The regulation of Dendritic Cell function by Cytokine signal

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The cytokine signals are regulated strictly by "Suppressor of Cytokine Signaling (SOCS)" family proteins. The aim of study is to clarify how cytokine signals modulated by SOCS control the development and function of regulatory dendritic cells (DC) as well as Treg cells, which serves immune tolerance^ (1) and prevent chronic inflammation in the gut to maintain the gut homeostasis in vivd^ (2).(1) Deletion of SOCS3, a suppressor of STAT3-related cytokine signal, in T cells resulted in augmented TGFβ production leading to preferential differentiation into regulatory Th3 cells. Moreover, DC lacking SOCS3 showed immature phenotype and elevated levels of TGFβ, that selectively expanded Th3 cells from naive T cells. In addition, constitutive activation of STAT3, a target signal molecule of SOCS3, in DC inhibited DC maturation. Importantly, injection of antigen-pulsed SOCS3-deficient DC in EAE model mice could ameliorate the development of autoimmune disease.(2) Spontaneous development of Th2-mediated chronic colitis in TCRa KO mice was deteriorated in the absence of SOCS1, a suppressor of STAT1/6-related cytokine signal. The deterioration of colitis was due to enhanced signal of not only Th2-type cytokine, IL-4 but also Th1-type cytokine, IFNγ, and LPS, suggesting that SOCS1 suppresses IBD by blocking both Thl and Th2 cytokine signals. Furthermore, mice lacking SOCS1 except for T and B cells showed IFN γ-dependent, severe colitis and spontaneous development of colorectal carcinomas accompanied with infiltration of inflammatory cells and upregulation of carcinogenesis-related enzymes such as iNOS and COX2. These results strongly suggest that SOCS1 is a unique antioncogene that prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNγ/STAT1 pathway.