| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Cytokine signaling mediated by STAT pathway is negatively regulated by SOCS proteins. In this project, we have investigated the role of SOCS3/5 that inhibit STAT3/4/6 pathway, in innate immunity during sepsis. Mice with a cell-specific overexpression of SOCS5 in T cells (SOCS5Tg) were resistant to the lethality relative to the wild-type (WT) mice. This was due to the enhanced innate immunity in SOCS5Tg mice whereby CD4+T cells with overexpressed SOCS5 augment type-1 immune response of neutrophils and macrophages. Enhanced type-1 response during sepsis was also seen in mice lacking chemokine receptor 8 (CCR8), suggesting an important role of chemokine signaling in innate immunity. In inflammation, resident macrophages, but not other cell types, play a regulatory role through a Stat3 signaling pathway by mediating the anti-inflammatory role of IL-10. Macrophages lacking STAT3 showed decreased expression of Fcy receptor and compliment receptor 1 (CCR1), which was conversely augmented in macrophages lacking SOCS3. This might be responsible for the augmented phagocytic activities of macrophages lacking STAT3/SOCS3. Mice with a cell-specific deletion of STAT3 in phagocytes augmented Thl and Th2 type acquired immune response, possibly due to enhanced APC activities off the cells. On the other hand, mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg mice) were resistant to sepsis due to decreased type-1 response in tissue, resulting in alleviated organ damage. The SOCS3Tg mice were also deleterious in drug-induced hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes.
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