Bynoté K K, Hackenberg J M, Korach K S, Lubahn D B, Lane P H, Gould K A
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198-5805, USA.
Genes Immun. 2008 Mar;9(2):137-52. doi: 10.1038/sj.gene.6364458. Epub 2008 Jan 17.
Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB x NZW)F(1) background, disruption of estrogen receptor-alpha (ER alpha or Esr1) attenuated glomerulonephritis and increased survival. ER alpha deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ER alpha promotes loss of immunologic tolerance. Furthermore, ER alpha deficiency in (NZB x NZW)F(1) females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ER alpha may promote lupus, at least in part, by inducing interferon-gamma, an estrogen-regulated cytokine that impacts this disease. ER alpha deficiency in (NZB x NZW)F(1) males increased survival and reduced anti-dsDNA antibodies, suggesting that ER alpha also modulates lupus in males. These studies demonstrate that ER alpha, rather than ER beta, plays a major role in regulating autoimmunity in (NZB x NZW)F(1) mice. Furthermore, our results suggest for the first time that ER alpha promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ER alpha, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.
雌激素会在人类以及该疾病的一些小鼠模型中引发狼疮。然而,关于雌激素受体在狼疮发病机制中的作用,人们所知甚少。在此,我们报告称,在具有狼疮易感性的(NZB×NZW)F1背景的雌性小鼠中,雌激素受体α(ERα或Esr1)的缺失减轻了肾小球肾炎并提高了生存率。ERα缺乏还延缓了抗组蛋白/DNA抗体的产生,这表明ERα会促进免疫耐受性的丧失。此外,(NZB×NZW)F1雌性小鼠中ERα的缺乏减弱了随后抗双链DNA(dsDNA)IgG抗体的产生,在该模型中,这些抗体与肾小球肾炎相关。我们提供的证据表明,ERα可能至少部分地通过诱导干扰素-γ来促进狼疮,干扰素-γ是一种受雌激素调节的细胞因子,对这种疾病有影响。(NZB×NZW)F1雄性小鼠中ERα的缺乏提高了生存率并减少了抗dsDNA抗体,这表明ERα也会调节雄性小鼠的狼疮。这些研究表明,在调节(NZB×NZW)F1小鼠的自身免疫方面,起主要作用的是ERα,而非ERβ。此外,我们的结果首次表明,ERα至少部分地通过影响最初的耐受性丧失来促进狼疮。这些数据表明,针对ERα的靶向治疗,很可能是在免疫系统内进行,可能对狼疮的预防和/或治疗有效。