Modulation of estrogen receptors alpha and beta. Effects on the immune system

Estrogen affects the development and function of the immune system. Gonadectomized mice treated with estrogen display suppressed T and B lymphopoiesis and inhibited T cell and granulocyte dependent inflammation, while mature B cells are stimulated to produce more immunoglobulins. These effects influence how estrogen affects autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. Estrogen mediates its effects through two homologous receptors named estrogen receptor ER-alpha and ER-beta. They are ligand activated transcription factors that induce expression of genes with specific estrogen response elements in the promotor. The aims of the study were to evaluate how specific estrogen receptor inactivation (knock-out) or selective estrogen receptors modulation (SERM) affect the development and function of the immune system and inflammatory responses in mice.We have used mice lacking ER-alpha (ERKO), ER-beta (BERKO) or both receptors (DERKO). Oophorectomized and sham-operated mice were treated with estradiol (E2) or a selective estrogen receptor modulator (SERM), raloxifene (LY) in doses equipotent for prevention of osteoporosis.It was demonstrated that male mice lacking ER-alpha have smaller thymi and spleens than their ER-alpha+ littermates. Treatment of oophorectomized BERKO mice with E2 revealed that ER-beta is needed to achieve complete estrogen-mediated thymus involution. In castrated male mice both ER-alpha and ER-beta are needed to achieve total estrogen induced inhibition of B lymphopoiesis, while only ER-alpha is needed to achieve the stimulatory effect of estrogen on immunoglobulin production.In contrast to E2, treatment with LY had only minor effects on suppression of T lymphopoiesis and lacked anti-inflammatory effects. We were also able to demonstrate estrogen-agonistic effects of LY in uterus, bone and on B lymphopoiesis, partial agonism on immunoglobulin production and antagonistic effects on uterus weight in sham-operated animals.Our studies show that the effects of estrogen on the immune system are mainly mediated via ER-alpha, but that signalling through ER-beta is necessary for complete inhibitory effect on B and T lymphopoiesis in bone marrow and thymus, respectively. We have also demonstrated that raloxifene lacks the anti-inflammatory properties of estrogen, but has its B lymphocyte stimulating effects.Our findings will be of importance in the search for an estrogen receptor ligand for treatment of inflammation and osteoporosis in rheumatic diseases