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Estrogen augments the T cell-dependent but not the T-independent immune response

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An Erratum to this article was published on 16 May 2010

Abstract

Estrogen plays a critical regulatory role in the development and maintenance of immunity. Its role in the regulation of antibody synthesis in vivo is still not completely clear. Here, we have compared the effect of estrogen on T cell-dependent (TD) and T cell-independent type 2 (TI-2) antibody responses. The results provide the first evidence that estrogen enhances the TD but not the TI-2 response. Ovariectomy significantly decreased, while estrogen re-administration increased the number of hapten-specific IgM- and IgG-producing cells in response to TD antigen. In vitro experiments also show that estrogen may have a direct impact on B and T cells by inducing rapid signaling events, such as Erk and AKT phosphorylation, cell-specific Ca2+ signal, and NFκB activation. These non-transcriptional effects are mediated by classical estrogen receptors and partly by an as yet unidentified plasma membrane estrogen receptor. Such receptor- mediated rapid signals may modulate the in vivo T cell-dependent immune response.

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Abbreviations

AEC:

3-Amino-9-ethylcarbazole

[Ca2+]i :

Intracellular free Ca2+

CLSM:

Confocal laser scanning microscopy

DCC-FCS:

Dextran-coated charcoal-treated foetal calf serum

αE2:

17α-Estradiol

βE2:

17β-Estradiol

eNOS:

Endothelial isoform of NO synthase

ERα:

Nuclear estrogen receptor α

ERβ:

Nuclear estrogen receptor β

HRT:

Hormone replacement therapy

KLH:

Keyhole limpet hemocyanin

OVX:

Ovariectomised

SHAM:

Sham-operated

SLE:

Systhemic lupus erythematosus

TD:

T cell dependent

TI-2:

T cell independent type 2

References

  1. Tanriverdi F, Silveira LF, MacColl GS, Bouloux PM (2003) The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity. J Endocrinol 176:293–304

    Article  PubMed  CAS  Google Scholar 

  2. Ansar AS, Penhale WJ, Talal N (1985) Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol 121:531–551

    Google Scholar 

  3. Lang TJ (2004) Estrogen as an immunomodulator. Clin Immunol 113:224–230

    Article  PubMed  CAS  Google Scholar 

  4. Grimaldi CM, Hicks R, Diamond B (2005) B cell selection and susceptibility to autoimmunity. J Immunol 174:1775–1781

    PubMed  CAS  Google Scholar 

  5. Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B (2002) Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest 109:1625–1633

    PubMed  CAS  Google Scholar 

  6. Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28:521–574

    Article  PubMed  CAS  Google Scholar 

  7. Gompel A, Piette JC (2007) Systemic lupus erythematosus and hormone replacement therapy. Menopause Int 13:65–70

    Article  PubMed  CAS  Google Scholar 

  8. Apelgren LD, Bailey DL, Fouts RL, Short L, Bryan N, Evans GF, Sandusky GE, Zuckerman SH, Glasebrook A, Bumol TF (1996) The effect of a selective estrogen receptor modulator on the progression of spontaneous autoimmune disease in MRL lpr/lpr mice. Cell Immunol 173:55–63

    Article  PubMed  CAS  Google Scholar 

  9. Li J, McMurray RW (2007) Effects of estrogen receptor subtype-selective agonists on autoimmune disease in lupus-prone NZB/NZW F1 mouse model. Clin Immunol 123:219–226

    Article  PubMed  CAS  Google Scholar 

  10. Maret A, Coudert JD, Garidou L, Foucras G, Gourdy P, Krust A, Dupont S, Chambon P, Druet P, Bayard F, Guéry JC (2003) Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells. Eur J Immunol 33:512–521

    Article  PubMed  CAS  Google Scholar 

  11. Salem ML (2004) Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy 3:97–104

    Article  PubMed  CAS  Google Scholar 

  12. Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones–a focus on rapid, nongenomic effects. Pharmacol Rev 52:513–556

    PubMed  CAS  Google Scholar 

  13. Losel RM, Falkenstein E, Feuring M, Schultz A, Tillmann HC, Rossol-Haseroth K, Wehling M (2003) Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 83:965–1016

