Molecular Consequences of Estrogen-Induced Interferon

描述(申请人提供)：性激素，如雌激素，被认为在基于性别的差异免疫能力和自身免疫中发挥重要作用。雌激素影响免疫系统的一个机制是调节细胞因子水平。我们最近报道了雌激素治疗的野生型C57BL/6小鼠增加了IFNGamma、mRNA和蛋白质的水平。这项拨款提案旨在从机制上研究雌激素如何改变lFNGamma的产生，以及增加IFNGamma的分子后果。雌激素诱导的干扰素非常重要，因为干扰素是一种主要的细胞因子，对几乎所有免疫系统的细胞都有生理作用：它参与抵抗细胞内感染，并参与许多自身免疫和炎症性疾病的病理效应。这一建议的假设是，雌激素处理的小鼠体内IFNGamma的增加是由于促进了特定的IFNGamma分泌细胞的数量增加，对促进IFNGamma的细胞因子和/或共刺激信号的反应增强。这种增加的结果将改变IFNGamma靶细胞的细胞和分子功能。这可能很明显地表现为IFNGamma反应基因和分子的表达增加，细胞凋亡模式改变和自身免疫易感性的改变。本提案的目的(1)将研究雌激素诱导的干扰素-γ的分子基础。目的(2)将确定在雌激素处理的小鼠中，在STAT1激活、IFNGamma反应基因以及IRF-1、IRF-2、COX-2和MHC分子的表达方面，IFNGamma靶细胞对IFNGamma的反应性是否发生改变。目的(3)利用雌激素处理的野生型、IFNGamma基因敲除小鼠和iNOS基因敲除小鼠，研究雌激素治疗小鼠淋巴细胞存活率的增加是否与诱导型一氧化氮有关。目的(4)将讨论雌激素治疗的非自身免疫小鼠是否容易发展为特定类型的诱导性自身免疫，以及这是否与IFNGamma有关。这一建议是新颖的，因为它将提供一个基于机制的理解，即雌激素如何促进IFNGamma及其在分子、细胞和生物水平上的后果。这项提议将有助于今后对人类健康的了解，特别是关于基于性别的免疫疾病的了解。

DESCRIPTION (provided by applicant): Sex hormones, such as estrogens, are believed to play a major role in gender-based differential immune competence and autoimmunity. One mechanism by which estrogens may influence the immune system is by regulating cytokine levels. We have recently reported that estrogen-treated wild type C57BL/6 mice have increased IFNgamma, mRNA and protein levels. This grant proposal is aimed at mechanistically studying how estrogen alters the production of lFNgamma and the molecular consequences of increased IFNgamma. Estrogen-induced IFNgamma is significant, since IFNgamma is a "master" cytokine with physiological effects on nearly all cells of the immune system: it is involved in resistance against intracellular infections, and in pathological effects of many autoimmune and inflammatory diseases. The hypothesis of this proposal is that increased IFNgamma in estrogen-treated mice is due to the promotion of increased numbers of specific IFNgamma secreting cells, an enhanced response to IFNgamma-promoting cytokines and/or co-stimulatory signals. A consequence of this increased IFNgamma will be altered cellular and molecular functions of IFNgamma target cells. This may be evident as increased expression of IFNgamma responsive genes and molecules, altered patterns of apoptosis and changes in susceptibility to autoimmunity. AIM (1) of this proposal will examine the molecular basis for estrogen-induced IFNgamma. AIM (2) will determine whether responsiveness of IFNgamma-target cells to IFNgamma is altered in estrogen-treated mice, with regard to STAT1 activation, IFNgamma-responsive genes, and expression of IRF-1, IRF-2, Cox-2, and MHC molecules. AIM (3) will investigate whether increased survival of lymphocytes from estrogen-treated mice is due to IFNgamma inducible nitric oxide, by using estrogen-treated wild type, IFNgamma knockout, and iNOS knockout mice. AIM (4) will address whether estrogen treated non-autoimmune mice are prone to develop selected types of induced-autoimmunity, and whether this is due to IFNgamma. This proposal is novel since it will provide a mechanistic-based understanding of how estrogen promotes IFNgamma and its consequences at molecular, cellular, and organismal levels. The proposal will benefit the future understanding of human health, especially with regard to gender-based immune diseases.