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¶
From the Department of Neurology,* Oregon Health and Science University, Portland, Oregon; Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon; the Department of Food Hygiene, Faculty of Veterinary Medicine, Warsaw Agricultural University, Warsaw, Poland; the Oregon Regional Primate Research Center, Beaverton, Oregon; the Division of Reproductive Science,¶ Oregon Health and Science University, Portland, Oregon; the Department of Microbiology and Immunology,|| Drexel University College of Medicine, Philadelphia, Pennsylvania; the Department of Medicine,** University of Vermont, Burlington, Vermont; and the Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon
Low-dose estrogen (E2) treatment significantly inhibits the clinical signs and histopathological lesions of experimental autoimmune encephalomyelitis (EAE), and is being used in clinical trials to treat multiple sclerosis. To assess the role of intracytoplasmic estrogen receptors in mediating suppression of EAE, we studied mice with disrupted estrogen receptor-
(Esr1) and -ß (Esr2) genes. We demonstrate that the protective effect of E2 is abrogated in B6.129-Esr1tm1Unc mice (Esr1-/-) but not in B6.129-Esr2tm1Unc mice (Esr2-/-). The loss of E2-mediated protection from EAE in Esr1-/- mice immunized with the encephalitogenic MOG-35–55 peptide was manifested phenotypically by the development of severe acute clinical signs and histopathological lesions even in the presence of moderately high serum E2 levels. This is in contrast to C57BL/6 wild-type (WT) mice and Esr2-/- mice in which E2 treatment resulted in comparable serum levels and markedly suppressed clinical signs of EAE and abolished inflammatory lesions in the CNS. This pattern showing a lack of E2-dependent inhibition of EAE in Esr1-/- mice was mirrored by an enhanced rather than a reduced secretion of TNF-, IFN-
, and interleukin (IL)-6 in MOG-specific splenocytes and a lack of inhibition of message for inflammatory cytokines, chemokines and chemokine receptors in CNS tissue. These results indicate that the immunomodulatory effects of E2 in EAE are dependent on Esr1 and not Esr2 signaling.
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