Molecular Consequences of Estrogen-Induced Interferony

超出所提供的空间。 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。我们最近报道了雌激素处理的野生型C57 BL/6小鼠具有增加的IFN γ mRNA和蛋白质水平。该资助提案旨在机械地研究雌激素如何改变IFNy的产生以及增加的IFNy的分子后果。雌激素诱导的IFNy是显著的，因为IFNy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，增强了对IFN γ促进细胞因子和/或共刺激信号的应答。这种增加的IFN γ的结果将改变IFN γ靶细胞的细胞和分子功能。这可能是明显的，因为IFN γ应答基因和分子的表达增加，细胞凋亡模式改变和对自身免疫的易感性改变。将研究雌激素诱导的IFN γ的分子基础。将确定在雌激素处理的小鼠中IFN γ-靶细胞对IFN γ的反应性是否在STAT 1活化、IFN γ-反应基因和IRF-1、IRF-2、考克斯-2和MHC分子的表达方面改变。_将通过使用雌激素处理的野生型、IFN γ敲除和iNOS敲除小鼠来研究来自雌激素处理的小鼠的淋巴细胞存活增加是否是由于IFN γ诱导的一氧化氮。1将解决雌激素治疗的非自身免疫小鼠是否容易发展选择类型的诱导性自身免疫，以及这是否是由于IFN γ。该提议是新颖的，因为它将提供对雌激素如何促进IFN γ及其在分子、细胞和生物体水平上的后果的基于机制的理解。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。网站（==

EXCEEDTHE SPACE PROVIDED. 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. PERFORMANCESITE( ========================================Section End===========================================