The Role of p38 MAP Kinase in IL-6 Gene Regulation

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DESCRIPTION (provided by applicant): Chronic production of cytokines mediates inflammatory diseases. Proinflammatory cytokine production in periodontal disease, as well as other chronic inflammatory bone diseases, results in a net bone loss that ultimately negatively affects host function. A complex cytokine network controlled by many cell types, dictates cellular response in bone resorption. Proinflammatory cytokines, such as interleukin (IL)-6, regulate bone resorption through interaction with downstream cytokines. Intracellular signaling pathways regulate IL-6 through a variety of potential mechanisms. This current proposal will focus on the role of p38 mitogen activated kinase (MAP) and how this kinase regulates IL-6 mRNA in osteoblasts, p38 has been shown to play a significant role in regulation of mRNA stability of several inflammatory mediators including IL-6, IL-8, and COX-2. Post-transcriptional control of mRNA stability has been implicated as a potential role of p38 MAP kinase. The molecular mechanisms that underlie p38 regulation are poorly understood, but increasing evident from other studies suggests that cis elements of the 3' untranslated region (UTR) may play a major role. Preliminary data obtained for this proposal indicates that a specific p38 MAP kinase inhibitor, SB203580, can inhibit IL-l-induced expression of IL-6 in a dose dependent manner. The mechanism has been shown to depend upon de novo protein synthesis and occurs at the post-transcriptional level where IL-6 mRNA stability in dramatic decreased in the presence of SB203580. Thus, this proposal will focus establishing the role of p38 MAP kinase in controlling IL-6 regulation. The proposed studies may be important because they could lead towards the development of novel pharmacological agents that regulate IL-6 expression at the post-transcriptional level. The specific aims of the proposal are the following: 1) To establish that p38 MAP kinase is a key regulator of IL-l-induced IL-6 production in osteoblastic cells through construction of dominate negative mutants of p38 MAP kinase and correlating p38 MAP kinase activity with IL-6 mRNA expression and stability, and 2) To determine the cis elements of IL-6 3' untranslated region (UTR) that mediate p38 MAP kinase-induced IL-6 mRNA stability. These studies will provide insight into how specific sequence elements of IL-6 are modulated by p38 MAP kinase and control mRNA decay rates.