IMMUNE REGULATION BY THE P38 MAP KINASE PATHWAYS

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In order to analyze the functional significance of the p38 MAP kinase pathways, mkk3 and mkk6 knockout mice were subjected to analysis. To examine the role of the kinases in innate immunity, bone marrow derived macrophages (Mφ) were prepared from mkk3-/-mkk6+/-mice and control mice. When mkk3-/-mkk6+/-derived Mφ were stimulated by LPS, secretion of TNFα as well as IL-12 was severely impaired. Further, inflammatory chemical mediators were also examined. iNOS expression, as judged by the real time RT-PCR, was significantly reduced. These results suggest that p38 MAP kinas pathways play significant roles in innate immunity, polarization of T helper T cells and inflammations. To see if p38 MAP kinase pathways are also involved in cellular apoptosis, a fibloblastoid cell line with mkk3-/-mkk6-/-genotype was generated. This cell line manifested impaired p38 activation upon TNFα stimulation but not by UV exposure, suggesting the possible roles for mkk4 for the residual activation of p38. Apoptosis upon starvation was clearly inhibited in the cells, which corresponded well with the tumorigenic activity of the cell when injected subcutaneously to nude mice. Collectively these results indicated that p38 MAP kinases not only plays role in immune regulation but also in apoptosis and tumor growth. Finally I identified molecules that are phosphorylated by various cytokines with similar kinetics to the p38 MAP kinases, namely STAM1 and Hrs, two molecules involved in vesicular transport. STAM and Hrs forms a tight complex and the degradation of STAM1 was controlled but the presence of Hrs. Since Hrs is expressed in T cells and regulate T cell survival, I concluded that not only p38 but also Hrs and STAMs are involved in immune regulation including T cell survival/apoptosis.