Regulation of the MAP kinase pathway in the CD4+ T cells

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Previous studies have demonstrated that the p38 and JNK MAP kinase pathways are prominently activated by TCR stimulation in Th1 cells but not in Th2 cells. These data suggest that the p38/JNK MAP kinase pathways are regulated in helper T cells depending on the cell context. Preliminary data show that GADD45gamma and GADD45beta are highly expressed in Thl cells versus Th2 cells. Since GADD45 family proteins were shown to activate both JNK and p38 when over-expressed in COS-7 cells, they hypothesize that these molecules are responsible for the elevated p38 and JNK activities in Th1 cells and likely critical for the function of Th1 cells. Consistent with the hypothesis, in Th1 cells, deletion of GADD45gamma significantly elevated the threshold of TCR stimulated activation of p38 and JNKs. In addition, GADD45gamma also mediates Th1 functions such as IFN-gamma production and delayed type hypersensitivity. In addition to their roles in the function of Th1 cells, they discovered that GADD45beta is induced by TNF-alpha in synoviocytes. Therefore, they hypothesize that GADD45 family molecules may regulate the activation of the p38/JNK MAP kinase pathways in synoviocytes by inflammatory cytokines. Since the p38/JNK MAP kinase pathways are involved in the pathogenesis of rheumatoid arthritis, they hypothesize that GADD45 family proteins are involved in the development of such disease. To further study the role of GADD45 pathway in mediating the activation of p38/JNK MAP kinases and its relevance to rheumatoid arthritis, they propose to: Aim 1. Study the role of GADD45 pathway in mediating TCR stimulation using genetic and bioinformatic approaches. Aim 2. Study the role of GADD45 protein in mediating the activation of the p38/JNK MAP kinase pathway by cytokines. Aim 3. Study the effect of mutation of GADD45gamma, GADD45beta, or MEKK4 in murine collagen induced arthritis.