TY - JOUR
T1 - Membrane estrogen receptor regulates experimental autoimmune encephalomyelitis through up-regulation of programmed death 1
AU - Wang, Chunhe
AU - Dehghani, Babak
AU - Li, Yuexin
AU - Kaler, Laurie J.
AU - Proctor, Thomas
AU - Vandenbark, Arthur A.
AU - Offner, Halina
PY - 2009/3/1
Y1 - 2009/3/1
N2 - 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 α. 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.
AB - 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 α. 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.
UR - http://www.scopus.com/inward/record.url?scp=64849102732&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=64849102732&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.0803205
DO - 10.4049/jimmunol.0803205
M3 - Article
C2 - 19234228
AN - SCOPUS:64849102732
SN - 0022-1767
VL - 182
SP - 3294
EP - 3303
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -