea‐pig. Inflamm. Res. 44: 131–138, 1995.
 349. Whitfield, J. F., J. P. MacManus, and R. H. Rixon. Cyclic AMP‐mediated stimulation of thymocyte proliferation by low concentrations of Cortisol. Proc. Soc. Exp. Biol. 134: 1170–1174, 1970.
 350. Wick, G., S. Schwarz, and G. Kroemer. Immunoendocrine communication via the hypothalamo‐pituitary‐adrenal axis in autoimmune diseases. Endocr. Rev. 14: 539–563, 1993.
 351. Wiegers, G. J., J.M.H.M. Reul, F. Holsboer, and E. R. de Kloet. Enhancement of rat splenic lymphocyte mitogenesis after short term preexposure to corticosteroids in vitro. Endocrinology, 135: 2351–2357, 1994.
 352. Wieland, S. U. Dobbeling, and S. Rusconi. Interference and synergism of glucocorticoid receptor and octamer factors. EMBO J. 10: 2513–2521, 1991.
 353. Wilckens, T, and R. de Rijk. Glucocorticoids and immune function: unknown dimensions and new frontiers. Immunol. Today 18: 418–424, 1997.
 354. Williams, T. J., and H. Yarwood. Effect of glucocorticoids on microvascular permeability. Am. Rev. Respir. Dis. 141: S39–S43, 1990.
 355. Wissink, S., E. C. van Heerde, B. van der Burg, and P. T. van der Saag. A dual mechanism mediates repression of NF‐κB activity by glucocorticoids. Mol. Endo Crinol. 12: 355–363, 1998.
 356. Wood, P. G., M. H. Karol, A. W. Kusnecov, and B. S. Rabin. Enhancement of antigen‐specific humoral and cell‐mediated immunity by electric footshock stress in rats. Brain Behav. Immun. 7: 121–134, 1993.
 357. Woolley, C. S., E. Gould, and B. S. McEwen. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 531: 225–231, 1990.
 358. Woolley, C. S., E. Gould, R. R. Sakai, R. L. Spencer, and B. S. McEwen. Effets of aldosterone or RU28362 treatment on adrenalectomy‐induced cell death in the dentate gyrus of the adult rat. Brain Res. 554: 312–315, 1991.
 359. Wu, C. Y., M. Sarfarti, C. Heusser, S. Fournier, M. Rubio‐Trujillo, R. Peleman, and G. Delespesse. Glucocorticoids increase the synthesis of immunoglobulin E by interleukin 4‐stimulated human lymphocytes. J. Clin. Invest. 87: 870–877, 1991.
 360. Yamamoto, Y. and H. Friedman. Steroids and infection. In: Psychoneuroimmunology, Stress and Infection, edited by H. Friedman, T. W. Klein and A. L. Friedman. CRC Press: Boca Raton, 1996.
 361. Yang, Y., M. Mercep, C. F. Ware, and J. D. Ashwell. Fas and activation‐induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorticoids. J. Exp. Med. 181: 1673–1682, 1995.
 362. Zatz, M. M. Effects of cortisone on lymphocyte homing. Isr. J. Med. Sci. 11: 1368–1372, 1975.
 363. Zhou, D., A. W. Kusnecov, M. R. Shurin, M. DePaoli, and B. S. Rabin. Exposure to physical and psychological stressors elevates plasma interleukin 6: relationship to the activation of hypothalamic‐pituitary‐adrenal axis. Endocrinology 133: 2523–2530, 1993.
 364. Zieg, G., G. Lack, R. J. Harbeck, E. W. Gelfand, and D. Y. Leung. In vivo effects of glucocorticoids on IgE production. J. Allergy Clin. Immunol. 94: 222–230, 1994.
 365. Zubiaga, A. M., E. Munoz, and B. T. Huber. IL‐4 and IL‐2 selectively rescue Th cell subsets from glucocorticoid‐induced apoptosis. J. Immunology 149: 107–112, 1992.
 366. Zuckerman, S. H., J. Shelhaas, and L. D. Butler. Differential regulation of lipopolysaccharide‐induced interleukin 1 and tumor necrosis factor synthesis: effects of endogenous and exogenous glucocortcioids and the role of the pituitary‐adrenal axis. Eur. J. Immunol. 19: 301–305, 1989.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Robert L. Spencer, Brian A. Kalman, Firdaus S. Dhabhar. Role of Endogenous Glucocorticoids in Immune System Function: Regulation and Counterregulation. Compr Physiol 2011, Supplement 23: Handbook of Physiology, The Endocrine System, Coping with the Environment: Neural and Endocrine Mechanisms: 381-423. First published in print 2001. doi: 10.1002/cphy.cp070418