Transforming growth factor beta (TGFbeta) is prototypic of a family of cytokines with immunoregulatory properties that are critical to the maintenance of normal immunological homeostasis. Targeted disruption of the TGFbeta gene in mice results in a phenotype characterized as a progressive multifocal inflammatory process typical of autoimmune disease with increased circulating autoantibodies and immune complex deposition, increased expression of both classes of MHC antigens, and increased numbers of circulating immature neutrophils and lymphocytes. The inflammatory response in the TGFbeta-knockout is lymphocyte mediated demonstrating the vital role of TGFbeta in regulating lymphocyte proliferation and activation, which contribute to the maintenance of self tolerance. In this proposal we wish to determine the molecular mechanism by which TGFbeta induces apoptosis in immature B cells thus resulting in clonal deletion and maintenance of self tolerance. We hypothesize that there are distinct intracellular domains of either a homo and/or heteromeric TGFbeta receptor complex which mediate apoptosis in the WEHI-231 B lymphocyte cells. We also propose that a distinct and previously unidentified caspase protease(s) is responsible for mediating the apoptotic actions of TGFbeta. It is the goal of this application to determine the type of TGFbeta-receptor complex and the intracellular regions of this complex necessary for TGFbeta-induced apoptosis in WEHI-231 cells. We also propose to isolate and characterize the caspase protease(s) which is activated by TGFbeta in these cells.
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