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. 1998 Oct;57(10):573–577. doi: 10.1136/ard.57.10.573

Relations between steroid hormones and cytokines in rheumatoid arthritis and systemic lupus erythematosus

M CUTOLO 1, A SULLI 1, B VILLAGGIO 1, B SERIOLO 1, S ACCARDO 1
PMCID: PMC1752484  PMID: 9893566

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Figure 1  .

Figure 1  

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Genetic, infectious, and dietary factors, as well as gonadal/adreanal steroid hormones, play a predisposing part in autoimmune diseases such as RA and SLE. Therefore, the involvement of the hypothalamus-pituitary-adrenal (HPA = adrenal steroids) and -gonadal (HPG = gonadal steroids) axis is crucial and interferes with the immune system response.

Figure 2  .

Figure 2  

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Role of Th1/Th2 cytokines in the regulation of cellular and humoral immunity. IL6, probably secreted by activated macrophages (Mϕ) is able to polarise naive CD4+ T cells (Th0) to effector Th2 cells, by inducing the initial production of IL4 in CD4+ T cells. IL12 triggers the differentiation of Th1 cells. Th1 and Th2 cells are mutually inhibitory. RA and SLE are Th1 and Th2 driven diseases, respectively.

Figure 3  .

Figure 3  

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Schematic representation of modulatory effects exerted by gonadal (testosterone) and adrenal (DHEA) steroid hormones on cytokine production, at the level of macrophages, Th1, and Th2 cells.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abbas A. K., Murphy K. M., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996 Oct 31;383(6603):787–793. doi: 10.1038/383787a0. [DOI] [PubMed] [Google Scholar]
  2. Bellido T., Jilka R. L., Boyce B. F., Girasole G., Broxmeyer H., Dalrymple S. A., Murray R., Manolagas S. C. Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. J Clin Invest. 1995 Jun;95(6):2886–2895. doi: 10.1172/JCI117995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brennan P., Bankhead C., Silman A., Symmons D. Oral contraceptives and rheumatoid arthritis: results from a primary care-based incident case-control study. Semin Arthritis Rheum. 1997 Jun;26(6):817–823. doi: 10.1016/s0049-0172(97)80025-x. [DOI] [PubMed] [Google Scholar]
  4. Bruce I. N., Laskin C. A. Sex hormones in systemic lupus erythematosus: a controversy for modern times. J Rheumatol. 1997 Aug;24(8):1461–1463. [PubMed] [Google Scholar]
  5. Casoli P., Tumiati B., La Sala G. Fatal exacerbation of systemic lupus erythematosus after induction of ovulation. J Rheumatol. 1997 Aug;24(8):1639–1640. [PubMed] [Google Scholar]
  6. Chrousos G. P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995 May 18;332(20):1351–1362. doi: 10.1056/NEJM199505183322008. [DOI] [PubMed] [Google Scholar]
  7. Cutolo M., Accardo S. Sex hormones, HLA and rheumatoid arthritis. Clin Exp Rheumatol. 1991 Nov-Dec;9(6):641–646. [PubMed] [Google Scholar]
  8. Cutolo M., Accardo S., Villaggio B., Barone A., Sulli A., Coviello D. A., Carabbio C., Felli L., Miceli D., Farruggio R. Androgen and estrogen receptors are present in primary cultures of human synovial macrophages. J Clin Endocrinol Metab. 1996 Feb;81(2):820–827. doi: 10.1210/jcem.81.2.8636310. [DOI] [PubMed] [Google Scholar]
  9. Cutolo M., Accardo S., Villaggio B., Clerico P., Indiveri F., Carruba G., Fecarotta E., Castagnetta L. Evidence for the presence of androgen receptors in the synovial tissue of rheumatoid arthritis patients and healthy controls. Arthritis Rheum. 1992 Sep;35(9):1007–1015. doi: 10.1002/art.1780350905. [DOI] [PubMed] [Google Scholar]
  10. Cutolo M., Balleari E., Giusti M., Intra E., Accardo S. Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum. 1991 Jan;34(1):1–5. doi: 10.1002/art.1780340102. [DOI] [PubMed] [Google Scholar]
