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Molecular Medicine

, Volume 18, Issue 3, pp 370–378 | Cite as

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

  • Vaishali R. Moulton
  • Dana R. Holcomb
  • Melissa C. Zajdel
  • George C. Tsokos
Research Article

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex multifactorial pathogenesis. T lymphocytes play a critical role in disease pathogenesis and display abnormal gene expression and poor interleukin (IL)-2 production. We previously showed that the expression of the transcriptional repressor cyclic AMP response element modulator α (CREMα) is increased in SLE T cells and contributes to reduced IL-2 production. Although estrogen is implicated in the onset and exacerbation of SLE, the precise nature of molecular events regulated by estrogen in immune cell function is not well understood. Here, we asked whether estrogen regulates the expression of CREMα in human T lymphocytes. We show that exposure of human T cells to 17-β-estradiol leads to a dose-dependent increase in CREMα mRNA expression, and this increase appears to be mediated through the estrogen receptors α and β. We show that the increased expression of CREMα is due to increased transcriptional activity of the CREM promoter and is mediated by increased expression and binding of the Sp1 transcriptional activator. We further show that estrogen treatment leads to a dose-dependent decrease in IL-2 mRNA and cytokine production by T cells. Finally, the effect of β-estradiol on CREMα is observed more frequently in T cells from women than from men. We conclude that estrogen can modulate the expression of CREMα and lead to IL-2 suppression in human T lymphocytes, thus revealing a molecular link between hormones and the immune system in SLE.

Notes

Acknowledgments

We thank Eric A Moulton for help with data analysis. This work was funded by National Institute of Health R01 grants AI49954 and AI068787 to GC Tsokos and an Arthritis Foundation fellowship to VR Moulton.

