Liver fibrosis is a progressive pathologic process that involves deposition of excess extracellular matrix leading to distorted architecture and culminating in cirrhosis. The role of transforming growth factor-␤ (TGF-␤) as a key molecule in the development and progression of hepatic fibrosis via the activation of hepatic stellate cells, among other fibroblast populations, is without controversy. We hereby show that TGF-␤1 induces an epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro. EMT state was marked by significant upregulation of ␣ 1 (I) collagen mRNA expression and type I collagen deposition. Similar changes were found in a "normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes are capable of EMT changes and type I collagen synthesis. We also show that in hepatocytes in the EMT state, TGF-␤1 induces the snail-1 transcription factor and activates the Smad2/3 pathway. Evidence for a central role of the TGF-␤1/Smad pathway is further supported by the inhibition of EMT by Smad4 silencing using small interference RNA technology. In conclusion, TGF-␤1, a known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating phenotypic changes and plasticity in the form of EMT, resulting in collagen deposition. Our findings support a potentially crucial role for EMT in the development and progression of hepatic fibrogenesis.Liver fibrosis results from increased deposition of type I collagen within the hepatic extracellular space and constitutes a common cardinal signature to all forms of liver injury, regardless of etiology (1). End-stage liver fibrosis is recognized clinically as cirrhosis. Since their initial description, hepatic stellate cells (HSC) 3 have dominated the field of liver fibrogenesis (2-4). Indeed, their role is central in hepatic fibrosis (5). Unfortunately, despite several discoveries pertaining to HSC activation and mechanisms of collagen deposition, no substantial anti-fibrotic therapies have been developed in order to halt the progression to cirrhosis and or reverse established fibrosis. Although resident tissue fibroblasts are traditionally considered as the principal source of fibrosis, there has been increasing interest in the ability of epithelial cells to assume not only a mesenchymal phenotype (known as epithelial-to-mesenchymal transition (EMT)) but also to undertake mesenchymal function(s), i.e. contribute to fibrosis formation. Indeed, EMT has been established as a major mechanism for the deposition of extracellular matrix in renal and pulmonary fibrosis injury models (6 -8).Several lines of evidence support an important role for TGF-␤1 signaling in the initiation and progression of liver fibrosis (9). In mature (i.e. adult) hepatocytes, TGF-␤1 is responsible for inhibition of cell proliferation and induction of apoptosis (10 -12). Interestingly, TGF-␤1 is the most established mediator and regulator of EMT (13). It has been shown that TGF-␤1 mediates EMT by inducing snail-1 transcription factor and tyrosine phosphorylation o...

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Hepatitis C virus (HCV) induces chronic liver disease in hosts which can eventually progresses to liver cirrhosis and hepatocellular carcinoma. However, progression of liver disease is slower in patients with persistently normal levels of alanine aminotransferase (ALT) than in those with active hepatitis. Although distinct immune responses against HCV have been proposed in asymptomatic infection, the role of circulating dendritic cells (DC) in the pathogenesis of these patients remains obscure. To address this issue, we compared the number and function of myeloid DC (MDC) and plasmacytoid DC (PDC) between uninfected individuals and HCV-infected patients with or without elevated ALT levels. Numbers of DC and DC progenitors were significantly lower in patients with chronic active hepatitis than in control subjects. However, no differences were found in the number of DC between normal controls and HCV-infected patients with persistently normal ALT levels. MDC from patients with active hepatitis were less able to polarize naive CD4 T cells into the Th1 phenotype, while their MDC and PDC primed more CD4 T cells producing IL-10 than those from normal controls. Such dysfunction of DC was also observed in patients with persistently normal ALT levels. In conclusion, circulating DC decrease in number predominantly in HCV-infected patients with active hepatitis, and the function of DC is impaired even in those with normal ALT levels.