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。 雌激素可能影响免疫系统的一种机制是调节细胞因子水平。 我们最近报道，雌激素治疗的野生型C57 BL/6小鼠的IFN γ，mRNA和蛋白质水平增加。 这项拨款提案旨在从机制上研究雌激素如何改变IFN γ的产生以及IFN γ增加的分子后果。雌激素诱导的IFN γ是重要的，因为IFN γ是对免疫系统的几乎所有细胞具有生理作用的“主”细胞因子：它参与抵抗细胞内感染，以及参与许多自身免疫和炎性疾病的病理作用。 该建议的假设是，雌激素处理的小鼠中IFN γ的增加是由于促进了特定IFN γ分泌细胞数量的增加，对IFN γ促进细胞因子和/或共刺激信号的应答增强。 这种增加的IFN γ的结果是IFN γ靶细胞的细胞和分子功能改变。 这可能是明显的，因为IFN γ应答基因和分子的表达增加，细胞凋亡模式的改变和对自身免疫敏感性的变化。 本计划的目的（1）将研究雌激素诱导IFN γ的分子基础。 目的（2）确定雌激素处理的小鼠中IFN-γ靶细胞对IFN-γ的反应性是否改变，包括STAT 1活化、IFN-γ反应基因和IRF-1、IRF-2、考克斯-2和MHC分子的表达。 目的（3）利用雌激素处理的野生型、IFN γ基因敲除和iNOS基因敲除小鼠，研究雌激素处理小鼠淋巴细胞存活率的增加是否是由于IFN γ诱导的一氧化氮所致。 目的（4）将阐明雌激素处理的非自身免疫小鼠是否倾向于产生选定类型的诱导性自身免疫，以及这是否是由于IFN γ。 这个建议是新颖的，因为它将提供一个机制为基础的理解雌激素如何促进IFN γ及其后果在分子，细胞和生物体水平。 该提案将有助于未来对人类健康的理解，特别是在基于性别的免疫疾病方面。

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.