Molecular Consequences of Estrogen-Induced Interferony

描述（由申请人提供）：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起主要作用。雌激素影响免疫系统的一种机制是通过调节细胞因子水平。我们最近报道了经雌激素处理的野生型C57BL/6小鼠IFNgamma、mRNA和蛋白水平升高。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IFNgamma增加的分子后果。雌激素诱导的ifnγ是重要的，因为ifnγ是一种“主”细胞因子，对免疫系统的几乎所有细胞都有生理作用：它参与抵抗细胞内感染，以及许多自身免疫性和炎症性疾病的病理作用。该提议的假设是，雌激素处理小鼠中IFNgamma的增加是由于促进特定IFNgamma分泌细胞数量的增加，对IFNgamma促进细胞因子和/或共刺激信号的反应增强。IFNgamma增加的结果将改变IFNgamma靶细胞的细胞和分子功能。这可能表现为IFNgamma应答基因和分子的表达增加，细胞凋亡模式改变以及自身免疫易感性的变化。本提案的AIM(1)将研究雌激素诱导的IFNgamma的分子基础。AIM(2)将确定雌激素处理小鼠中IFNgamma靶细胞对IFNgamma的反应性是否发生改变，包括STAT1激活、IFNgamma应答基因以及IRF-1、IRF-2、Cox-2和MHC分子的表达。AIM(3)将通过使用雌激素处理的野生型、IFNgamma敲除小鼠和iNOS敲除小鼠，研究雌激素处理小鼠淋巴细胞存活率的增加是否归因于IFNgamma诱导的一氧化氮。AIM(4)将探讨雌激素治疗的非自身免疫小鼠是否容易产生特定类型的诱导自身免疫，以及这是否与IFNgamma有关。这一建议是新颖的，因为它将提供基于机制的理解雌激素如何促进IFNgamma及其在分子，细胞和有机体水平上的后果。这项建议将有助于今后对人类健康的了解，特别是对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.