Innate Immunity, Liver Injury, Fibrosis, and Repair ? ? Our laboratory is actively studying: 1) the role of innate immune cells (NK/NKT cells) and cytokines [interferon (IFN)/ signal transducer and activator of transcription 1 (STAT1)] in liver injury, fibrosis, and regeneration; 2) the effects of ethanol on innate immunity in the liver. ? Regardless of etiology, all forms of chronic liver injury lead to liver fibrosis accompanied by an excessive accumulation of extracellular matrix proteins, including collagen. Recent evidence suggests that liver fibrosis, and even cirrhosis, can be reversible. While activation of hepatic stellate cells has been known to play a central role in the development and progression of liver fibrosis, the clearance of hepatic stellate cells by apoptosis has been suggested to be a key step involved in reversing liver fibrosis. However, the factors responsible for hepatic stellate cell apoptosis during liver fibrosis remain largely unknown. Our recent findings indicated that NK cells play an important role in inducing hepatic stellate cell apoptosis during liver fibrosis. Using an in vitro culture model, we demonstrated that NK cells kill early-activated hepatic stellate cells, but not quiescent or chronically activated stellate cells. Furthermore, this appeared to be due to the fact that early-activated hepatic stellate cells, but not quiescent or chronically-activated stellate cells, express high levels of the NK cell activating ligand, Raet1, which activates NK cell killing. Raet1 proteins were originally isolated from mouse embryonic carcinoma F9 cells treated with retinoic acid and later identified as the NKG2D ligand to activate NK cells. Currently, we are exploring the molecular mechanisms underlying induction of Raet1 in early-activated stellate cells during liver fibrosis. ? ? Natural killer cells also inhibit liver fibrosis by producing the anti-fibrotic cytokine, (IFN-gamma). However, the downstream signaling pathway responsible for IFN-gamma inhibition of liver fibrosis is not clear. Using genetically modified mice, we demonstrated that STAT1 is a key signal contributing to the anti-fibrotic effects of IFN-gamma in the liver. Moreover, STAT1 is essential for the inhibition of hepatic stellate cell proliferation in vitro by IFN-gamma, and activation of STAT1 stimulates NK cell killing of early-activated stellate cells. ? ? It is well documented that chronic alcohol consumption accelerates liver fibrosis in patients with hepatitis C virus (HCV) infection. Multiple mechanisms have been proposed to explore the underlying mechanisms mediating ethanol!|s effects. Our laboratory has hypothesized that chronic alcohol consumption accelerates liver fibrosis by inhibiting the anti-fibrotic effects of innate immune cells (NK/IFN-gamma). Our recent findings showed that chronic ethanol administration inhibited NK cell activity in the liver and enhanced murine cytomegalovirus-induced hepatitis. Currently, we are exploring the effects of chronic alcohol consumption on the anti-fibrotic effects of NK and IFN-gamma in the liver. ? ? The liver has the unique ability to repair and regenerate after injury or loss of tissue, playing an essential role in recovery from liver disease such as liver fibrosis. Accumulating evidence suggests that liver regeneration is suppressed in patients with HCV infection; however, the underlying mechanisms are poorly understood. Previously, we demonstrated that liver regeneration is suppressed in mice infected with cytomegalovirus or injected with double stranded RNA poly I:C, which mimics viral infection. Furthermore, additional data suggest that activation of NK cells by poly I:C or vial infection inhibited liver regeneration through an IFN-gamma-dependent mechanism. We extended this study to further explore signals downstream of IFN-gamma that may be involved in the inhibition of liver regeneration. Our findings revealed that STAT1 and its downstream gene IRF-1 and p21cip1 are directly involved in IFN-gamma inhibition of liver regeneration. This is of particular interest as it is known that STAT1 protein is highly induced in HCV cirrhotic livers, and that levels of STAT1 protein correlate positively with liver injury, and negatively with hepatocyte proliferation in HCV patients with cirrhosis. ? ? Finally, in collaboration with Dr. Tian, we demonstrated that NK cell activation negatively regulates T cell hepatitis, and that treatment with interleukin (IL)-15 prevents the liver from T cell hepatitis-induced injury . In collaboration with Dr. Deng at NIDDK, we demonstrated that Smad4 and Pten signaling play important roles in the inhibition of cholangiocellular carcinoma in mice
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