Regulation of RANKL Expression in T-Lymphocytes

免疫系统细胞的细胞因子表达在免疫应答的调控中起着至关重要的作用。许多细胞因子对外界刺激的表达受转录和转录后事件的调节。调控许多细胞因子、原癌基因和生长因子mRNA表达水平的主要转录后机制是通过控制mRNA的稳定性。mrna的快速周转部分是由3'非翻译区的富A + u元素决定的。本提案的总体目标是了解调节炎症过程的细胞因子表达的调节机制，如促炎干扰素和抗炎IL-10。这些细胞因子具有相反的作用并相互对抗。S的生产和功能。我们的初步数据表明，与正常细胞的稳定性相比，黑色素瘤细胞中IL-10水平的升高是由于IL-10 mRNA的稳定性增加。对编码IL- 10、IL- 10受体和干扰素的mrna的分析发现，在它们的3'-非翻译区存在富A + U元素。总的假设是，mRNA转换的调节起着重要的作用

Cytokine expression by cells of the immune system plays a crucial role in the regulation of immune responses. Expression of many cytokines in response to external stimuli is regulated by transcription as well as post-transcriptional events. A major post-transcriptional mechanism for regulating the level of expression of many cytokines, protooncogene and growth factor mRNAs is through the control of mRNA stability. The rapid turnover of mRNAs is determined in part by A + U-rich elements in the 3' untranslated region. The overall goal of this proposal is to understand the mechanisms of regulation of expression of cytokines that regulate inflammatory processes such as proinflammatory interferons and anti-inflammatory IL-10. These cytokines have opposing effects and antagonize each other?s production and functions. Our preliminary data indicate that elevated levels of IL-10 in melanoma cells are due to increased stability of the IL-10 mRNA compared to the stability in normal cells. Analysis of mRNAs encoding IL- 10, IL- 10 receptors and interferon has revealed the existence of A + U rich elements in their 3'- untranslated regions. The overall hypothesis that the regulation of mRNA turnover plays a critical role in modulation of the expression of IL-10, IL 10 receptors and IFNs will be tested. Specific aims of this study are: to determine how the expression of IL-10 and IL-10 receptors are regulated in response to external stimuli in immune cells; to determine how IFNs modulate the expression of IL-10 and IL-10 receptors and underlying mechanisms; to determine how the expression of IFNs are modulated in response to external stimuli. IFNs have many therapeutic applications in viral, neoplastic and autoimmune diseases; IL-10 is in clinical trial to treat a number of autoimmune diseases. Determining the mechanisms by which the expression of these cytokines is regulated will be useful in both understanding the complexity of the immune system and the interrelationships of these important cytokines. Furthermore, understanding the role of mRNA turnover in regulation of the immune system will provide an opportunity to develop new therapeutics to control these processes and treat a variety of diseases such as rheumatoid arthritis and other immune disorders.