  11. Cutolo M., Castagnetta L. Immunomodulatory mechanisms mediated by sex hormones in rheumatoid arthritis. Ann N Y Acad Sci. 1996 Apr 30;784:237–251. doi: 10.1111/j.1749-6632.1996.tb16239.x. [DOI] [PubMed] [Google Scholar]
  12. Cutolo M. Do sex hormones modulate the synovial macrophages in rheumatoid arthritis? Ann Rheum Dis. 1997 May;56(5):281–284. doi: 10.1136/ard.56.5.281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cutolo M., Masi A. T. Do androgens influence the pathophysiology of rheumatoid arthritis? Facts and hypotheses. J Rheumatol. 1998 Jun;25(6):1041–1047. [PubMed] [Google Scholar]
  14. Cutolo M., Sulli A., Seriolo B., Accardo S., Masi A. T. Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol. 1995 Mar-Apr;13(2):217–226. [PubMed] [Google Scholar]
  15. Cutolo M. The role of the hypothalamus-pituitary-adrenocortical and -gonadal axis in rheumatoid arthritis. Clin Exp Rheumatol. 1998 Jan-Feb;16(1):3–6. [PubMed] [Google Scholar]
  16. Cutolo M. The roles of steroid hormones in arthritis. Br J Rheumatol. 1998 Jun;37(6):597–599. doi: 10.1093/rheumatology/37.6.597. [DOI] [PubMed] [Google Scholar]
  17. Cutolo M., Villaggio B., Barone A., Sulli A., Accardo S., Granata O. M., Castagnetta L. Primary cultures of human synovial macrophages metabolize androgens. Ann N Y Acad Sci. 1996 Apr 30;784:534–541. doi: 10.1111/j.1749-6632.1996.tb16277.x. [DOI] [PubMed] [Google Scholar]
  18. Dalal M., Kim S., Voskuhl R. R. Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J Immunol. 1997 Jul 1;159(1):3–6. [PubMed] [Google Scholar]
  19. Dalal M., Kim S., Voskuhl R. R. Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J Immunol. 1997 Jul 1;159(1):3–6. [PubMed] [Google Scholar]
  20. Daynes R. A., Dudley D. J., Araneo B. A. Regulation of murine lymphokine production in vivo. II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells. Eur J Immunol. 1990 Apr;20(4):793–802. doi: 10.1002/eji.1830200413. [DOI] [PubMed] [Google Scholar]
  21. Elenkov I. J., Hoffman J., Wilder R. L. Does differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period? Mol Med Today. 1997 Sep;3(9):379–383. doi: 10.1016/s1357-4310(97)01089-7. [DOI] [PubMed] [Google Scholar]
  22. Fox D. A. The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum. 1997 Apr;40(4):598–609. doi: 10.1002/art.1780400403. [DOI] [PubMed] [Google Scholar]
  23. Greig P. C., Herbert W. N., Robinette B. L., Teot L. A. Amniotic fluid interleukin-10 concentrations increase through pregnancy and are elevated in patients with preterm labor associated with intrauterine infection. Am J Obstet Gynecol. 1995 Oct;173(4):1223–1227. doi: 10.1016/0002-9378(95)91358-0. [DOI] [PubMed] [Google Scholar]
  24. Harbuz M. S., Perveen-Gill Z., Lightman S. L., Jessop D. S. A protective role for testosterone in adjuvant-induced arthritis. Br J Rheumatol. 1995 Dec;34(12):1117–1122. doi: 10.1093/rheumatology/34.12.1117. [DOI] [PubMed] [Google Scholar]
  25. Harris E. D., Jr Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med. 1990 May 3;322(18):1277–1289. doi: 10.1056/NEJM199005033221805. [DOI] [PubMed] [Google Scholar]
  26. Houssiau F. A., Lefebvre C., Vanden Berghe M., Lambert M., Devogelaer J. P., Renauld J. C. Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus. 1995 Oct;4(5):393–395. doi: 10.1177/096120339500400510. [DOI] [PubMed] [Google Scholar]
  27. Hu S. K., Mitcho Y. L., Rath N. C. Effect of estradiol on interleukin 1 synthesis by macrophages. Int J Immunopharmacol. 1988;10(3):247–252. doi: 10.1016/0192-0561(88)90055-0. [DOI] [PubMed] [Google Scholar]
  28. Huong D. L., Wechsler B., Piette J. C., Arfi S., Gallinari C., Darbois Y., Frances C., Godeau P. Risks of ovulation-induction therapy in systemic lupus erythematosus. Br J Rheumatol. 1996 Nov;35(11):1184–1186. doi: 10.1093/rheumatology/35.11.1184. [DOI] [PubMed] [Google Scholar]
