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Membrane Estrogen Receptor Regulates Experimental Autoimmune Encephalomyelitis through Up-regulation of Programmed Death 1¹

Chunhe Wang^2,3,*,, Babak Dehghani^2,*,, Yuexin Li^*,, Laurie J. Kaler^*, Thomas Proctor^*, Arthur A. Vandenbark^*,, and Halina Offner^3,*,,

^* Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239; and Department of Neurology, Department of Molecular Microbiology and Immunology, and Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239

Although estrogens exert a pronounced protective effect on multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), their therapeutic application has been limited by undesirable side effects thought to be mediated primarily through estradiol binding to intracellular estrogen receptor . In this study, we found that signaling through the putative membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), was sufficient to mediate protection against EAE, which was significantly impaired in GPR30 gene-deficient mice. Treatment with G-1, an agonist that selectively activates GPR30 without engagement of the intracellular estrogen receptors, retained the ability of estradiol to protect against clinical and histological EAE without estradiol-associated side effects, deviated cytokine profiles, and enhanced suppressive activity of CD4⁺Foxp3⁺ T regulatory cells through a GPR30- and programmed death 1-dependent mechanism. This study is the first to evaluate the protective effect of GPR30 activation on EAE, and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in multiple sclerosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants NS45445 and NS49210; National Multiple Sclerosis Society Grant RG3405; Nancy Davis Center Without Walls; and the Biomedical Laboratory R&D Service, Department of Veterans Affairs.

² C.W. and B.D. are co-first authors.

³ Address correspondence and reprint requests to Dr. Halina Offner, R&D31, Portland Veterans Affairs Medical Center, 3710 S.W. U.S. Veterans Hospital Road, Portland, OR 97239; E-mail address: offnerva{at}ohsu.edu or Dr. Chunhe Wang; R&D31, Portland Veterans Affairs Medical Center, 3710 S.W. Veterans Hospital Road, Portland, OR 97239; E-mail address: wangch{at}ohsu.edu

⁴ Abbreviations used in this paper: MS, multiple sclerosis; CDI, cumulative disease index; EAE, experimental autoimmune encephalomyelitis; iER, intracellular estrogen receptor; LFB-PAS, Luxol fast blue plus periodic acid Schiff; LN, lymph node; mER, membrane estrogen receptor; MFI, mean fluorescence intensity; MOG, myelin oligodendrocyte glycoprotein; mMOG, mouse MOG; NFL, neurofilament; PTX, pertussis toxin; Treg, T regulatory; WT, wild type; GPR30, G protein-coupled receptor 30.