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
Tanriverdi F, Silveira LF, MacColl GS, Bouloux PM (2003) The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity. J Endocrinol 176:293–304
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
Lang TJ (2004) Estrogen as an immunomodulator. Clin Immunol 113:224–230
Grimaldi CM, Hicks R, Diamond B (2005) B cell selection and susceptibility to autoimmunity. J Immunol 174:1775–1781
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
Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28:521–574
Gompel A, Piette JC (2007) Systemic lupus erythematosus and hormone replacement therapy. Menopause Int 13:65–70
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
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
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
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
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
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
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
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
Pernis AB (2007) Estrogen and CD4+ T cells. Curr Opin Rheumatol 19:414–420
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
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
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
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
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
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
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
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
Stevis PE, Deecher DC, Suhadolnik L, Mallis LM, Frail DE (1999) Differential effects of estradiol and estradiol-BSA conjugates. Endocrinology 140:5455–5458
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
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
Moggs JG, Orphanides G (2001) Estrogen receptors: orchestrators of pleiotropic cellular responses. EMBO Rep 2:775–781
Kelly MJ, Levin ER (2001) Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 12:152–156
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
Benten WP, Stephan C, Wunderlich F (2002) B cells express intracellular but not surface receptors for testosterone and estradiol. Steroids 67:647–654
Stice JP, Knowlton AA (2008) Estrogen, NFkappaB, and the heat shock response. Mol Med 14:517–527
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
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
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
Whitacre CC (2001) Sex differences in autoimmune disease. Nat Immunol 2:777–780
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
Obukhanych TV, Nussenzweig MC (2006) T-independent type II immune responses generate memory B cells. J Exp Med 203:305–310
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
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
Plas DR, Rathmell JC, Thompson CB (2002) Homeostatic control of lymphocyte survival, potential origins and implications. Nat Immunol 3:515–521
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
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
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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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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DOI: https://doi.org/10.1007/s00018-010-0270-5