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, retinoic acid early inducible gene 1 (RAE1), which activates NK cell killing. RAE1 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 (see Radaeva et al., 2006). Currently, we are exploring the roles of NKT cells in chronic liver injury and liver fibrosis. Our preliminary findings show that NKT cells play a diverse role in acute liver injury, but are depleted in chronic liver injury induced by carbon tetrachloride, suggesting that NKT cells may play a role in inhibiting the early stage of liver fibrosis but not the late stage of disease. ? ? 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 explain the underlying mechanisms mediating ethanols effects. Our laboratory has demonstrated that chronic alcohol consumption attenuates the anti-fibrotic effects of innate immune cells (NK/IFN-), which could be an important mechanism contributing to alcohol acceleration of liver fibrosis in patients with chronic HCV infection (see Jeong et al., 2008).
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