The protective effect of 17b-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-a
The protective effect of 17b-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-a
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DOI：
10.1016/s0002-9440(10)63516-x
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发表时间：
2003-10-01
影响因子：
6
通讯作者：
Offner, H
中科院分区：
文献类型：
--
作者：
Polanczyk, M;Zamora, A;Offner, H
小剂量雌激素(E2)治疗可显著抑制实验性自身免疫性脑脊髓炎(EAE)的临床体征和组织病理学损害，并正在用于治疗多发性硬化症的临床试验。为了评估胞浆内雌激素受体在介导抑制EAE中的作用，我们研究了雌激素受体α(ESR1)和β(ESR2)基因突变的小鼠。我们证明，在B6.129-ESR1(Tm1Unc)小鼠(ESR1-/-)中，E2的保护作用被取消，但在B6.129-Esr2(Tm1Unc)小鼠(Esr2(-/-))中没有。在ESR1(-/-)小鼠中，用脑源性MOG-35-55肽免疫的ESR1(-/-)小鼠失去了EAE的E2介导的保护作用，表现为出现严重的急性临床症状和组织病理损害，即使在中等水平的血清E2水平存在的情况下也是如此。这与C57BL/6野生型(WT)小鼠和ESR2(-/-)小鼠形成对比，在这两种小鼠中，E2治疗导致了相似的血清水平，并显著抑制了EAE的临床症状，并消除了中枢神经系统的炎性病变。这种模式显示ESR1-/-小鼠缺乏对EAE的E2依赖抑制，反映在MOG特异性脾细胞中分泌的肿瘤坏死因子-α、干扰素-γ和白介素6增加而不是减少；在中枢神经系统组织中缺乏炎性细胞因子、趋化因子和趋化因子受体的抑制信息。这些结果表明，E2对EAE的免疫调节作用依赖于ESR1信号，而不是ESR2信号。
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-alpha (Esr1) and -beta (Esr2) genes. We demonstrate that the protective effect of E2 is abrogated in B6.129-Esr1(tm1Unc) mice (Esr1-/-) but not in B6.129-Esr2(tm1Unc) 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-alpha, IFN-gamma, 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.