Immunomodulation by estrogen and estren

Abstract: Estrogen affects the development and regulation of the immune system. Treatment of gonadectomized mice with estrogen results in suppression of T and B lymphopoiesis, as well as decreased delayed type hypersensitivity reaction, granulocyte mediated inflammation and levels of IL-6 in serum. Conversely, immunoglobulin production is stimulated by estrogen. The effects of estrogen are mediated through the estrogen receptors (ER), ERa and ERb, which are ligand activated transcription factors that induce expression of specific estrogen responsive genes. The aims of this thesis were to investigate the role of ERs on B lymphopoiesis and immunoglobulin production, as well as on the aged immune system. Furthermore, the ER specific effects of the synthetic molecule estren on T and B lymphopoiesis, T cell-mediated inflammation and submandibular glands were studied. ER knock-out mice lacking ERa, ERb or both ERa and ERb, were gonadectomized and treated with 17b-estradiol-3-benzoate (E2) or 4-estren-3a,17b-diol (estren). We found that both ERa and ERb are required for the estrogen-induced decreased frequency of B lymphopoietic cells in the bone marrow. ERa alone is necessary for the estrogen-mediated, as well as for the age-induced, increased frequency of immunoglobulin producing B cells. We could also show that estren inhibits inflammation through ER-mediated pathways, while the inhibitory effects on T and B lymphopoiesis are not dependent on ERs. Furthermore, estren promotes an androgen phenotype in submandibular glands that is independent of ERs. In conclusion, our results show that the effects of estrogen on the immune system are mainly mediated via ERa, but signalling through ERb is necessary for complete inhibitory effect on B lymphopoiesis. Furthermore, estren treatment induces effects on lymphopoiesis and submandibular glands that are not mediated through ERs, but instead possibly through the androgen receptor.