  29. Kanik K. S., Hagiwara E., Yarboro C. H., Schumacher H. R., Wilder R. L., Klinman D. M. Distinct patterns of cytokine secretion characterize new onset synovitis versus chronic rheumatoid arthritis. J Rheumatol. 1998 Jan;25(1):16–22. [PubMed] [Google Scholar]
  30. Keller E. T., Chang C., Ershler W. B. Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem. 1996 Oct 18;271(42):26267–26275. doi: 10.1074/jbc.271.42.26267. [DOI] [PubMed] [Google Scholar]
  31. Khamashta M. A., Ruiz-Irastorza G., Hughes G. R. Systemic lupus erythematosus flares during pregnancy. Rheum Dis Clin North Am. 1997 Feb;23(1):15–30. doi: 10.1016/s0889-857x(05)70312-4. [DOI] [PubMed] [Google Scholar]
  32. Lahita R. G., Bradlow H. L., Ginzler E., Pang S., New M. Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum. 1987 Mar;30(3):241–248. doi: 10.1002/art.1780300301. [DOI] [PubMed] [Google Scholar]
  33. Lahita R. G., Bradlow H. L., Kunkel H. G., Fishman J. Increased 16 alpha-hydroxylation of estradiol in systemic lupus erythematosus. J Clin Endocrinol Metab. 1981 Jul;53(1):174–178. doi: 10.1210/jcem-53-1-174. [DOI] [PubMed] [Google Scholar]
  34. Lazarus M., Hajeer A. H., Turner D., Sinnott P., Worthington J., Ollier W. E., Hutchinson I. V. Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol. 1997 Dec;24(12):2314–2317. [PubMed] [Google Scholar]
  35. Li Z. G., Danis V. A., Brooks P. M. Effect of gonadal steroids on the production of IL-1 and IL-6 by blood mononuclear cells in vitro. Clin Exp Rheumatol. 1993 Mar-Apr;11(2):157–162. [PubMed] [Google Scholar]
  36. Liblau R. S., Singer S. M., McDevitt H. O. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. 1995 Jan;16(1):34–38. doi: 10.1016/0167-5699(95)80068-9. [DOI] [PubMed] [Google Scholar]
  37. Lin H., Mosmann T. R., Guilbert L., Tuntipopipat S., Wegmann T. G. Synthesis of T helper 2-type cytokines at the maternal-fetal interface. J Immunol. 1993 Nov 1;151(9):4562–4573. [PubMed] [Google Scholar]
  38. Masi A. T., Chrousos G. P. Hypothalamic-pituitary-adrenal-glucocorticoid axis function in rheumatoid arthritis. J Rheumatol. 1996 Apr;23(4):577–581. [PubMed] [Google Scholar]
  39. Masi A. T., Da Silva J. A., Cutolo M. Perturbations of hypothalamic-pituitary-gonadal (HPG) axis and adrenal androgen (AA) functions in rheumatoid arthritis. Baillieres Clin Rheumatol. 1996 May;10(2):295–332. doi: 10.1016/s0950-3579(96)80019-7. [DOI] [PubMed] [Google Scholar]
  40. Masi A. T., Feigenbaum S. L., Chatterton R. T., Cutolo M. Integrated hormonal-immunological-vascular (H-I-V triad) systems interactions in the rheumatic diseases. Clin Exp Rheumatol. 1995 Mar-Apr;13(2):203–216. [PubMed] [Google Scholar]
  41. Masi A. T. Incidence of rheumatoid arthritis: do the observed age-sex interaction patterns support a role of androgenic-anabolic steroid deficiency in its pathogenesis? Br J Rheumatol. 1994 Aug;33(8):697–699. doi: 10.1093/rheumatology/33.8.697. [DOI] [PubMed] [Google Scholar]
  42. Masi A. T., Kaslow R. A. Sex effects in systemic lupus erythematosus: a clue to pathogenesis. Arthritis Rheum. 1978 May;21(4):480–484. doi: 10.1002/art.1780210413. [DOI] [PubMed] [Google Scholar]
  43. Mastorakos G., Chrousos G. P., Weber J. S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab. 1993 Dec;77(6):1690–1694. doi: 10.1210/jcem.77.6.8263159. [DOI] [PubMed] [Google Scholar]
  44. Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  45. Petri M., Robinson C. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum. 1997 May;40(5):797–803. doi: 10.1002/art.1780400504. [DOI] [PubMed] [Google Scholar]
  46. Piccinni M. P., Giudizi M. G., Biagiotti R., Beloni L., Giannarini L., Sampognaro S., Parronchi P., Manetti R., Annunziato F., Livi C. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J Immunol. 1995 Jul 1;155(1):128–133. [PubMed] [Google Scholar]
  47. Ramírez F., Fowell D. J., Puklavec M., Simmonds S., Mason D. Glucocorticoids promote a TH2 cytokine response by CD4+ T cells in vitro. J Immunol. 1996 Apr 1;156(7):2406–2412. [PubMed] [Google Scholar]
