Cytokines mediate virtually every facet of immunity including lymphoid development, homeostasis, differentiation, tolerance and memory. Interleukin (IL)-12 production during infection determines the type and duration of adaptive immune response through the induction of the pro-inflammatory cytokine, interferon(IFN)-gamma. Defects in signaling via IL-12/IFN-gamma are associated with susceptibility to infections. Of equal concern is that dysregulation of IL-12/IFN-gamma is associated with the development of autoimmunity. Therefore, a comprehensive understanding of the IL-12 signaling pathway is crucial for the development of novel treatment strategies. Currently, our knowledge of IL-12 signaling intermediates is quite incomplete. In an attempt to gain insight into the molecular basis of IL-12's action we identified the serinethreonine kinase, Tpl2, as an IL-12-inducible gene. Because of its function as a kinase, we hypothesize that Tpl2 is a critical intermediate in IL-12 signaling per se that is required for IFN-gamma production, resistance to infection, and, in pathologic settings, the development of autoimmune disease. In order to broaden our understanding of the molecular biology of Tpl2 as it relates to IL-12-mediated IFN-gamma production we propose (1) to define the biochemical pathway that links Tpl2 to IL-12 signaling and (2) to characterize the role of Tpl2 in IFN-gamma production by T and NK cells and its contribution to host defense and the development of autoimmunity. Preliminary data confirm that Tpl2 is regulated by IL-12 in both T and NK cells and is required for the production of IFN-gamma by T cells. We will use standard biochemical techniques including immunoblotting and kinase assay to dissect the signaling role of Tpl2. We will further test our hypotheses by observing the immune responses of Tpl2-deficient mice in murine models of infectious disease and autoimmunity. Due to its causative role in autoimmunity, blockade of IL-12 signaling would be an attractive means for intervention. Because kinases have been implicated in the development of inflammatory diseases, the modulation of kinase activity has become an active area of research in new drug design. If the proposed work demonstrates that Tpl2 is critical in the development of autoimmune disease through the regulation of IL-12-induced production of IFN-gamma, then it will provide a rationale for the development of a Tpl2 selective kinase inhibitor for use in the treatment of human autoimmune diseases.
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