References

  1. 1.
    Crispin JC, et al. (2010) Pathogenesis of human systemic lupus erythematosus: recent advances. Trends Mol. Med. 16:47–57.CrossRefPubMedGoogle Scholar
  2. 2.
    Davidson A, Diamond B. (2001) Autoimmune diseases. N. Engl. J. Med. 345:340–50.CrossRefPubMedGoogle Scholar
  3. 3.
    Jungers P, et al. (1985) Hormonal modulation in systemic lupus erythematosus: preliminary clinical and hormonal results with cyproterone acetate. Arthritis Rheum. 28:1243–50.CrossRefPubMedGoogle Scholar
  4. 4.
    Mund A, Simson J, Rothfield N. (1963) Effect of pregnancy on course of systemic lupus erythematosus. JAMA. 183:917–20.CrossRefPubMedGoogle Scholar
  5. 5.
    Mok CC, Lau CS, Ho CT, Wong RW. (1999) Do flares of systemic lupus erythematosus decline after menopause? Scand. J. Rheumatol. 28:357–62.CrossRefPubMedGoogle Scholar
  6. 6.
    Cohen-Solal JF, Jeganathan V, Grimaldi CM, Peeva E, Diamond B. (2006) Sex hormones and SLE: influencing the fate of autoreactive B cells. Curr. Top. Microbiol. Immunol. 305:67–88.PubMedGoogle Scholar
  7. 7.
    Lahita RG, Bradlow HL, Kunkel HG, Fishman J. (1979) Alterations of estrogen metabolism in systemic lupus erythematosus. Arthritis Rheum. 22:1195–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Buyon JP, et al. (2005) The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann. Intern. Med. 142:953–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Rider V, Jones SR, Evans M, Abdou NI. (2000) Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells. Clin. Immunol. 95:124–34.CrossRefPubMedGoogle Scholar
  10. 10.
    Rider V, et al. (2001) Estrogen increases CD40 lig- and expression in T cells from women with systemic lupus erythematosus. J. Rheumatol. 28:2644–9.PubMedGoogle Scholar
  11. 11.
    Pung OJ, Tucker AN, Vore SJ, Luster MI. (1985) Influence of estrogen on host resistance: increased susceptibility of mice to Listeria monocytogenes correlates with depressed production of interleukin 2. Infect. Immun. 50:91–6.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Khan D, Dai R, Karpuzoglu E, Ahmed SA. (2010) Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in WT mice. Eur. J. Immunol. 40:2549–56.CrossRefPubMedGoogle Scholar
  13. 13.
    Malek TR, Bayer AL. (2004) Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4:665–74.CrossRefPubMedGoogle Scholar
  14. 14.
    Crispin JC, Tsokos GC. (2009) Transcriptional regulation of IL-2 in health and autoimmunity. Autoimmun. Rev. 8:190–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Katsiari CG, Tsokos GC. (2006) Transcriptional repression of interleukin-2 in human systemic lupus erythematosus. Autoimmun. Rev. 5:118–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Katsiari CG, Kyttaris VC, Juang YT, Tsokos GC. (2005) Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus. J. Clin. Invest. 115:3193–204.CrossRefPubMedGoogle Scholar
  17. 17.
    Juang YT, et al. (2005) Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. J. Clin. Invest. 115:996–1005.CrossRefPubMedGoogle Scholar
  18. 18.
    Kyttaris VC, Wang Y, Juang YT, Weinstein A, Tsokos GC. (2006) CAMP response element modulator a expression in patients with systemic lupus erythematosus. Lupus. 15:840–4.CrossRefPubMedGoogle Scholar
  19. 19.
    Juang YT, et al. (2011) Transcriptional activation of the cAMP-responsive modulator promoter in human T cells is regulated by protein phosphatase 2A-mediated dephosphorylation of SP-1 and reflects disease activity in patients with systemic lupus erythematosus. J. Biol. Chem. 286:1795–801.CrossRefPubMedGoogle Scholar
  20. 20.
    Thomas P, Pang Y, Filardo EJ, Dong J. (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology. 146:624–32.CrossRefPubMedGoogle Scholar
  21. 21.
    Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 307:1625–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Nilsson S, et al. (2001) Mechanisms of estrogen action. Physiol. Rev. 81:1535–65.CrossRefPubMedGoogle Scholar
  23. 23.
    Pernis AB. (2007) Estrogen and CD4+ T cells. Curr. Opin. Rheumatol. 19:414–20.CrossRefPubMedGoogle Scholar
  24. 24.
    Tyson-Capper AJ, Bailey J, Krainer AR, Robson SC, Europe-Finner GN. (2005) The switch in alternative splicing of cyclic AMP-response element modulator protein CREM{tau}2{alpha} (activator) to CREM{alpha} (repressor) in human myometrial cells is mediated by SRp40. J. Biol. Chem. 280:34521–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Tenbrock K, Juang YT, Tolnay M, Tsokos GC. (2003) The cyclic adenosine 5′-monophosphate response element modulator suppresses IL-2 production in stimulated T cells by a chromatin-dependent mechanism. J. Immunol. 170:2971–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Tenbrock K, Juang YT, Gourley MF, Nambiar MP, Tsokos GC. (2002) Antisense cyclic adenosine 5′-monophosphate response element modulator up-regulates IL-2 in T cells from patients with systemic lupus erythematosus. J. Immunol. 169:4147–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Robertson JA, Farnell Y, Lindahl LS, Ing NH. (2002) Estradiol up-regulates estrogen receptor messenger ribonucleic acid in endometrial carcinoma (Ishikawa) cells by stabilizing the message. J. Mol. Endocrinol. 29:125–35.CrossRefPubMedGoogle Scholar
  28. 28.
    Lieberman LA, Tsokos GC. (2010) The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J. Biomed. Biotechnol. 2010:740619.CrossRefPubMedGoogle Scholar
  29. 29.
    Iliopoulos AG, Tsokos GC. (1996) Immunopathogenesis and spectrum of infections in systemic lupus erythematosus. Semin. Arthritis Rheum. 25:318–36.CrossRefPubMedGoogle Scholar
  30. 30.
    La Cava A. (2011) Regulatory immune cell subsets in autoimmunity. Autoimmunity. 44:1–2.CrossRefPubMedGoogle Scholar
  31. 31.
    Kovacs B, Vassilopoulos D, Vogelgesang SA, Tsokos GC. (1996) Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-alpha. Clin. Immunol. Immunopathol. 81:293.CrossRefPubMedGoogle Scholar
  32. 32.
    Kyttaris VC, Wang Y, Juang YT, Weinstein A, Tsokos GC. (2007) Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. J. Immunol. 178:1960–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Cron RQ. (2003) CD154 transcriptional regulation in primary human CD4 T cells. Immunol. Res. 27:185–202.CrossRefPubMedGoogle Scholar
  34. 34.
    Grimaldi CM, Jeganathan V, Diamond B. (2006) Hormonal regulation of B cell development: 17 beta-estradiol impairs negative selection of high-affinity DNA-reactive B cells at more than one developmental checkpoint. J. Immunol. 176:2703–10.CrossRefPubMedGoogle Scholar
  35. 35.
    Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. (2002) Estrogen alters thresholds for B cell apoptosis and activation. J. Clin. Invest. 109:1625–33.CrossRefPubMedGoogle Scholar
  36. 36.
    Rider V, et al. (2006) Differential expression of estrogen receptors in women with systemic lupus erythematosus. J. Rheumatol. 33:1093–101.PubMedGoogle Scholar
  37. 37.
    Murphy AJ, Guyre PM, Wira CR, Pioli PA. (2009) Estradiol regulates expression of estrogen receptor ERalpha46 in human macrophages. PLoS One. 4:e5539.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Vaishali R. Moulton
    • 1
  • Dana R. Holcomb
    • 1
  • Melissa C. Zajdel
    • 1
  • George C. Tsokos
    • 1
  1. 1.Division of Rheumatology, Department of MedicineBeth Israel Deaconess Medical CenterBostonUSA

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