    PubMed  Google Scholar 

  14. Curran EM, Berghaus LJ, Vernetti NJ, Saporita AJ, Lubahn DB, Estes DM (2001) Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway. Cell Immunol 214:12–20

    Article  PubMed  CAS  Google Scholar 

  15. Mor G, Sapi E, Abrahams VM, Rutherford T, Song J, Hao XY, Muzaffar S, Kohen F (2003) Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes. J Immunol 170:114–122

    PubMed  CAS  Google Scholar 

  16. Pernis AB (2007) Estrogen and CD4+ T cells. Curr Opin Rheumatol 19:414–420

    Article  PubMed  CAS  Google Scholar 

  17. Samy TS, Schwacha MG, Cioffi WG, Bland KI, Chaudry IH (2000) Androgen and estrogen receptors in splenic T lymphocytes: effects of flutamide and trauma-hemorrhage. Shock 14:465–470

    Article  PubMed  CAS  Google Scholar 

  18. Suenaga R, Rider V, Evans MJ, Abdou NI (2001) In vitro-activated human lupus T cells express normal estrogen receptor proteins which bind to the estrogen response element. Lupus 10:116–122

    Article  PubMed  CAS  Google Scholar 

  19. Tornwall J, Carey AB, Fox RI, Fox HS (1999) Estrogen in autoimmunity, expression of estrogen receptors in thymic and autoimmune T cells. J Gend Specif Med 2:33–40

    PubMed  CAS  Google Scholar 

  20. Erlandsson MC, Jonsson CA, Islander U, Ohlsson C, Carlsten H (2003) Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice. Immunology 108:346–351

    Article  PubMed  CAS  Google Scholar 

  21. Improta-Brears T, Whorton AR, Codazzi F, York JD, Meyer T, McDonnell DP (1999) Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium. Proc Natl Acad Sci USA 96:4686–4691

    Article  PubMed  CAS  Google Scholar 

  22. Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH (2004) Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 13:635–638

    Article  PubMed  CAS  Google Scholar 

  23. Suzuki T, Yu HP, Hsieh YC, Choudhry MA, Bland KI, Chaudry IH (2008) Mitogen activated protein kinase (MAPK) mediates non-genomic pathway of estrogen on T cell cytokine production following trauma-hemorrhage. Cytokine 42:32–38

    Article  PubMed  CAS  Google Scholar 

  24. Cheskis BJ, Greger J, Cooch N, McNally C, Mclarney S, Lam HS, Rutledge S, Mekonnen B, Hauze D, Nagpal S, Freedman LP (2008) MNAR plays an important role in ERa activation of Src/MAPK and PI3K/Akt signaling pathways. Steroids 73:901–905

    Article  PubMed  CAS  Google Scholar 

  25. Stevis PE, Deecher DC, Suhadolnik L, Mallis LM, Frail DE (1999) Differential effects of estradiol and estradiol-BSA conjugates. Endocrinology 140:5455–5458

    Article  PubMed  CAS  Google Scholar 

  26. Gombos I, Detre C, Vámosi Gy, Matko J (2004) Rafting MHC-II domains in the APC (presynaptic) plasma membrane and the thresholds for T cell activation and immunological synapse formation. Immunol Lett 92:117–124

    Article  PubMed  CAS  Google Scholar 

  27. Simoncini T, Fornari L, Mannella P, Varone G, Caruso A, Liao JK, Genazzani AR (2002) Novel non-transcriptional mechanisms for estrogen receptor signaling in the cardiovascular system. Interaction of estrogen receptor alpha with phosphatidylinositol 3-OH kinase. Steroids 67:935–939

    Article  PubMed  CAS  Google Scholar 

  28. Moggs JG, Orphanides G (2001) Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO Rep 2:775–781

    Article  PubMed  CAS  Google Scholar 

  29. Kelly MJ, Levin ER (2001) Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 12:152–156

    Article  PubMed  CAS  Google Scholar 

  30. Thomas W, Coen N, Faherty S, Flatharta CO, Harvey BJ (2006) Estrogen induces phospholipase A2 activation through ERK1/2 to mobilize intracellular calcium in MCF-7 cells. Steroids 71:256–265

