IRF-1 AND PROLACTIN IN T-CELL ACTIVATION

肽激素催乳素（Prl）对两者都有深远的影响。 细胞增殖和分化的各种组织，但其 作为免疫调节剂的作用最近才受到关注。 其 潜在的重要性得到以下观察结果的支持，即Prl受体 属于新近鉴定的细胞因子受体超家族。 为模特 用于研究Prl如何调节T细胞增殖反应的系统 淋巴细胞，我们使用的是需要Prl 促进增长。 我们从Nb 2 T细胞中分离了一个cDNA， 通过Prl的戏剧性诱导，并发现该cDNA编码 转录因子干扰素调节因子-1（IRF-1），以前 显示在调节干扰素（IFN）基因表达中是重要的， 成纤维细胞 我们进一步证明了IRF-1是由T细胞诱导的， 小鼠脾细胞和胸腺细胞中的丝裂原Con A。 我们的研究表明 IRF-1可能是一个与生长相关的主开关基因， 在T细胞活化和增殖中起重要调节作用。 非常 关于是什么调节T细胞中的IRF-1基因表达， IRF-1转录因子反过来调节，以及IRF-1如何促进 催乳素刺激的细胞增殖。 本提案的主要目的是 目的是阐明IRF-1在Prl介导的T细胞活化中的作用， 有丝分裂原 本研究拟从以下几个方面进行研究：1）分析该基因的启动子区， IRF-1基因，以鉴定介导Prl刺激的调控序列，和 为了表征与Prl反应性蛋白相互作用的核蛋白， 分析IRF-1蛋白的生化特性， 强调翻译后修饰（磷酸化）作为另一个 Prl的调节水平; 3）研究IRF-1的功能作用 在T细胞活化和增殖中，通过改变IRF-1水平， 检测其对细胞生长的影响。 这些研究表明， 全面的分子和免疫学方法来定义 IRF-1的结构和功能关系，并阐明了IRF-1的 Prl的免疫调节特性。 了解Prl如何调节T 通过IRF-1调节淋巴细胞功能和增殖 激活T细胞，将提供新的见解，复杂的 神经内分泌和免疫系统之间的调节回路。

The peptide hormone prolactin (Prl) exerts a profound effect on both cellular proliferation and differentiation in a variety of tissues, but its role as a immunomodulator has only recently received attention. Its potential importance is supported by the observation that the Prl receptor belongs to the newly identified cytokine receptor superfamily. As a model system for studying how Prl modulates the proliferative response of T lymphocytes, we are using the rat Nb2 T lymphoma cells which require Prl for growth. We isolated a cDNA from Nb2 T cells which showed rapid and dramatic induction by Prl, and found that this cDNA encoded the transcription factor interferon regulatory factor-1 (IRF-1), previously shown to be important in regulating interferon (IFN) gene expression in fibroblasts. We further demonstrated that IRF-1 is induced by the T cell mitogen Con A in murine splenocytes and thymocytes. Our studies suggest that IRF-1 may be a growth-related master switch gene which plays an important regulatory role in T cell activation and proliferation. Very little is known about what regulates IRF-1 gene expression in T cells, what the IRF-1 transcription factor regulates in turn, and how IRF-1 promotes Prl-stimulated cell proliferation. The primary objective of this proposal is to elucidate the role of IRF-1 in T cell activation mediated by Prl and mitogens. Studies are proposed to: 1) analyze the promoter region of the IRF-1 gene, to identify regulatory sequences mediating Prl stimulation, and to characterize the nuclear proteins interacting with the Prl responsive DNA elements; 2) analyze the biochemical properties of IRF-1 protein, with emphasis on posttranslational modification (phosphorylation) as another level of regulation by Prl; and 3) investigate the functional role of IRF-1 in T cell activation and proliferation, by altering IRF-1 levels and examining its effect on cell growth. These studies represent a comprehensive molecular and immunological approach to defining the structure and function relationship of IRF-1 and elucidating the immunoregulatory properties of Prl. Understanding how Prl regulates T lymphocyte function and proliferation through regulation of IRF-1 activation in T cells, will provide new insights into the intricate regulatory circuits between the neuroendocrine and immune systems.