Molecular Consequences of Estrogen-Induced Interferony

性激素，如雌激素，被认为在基于性别的差异免疫中起着重要作用。 能力和自身免疫力。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。我们最近报道了雌激素治疗的野生型C57BL/6小鼠有 增加IFNy的mRNA和蛋白水平。这项拨款提案旨在机械地研究如何 雌激素改变LFNY的产生以及雌激素诱导的IFNz增加的分子后果 由于干扰素是一种“主控”细胞因子，对几乎所有细胞都有生理作用，因此干扰素/干扰素意义重大。 免疫系统：它参与抵抗细胞内感染，并参与 许多自身免疫性和炎症性疾病。这项提议的假设是，增加的IFNy在 雌激素治疗的小鼠是由于促进了特异性IFNy分泌细胞的增加，以及 增强对干扰素？促进细胞因子和/或促性腺激素刺激信号的反应。这是一个后果 干扰素的细胞和分子功能是否会发生改变？目标单元格。这可能是 明显表现为IFNy反应基因和分子表达增加，细胞凋亡模式改变 以及自身免疫易感性的变化。_这项提议的分子基础将研究 雌激素诱导的IFNY。_将确定IFNy-目标细胞对IFNy的反应性是否改变 在雌激素处理的小鼠中，关于STAT1的激活、IFNY反应基因和IRF-1的表达， IRF-2、COX-2和MHC分子。_将调查淋巴球存活率增加是否来自 雌激素处理的小鼠是由于IFNy诱导的一氧化氮，通过使用雌激素处理的野生型IFNy 基因敲除和iNOS基因敲除小鼠。_1将讨论雌激素治疗的非自身免疫小鼠是否 倾向于发生特定类型的诱导性自身免疫性疾病，以及这是否由IFNY引起。这项建议是 因为它将提供一种基于机制的理解，即雌激素如何促进IFNY及其 在分子、细胞和生物层面上的后果。这项建议将有利于今后的理解 在人类健康方面，特别是在基于性别的免疫疾病方面。

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 IFNy mRNA and protein levels. This grant proposal is aimed at mechanistically studying how estrogen alters the production of lFNy and the molecular consequences of increased IFNz Estrogen-induced IFN'/is significant, since IFNy is a "master" cytokine with physiological effects on nearly all ceils 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 IFNy in estrogen-treated mice is due to the promotion of increased numbers of specific IFNy secreting cells, an enhanced response to IFN? -promoting cytokines and/or eo-stimulatory signals. A consequence of this increased IFNy will be altered cellular and molecular functions of IFN? target cells. This may be evident as increased expression of IFNy responsive genes and molecules, altered patterns of apoptosis and changes in susceptibility to autoimmunity. _ of this proposal will examine the molecular basis for estrogen-induced IFNy. _ will determine whether responsiveness of IFNy-target ceils to IFNy is altered in estrogen-treated mice, with regard to STAT1 activation, IFNy-responsive genes, and expression of IRF-1, IRF-2, Cox-2, and MHC molecules. _ will investigate whether increased survival oflymphocvtes from estrogen-treated mice is due to IFNy inducible nitric oxide, by using estrogen-treated wild type, IFNy knockout, and iNOS knockout mice. _1 will address whether estrogen treated non-autoimmune mice are prone to develop selected types ofinduced-autoimmuni_ and whether this is due to IFNy. This proposal is novel since it will provide a mechanistic-based understanding of how estrogen promotes IFNy 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.