Innate immunity and cytokines in liver injury, fibrosis, and repair The liver is an organ with strong innate immunity, which plays an important role in host defense against microbial infection and tumor transformation. Emerging evidence suggests that innate immunity as well as a variety of cytokines produced by innate immune cells also contribute to the pathogenesis of acute and chronic liver diseases. Our laboratory has been actively studying the role of innate immunity and its associated cytokines in liver injury and repair. During the fiscal year, we have demonstrated that invariant natural killer T (iNKT) cells play divergent roles in liver fibrosis and that myeloid cell STAT3 inhibits T cell hepatitis by regulating Th1 cytokine and interleukin-17. Divergent roles of invariant natural killer T (NKT) cells in liver fibrosis Liver fibrosis is a common scarring response to all forms of chronic liver injury and is always associated with inflammation that contributes to fibrogenesis. Although a variety of cell populations infiltrate the liver during inflammation, it is generically clear that CD8 T lymphocytes promote while natural killer (NK) cells inhibit liver fibrosis. However, the role of invariant natural killer T (iNKT) cells, which are abundant in the liver, in hepatic fibrogenesis, remains obscure. Recently we have demonstrated that iNKT-deficient mice are more susceptible to carbon tetrachloride (CCl(4))-induced acute liver injury and inflammation. The protective effect of naturally activated iNKT in this model is likely mediated via suppression of the proinflammatory effect of activated hepatic stellate cells. Interestingly, strong activation of iNKT through injection of iNKT activator alpha-galactosylceramide (alpha-GalCer) accelerates CCl(4)-induced acute liver injury and fibrosis. In contrast, chronic CCl(4) administration induces a similar degree of liver injury in iNKT-deficient and wild-type mice, and only a slightly higher grade of liver fibrosis in iNKT-deficient mice than wild-type mice 2 weeks but not 4 weeks after CCl(4) injection, although iNKT cells are able to kill activated stellate cells. An insignificant role of iNKT in chronic liver injury and fibrosis may be attributable to hepatic iNKT cell depletion. Finally, chronic alpha-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after alpha-GalCer injection. Conclusion: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by alpha-GalCer accelerates CCl(4)-induced acute liver injury, inflammation, and fibrosis. During chronic liver injury, hepatic iNKT cells are depleted and play a role in inhibiting liver fibrosis in the early stage but not the late stage of fibrosis. Myeloid STAT3 inhibits T cell-mediated hepatitis by regulating Th1 cytokine and interleukin-17 T-cell-mediated hepatitis is a leading cause of acute liver failure;there is no effective treatment and the mechanisms underlying its pathogenesis are obscure.
The aim of this study was to investigate the immune-cell signaling pathways involved-specifically the role of signal transducer and activator of transcription 3 (STAT3)- in T-cell-mediated hepatitis in mice. T-cell-mediated hepatitis was induced in mice by injection of concanavalin A (Con A). Mice with myeloid cell-specific and T-cell-specific deletion of STAT3 were generated. We demonstrated that STAT3 was activated in myeloid and T cells following Con A injection. Deletion of STAT3 specifically from myeloid cells exacerbated T-cell hepatitis and induced STAT1-dependent production of a Th1 cytokine (IFN-gamma), and to a lesser extent of Th17 cytokines (IL-17 and IL-22), in a STAT1-independent manner. In contrast, deletion of STAT3 in T cells reduced T-cell mediated hepatitis and IL-17 production. Furthermore, deletion of IFN-gamma completely abolished Con A-induced T-cell hepatitis whereas deletion of IL-17 slightly but significantly reduced such injury. In vitro experiments indicated that IL-17 promoted liver inflammation but inhibited hepatocyte apoptosis. In conclusion: Myeloid STAT3 activation inhibits T-cell-mediated hepatitis via suppression of a Th1 cytokine (IFN-gamma) in a STAT1-dependent manner whereas STAT3 activation in T cells promotes T-cell hepatitis to a lesser extent, via induction of IL-17. Therefore, activation of STAT3 in myeloid cells could be a novel therapeutic strategy for patients with T-cell hepatitis.
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