  48. Richaud-Patin Y., Alcocer-Varela J., Llorente L. High levels of TH2 cytokine gene expression in systemic lupus erythematosus. Rev Invest Clin. 1995 Jul-Aug;47(4):267–272. [PubMed] [Google Scholar]
  49. Rincón M., Anguita J., Nakamura T., Fikrig E., Flavell R. A. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J Exp Med. 1997 Feb 3;185(3):461–469. doi: 10.1084/jem.185.3.461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Romagnani S. Induction of TH1 and TH2 responses: a key role for the 'natural' immune response? Immunol Today. 1992 Oct;13(10):379–381. doi: 10.1016/0167-5699(92)90083-J. [DOI] [PubMed] [Google Scholar]
  51. Rook G. A., Hernandez-Pando R., Lightman S. L. Hormones, peripherally activated prohormones and regulation of the Th1/Th2 balance. Immunol Today. 1994 Jul;15(7):301–303. doi: 10.1016/0167-5699(94)90075-2. [DOI] [PubMed] [Google Scholar]
  52. Sanchez-Guerrero J., Karlson E. W., Liang M. H., Hunter D. J., Speizer F. E., Colditz G. A. Past use of oral contraceptives and the risk of developing systemic lupus erythematosus. Arthritis Rheum. 1997 May;40(5):804–808. doi: 10.1002/art.1780400505. [DOI] [PubMed] [Google Scholar]
  53. Schulze-Koops H., Lipsky P. E., Kavanaugh A. F., Davis L. S. Elevated Th1- or Th0-like cytokine mRNA in peripheral circulation of patients with rheumatoid arthritis. Modulation by treatment with anti-ICAM-1 correlates with clinical benefit. J Immunol. 1995 Nov 15;155(10):5029–5037. [PubMed] [Google Scholar]
  54. Simon A. K., Seipelt E., Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. doi: 10.1073/pnas.91.18.8562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Straub R. H., Zeuner M., Antoniou E., Schölmerich J., Lang B. Dehydroepiandrosterone sulfate is positively correlated with soluble interleukin 2 receptor and soluble intercellular adhesion molecule in systemic lupus erythematosus. J Rheumatol. 1996 May;23(5):856–861. [PubMed] [Google Scholar]
  56. Suzuki T., Suzuki N., Engleman E. G., Mizushima Y., Sakane T. Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1995 Feb;99(2):251–255. doi: 10.1111/j.1365-2249.1995.tb05541.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Urowitz M. B., Gladman D. D., Farewell V. T., Stewart J., McDonald J. Lupus and pregnancy studies. Arthritis Rheum. 1993 Oct;36(10):1392–1397. doi: 10.1002/art.1780361011. [DOI] [PubMed] [Google Scholar]
  58. Wegmann T. G., Lin H., Guilbert L., Mosmann T. R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993 Jul;14(7):353–356. doi: 10.1016/0167-5699(93)90235-D. [DOI] [PubMed] [Google Scholar]
  59. Wilder R. L. Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis. J Rheumatol Suppl. 1996 Mar;44:10–12. [PubMed] [Google Scholar]
  60. Wilder R. L. Neuroendocrine-immune system interactions and autoimmunity. Annu Rev Immunol. 1995;13:307–338. doi: 10.1146/annurev.iy.13.040195.001515. [DOI] [PubMed] [Google Scholar]
  61. al-Janadi M., al-Balla S., al-Dalaan A., Raziuddin S. Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases. J Clin Immunol. 1993 Jan;13(1):58–67. doi: 10.1007/BF00920636. [DOI] [PubMed] [Google Scholar]
  62. van Vollenhoven R. F., Engleman E. G., McGuire J. L. An open study of dehydroepiandrosterone in systemic lupus erythematosus. Arthritis Rheum. 1994 Sep;37(9):1305–1310. doi: 10.1002/art.1780370906. [DOI] [PubMed] [Google Scholar]
  63. van Vollenhoven R. F., Engleman E. G., McGuire J. L. Dehydroepiandrosterone in systemic lupus erythematosus. Results of a double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheum. 1995 Dec;38(12):1826–1831. doi: 10.1002/art.1780381216. [DOI] [PubMed] [Google Scholar]
  64. van Vollenhoven R. F., Morabito L. M., Engleman E. G., McGuire J. L. Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatol. 1998 Feb;25(2):285–289. [PubMed] [Google Scholar]

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