Regulation of RANKL Expression in T-Lymphocytes

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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.