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主要作用。 能力和自身免疫。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， 增加IFN γ mRNA和蛋白质水平。这项拨款提案旨在机械地研究如何 雌激素改变IFNy的产生和IFNz增加的分子后果 IFN γ是重要的，因为IFN γ是对几乎所有的细胞都具有生理作用的“主”细胞因子。 免疫系统：它参与抵抗细胞内感染，并在病理作用， 许多自身免疫性和炎症性疾病。这一提议的假设是， 雌激素处理的小鼠的免疫应答是由于促进了特异性IFN γ分泌细胞数量的增加， 增强对干扰素的反应？- 促进细胞因子和/或共刺激信号。其结果 增加IFN γ将改变IFN的细胞和分子功能？靶细胞这可能是 明显表现为IFN γ应答基因和分子表达增加，细胞凋亡模式改变， 和自身免疫易感性的变化。本提案的第一部分将审查以下方面的分子基础： 雌激素诱导的IFN γ。_将确定IFN γ-靶细胞对IFN γ的反应性是否改变 在雌激素处理的小鼠中，关于STAT 1活化、IFN γ应答基因和IRF-1表达， IRF-2、考克斯-2和MHC分子。_将研究是否增加淋巴细胞的存活率， 雌激素处理的小鼠是由于IFN γ诱导的一氧化氮，通过使用雌激素处理的野生型IFN γ 敲除小鼠和iNOS敲除小鼠。_1将解决雌激素治疗的非自身免疫小鼠是否 倾向于发展选定类型的诱导自身免疫，以及这是否是由于IFN γ。这项建议是 新的，因为它将提供一个机制为基础的了解如何雌激素促进IFN γ和其 在分子、细胞和有机体水平上的后果。该建议将有利于未来的理解 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.