Hepatic fibrosis is a reaction to chronic hepatic injury induced by a variety of stimuli including viral hepatitis, alcohol, autoimmune and metabolic disease . Fibrogenesis is usually preceded by hepatocyte injury and an inflammatory envi ronment. Although there is an abundance of data demonstrating that LPS is elevated in patients with cirrhosis [43-45] and a key player in liver injury and inflammation, there are only a few studies addressing the role of LPS signaling in liver fibrosis. Studies from the middle of the last century have suggested a role for bacteria in the development of fibrosis induced by CCl4 or choline-deficient diet [17, 18]. Furthermore, it has been shown that TLR4 is expressed on two key mediators of hepatic fibrogenesis, Kupffer cells and hepatic stellate cells. Kupffer cells initiate fibrogenesis by secreting proinflammatory and profibrogenic cytokines which act on other cells types including the hepatic stellate cell (as outlined in Fig. 3). The role of LPS and TLR4 in the early stage of alcoholic liver disease has been clearly demonstrated in the TLR4-mutated C3H/HeJ strain, but fibrogenesis has not yet been studied in this mouse model . Activated hepatic stellate cells are the main source of collagen in the fibrotic liver and are highly responsive to LPS through a TLR4-dependent pathway [33, 34]. In hepatic stellate cells, LPS induces IL-8 and MCP-1 production and activates transcription factor NF-kB and c-Jun through TLR4 indicating that LPS exerts direct effects on hepatic stellate cells during fibrogenesis . The central question whether LPS and TLRs are involved in the activation process of hepatic stellate cells has not been studied yet and is required to understand the role of TLR signaling in hepatic fibrogenesis. Another interesting question is whether hepatic stellate cells express TLR2 and may thus be stimulated during Hepatitis C virus (HCV) infection by the TLR2 ligands HCV core and NS3 [46, 47].
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