    Article  PubMed  CAS  Google Scholar 

  31. Benten WP, Stephan C, Wunderlich F (2002) B cells express intracellular but not surface receptors for testosterone and estradiol. Steroids 67:647–654

    Article  PubMed  CAS  Google Scholar 

  32. Stice JP, Knowlton AA (2008) Estrogen, NFkappaB, and the heat shock response. Mol Med 14:517–527

    Article  PubMed  CAS  Google Scholar 

  33. Hirano S, Furutama D, Hanafusa T (2007) Physiologically high concentrations of 17beta-estradiol enhance NF-kappaB activity in human T cells. Am J Physiol Regul Integr Comp Physiol 292:R1465–R1471

    PubMed  CAS  Google Scholar 

  34. Karpuzoglu-Sahin E, Zhi-Jun Y, Lengi A, Sriranganathan N, Ansar Ahmed S (2001) Effects of long term estrogen treatment on IFNγ, IL-2 and IL-4 gene expression and on protein synthesis in spleen and thymus of normal C57BL/6 mice. Cytokine 14:208–217

    Article  PubMed  CAS  Google Scholar 

  35. Grimaldi CM, Michael DJ, Diamond B (2001) Cutting edge: expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J Immunol 167:1886–1890

    PubMed  CAS  Google Scholar 

  36. Whitacre CC (2001) Sex differences in autoimmune disease. Nat Immunol 2:777–780

    Article  PubMed  CAS  Google Scholar 

  37. Crabtree TD, Pelletier SJ, Gleason TG, Pruett TL, Sawyer RG (1999) Gender-dependent differences in outcome after the treatment of infection in hospitalized patients. JAMA 282:2143–2148

    Article  PubMed  CAS  Google Scholar 

  38. Obukhanych TV, Nussenzweig MC (2006) T-independent type II immune responses generate memory B cells. J Exp Med 203:305–310

    Article  PubMed  Google Scholar 

  39. Titolo D, Mayer CM, Dhillon SS, Cai F, Belsham DD (2008) Estrogen facilitates both phosphatidylinositol 3-kinase/Akt and ERK1/2 mitogen-activated protein kinase membrane signaling required for long-term neuropeptide Y transcriptional regulation in clonal, immortalized neurons. J Neurosci 28:6473–6482

    Article  PubMed  CAS  Google Scholar 

  40. Zhao H, Sapolsky RM, Steinberg GK (2006) Phosphoinositide-3-kinase/akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol 34:249–270

    Article  PubMed  CAS  Google Scholar 

  41. Plas DR, Rathmell JC, Thompson CB (2002) Homeostatic control of lymphocyte survival, potential origins and implications. Nat Immunol 3:515–521

    Article  PubMed  CAS  Google Scholar 

  42. Cerillo G, Rees A, Manchanda N, Reilly C, Brogan I, White A, Needham M (1998) The oestrogen receptor regulates NFkappaB and AP-1 activity in a cell-specific manner. J Steroid Biochem Mol Biol 67:79–88

    Article  PubMed  CAS  Google Scholar 

  43. Barabás K, Szegõ EM, Kaszás A, Nagy GM, Juhász GD, Abrahám IM (2006) Sex differences in oestrogen-induced p44/42 MAPK phosphorylation in the mouse brain in vivo. J Neuroendocrinol 18:621–628

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Hungarian National Science and Research Development Foundation (OTKA T047217 and T049696), the NKFP-1-A/040/2004, Pázmány grant 06/2006 from Hungarian National Office of Research and Technology Development, and by the Department of Physiology at University of Otago and University of Otago Research Grant. The financial support of the Hungarian Academy of Sciences is also gratefully acknowledged. The authors thank Arpad Mikesy for the care and maintenance of mice.

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Correspondence to István M. Ábrahám or Gabriella Sármay.

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M. Ádori and E. Kiss contributed equally.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00018-010-0397-4

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Ádori, M., Kiss, E., Barad, Z. et al. Estrogen augments the T cell-dependent but not the T-independent immune response. Cell. Mol. Life Sci. 67, 1661–1674 (2010). https://doi.org/10.1007/s00018-010-0270-5

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