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GPR30 Contributes to Estrogen-Induced Thymic Atrophy

Neuroimmunology Research (C.W., B.D., E.B., S.S., A.A.V., H.O.), Veterans Affairs Medical Center, Portland, Oregon 97239; Departments of Neurology (C.W., B.D., A.A.V., H.O.), Physiology & Pharmacology (E.A.R., M.J.K.), Molecular Microbiology & Immunology (A.A.V.), and Anesthesiology & Peri-Operative Medicine (S.J.M., H.O.), Oregon Health & Science University, Portland, Oregon 97239; and Procter & Gamble Pharmaceuticals (I.J.M., D.B.C., L.A.E., J.S.R.), Mason, Ohio 45040

Address all correspondence and requests for reprints to: Dr. Chunhe Wang, Neuroimmunology Research R&D-31, 3710 Southwest U.S. Veterans Hospital Road, Portland, Oregon 97239. E-mail address: wangch{at}ohsu.edu.

The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, reduce thymus weight, cellularity, and CD4 and CD8 phenotype expression, have not been well defined. In this study, the roles played by the membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), and the intracellular estrogen receptors, estrogen receptor (ER) and β (ERβ), in 17β-estradiol (E2)-induced thymic atrophy were distinguished by construction and the side-by-side comparison of GPR30-deficient mice with ER and ERβ gene-deficient mice. Our study shows that whereas ER mediated exclusively the early developmental blockage of thymocytes, GPR30 was indispensable for thymocyte apoptosis that preferentially occurs in T cell receptor β chain^–/low double-positive thymocytes. Additionally, G1, a specific GPR30 agonist, induces thymic atrophy and thymocyte apoptosis, but not developmental blockage. Finally, E2 treatment attenuates the activation of nuclear factor- B in CD25^–CD4^–CD8^– double-negative thymocytes through an ER-dependent yet ERβ- and GPR30-independent pathway. Differential inhibition of nuclear factor-B by ER and GPR30 might underlie their disparate physiological effects on thymocytes. Our study distinguishes, for the first time, the respective contributions of nuclear and membrane E2 receptors in negative regulation of thymic development.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol

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