Control of immunological tolerance and its breakdown by cytokine

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Interleukin-2 (IL-2), which was identified as T cell growth factor, plays a important role of the expansion and maintenance in immune response. IL-2-deficient-mice developed colonic inflamation closely resemblling ulcerative colitis in human. The inflamatory disease is characterized by high number of activated T and B cells and elevated immunoglobulin secretion, suggesting that the disease results from an abnormal immune response to a normal antigenic stimulus. On the other hand, immunosuppressive agents, which suppress the effects of IL-2, usually improve various autoimmune disorders. Therefore dysfunction or unusual activation in IL-2 signal transduction has influence on immunological tolerance directly. In this context, we have investigated the molecular machinery of the T cell growth and growth suppression by IL-2 to elucidate the basal mechanism of autoimmune disease. 1)we have established the screening system for the molecule(s) that involved in IL-2 signal transduction using the TPA-Mat, IL-2 and TPA dependent T cell line. 2)we found that the apoptosis of MT-1β resulted from AICD. 3) Although there was no significant difference in IL-2 dependent T cell proliferation among Mkk3^<-/->,Mkk6^<-/-> and wild type mice, the T cells from Mkk3^<-/-> mice were more resistant to apoptosis induced by IL-2 withdrawal. 4)The loss of Mkk3 and Mkk6 during embryogenesis was lethal before embryonic day E11.5. Major defects in the formation of the placenta, heart and deficiencies in the development of the embryonic vasculature were observed. Especially, the labyrinth and spongiotrophoblast layers were markedly decreased in the mutant compared with the wild type. TNF-α did not stimulate activation of p38 MAPK. UV radiation caused p38 MAPK activation in the cells from Mkk3^<-/-> and Mkk6^<-/-> mice, although the extent of p38 MAPK activation was diminished compared with wild-type cells.