Abstract
Our previous studies have shown the induction and maturation of transforming growth factor-beta 1 (TGF-β1) in HCV-infected human hepatoma cells. In this study, we have investigated the molecular mechanism of TGF-β1 gene expression in response to HCV infection. We demonstrate that HCV-induced transcription factors AP-1, Sp1, NF-κB and STAT-3 are involved in TGF-β1 gene expression. Using chromatin immunoprecipitation (ChIP) assay, we further show that AP-1 and Sp1 interact with TGF-b1 promoter in vivo in HCV-infected cells. In addition, we demonstrate that HCV-induced TGF-β1 gene expression is mediated by the activation of cellular kinases such as p38 MAPK, Src, JNK, and MEK1/2. Next, we determined the role of secreted bioactive TGF-β1 in human hepatic stellate cells (HSCs) activation and invasion. Using siRNA approach, we show that HCV-induced bioactive TGF-β1 is critical for the induction of alpha smooth muscle actin (α-SMA) and type 1 collagen, the markers of HSCs activation and proliferation. We further demonstrate the potential role of HCV-induced bioactive TGF-β1 in HSCs invasion/cell migration using a transwell Boyden chamber. Our results also suggest the role of HCV-induced TGF-β1 in HCV replication and release. Collectively, these observations provide insight into the mechanism of TGF-β1 promoter activation, as well as HSCs activation and invasion, which likely manifests in liver fibrosis associated with HCV infection.
Highlights
HCV infection causes chronic hepatitis in a significant number of infected individuals, which may gradually progress to liver fibrosis, cirrhosis and subsequently to hepatocellular carcinoma (HCC) [1]
The results showed increased expression of LX-2 cells activation markers, a-smooth muscle actin (a-SMA) and collagen type 1 a 1 (Col1A1) mRNA, which was reduced in LX-2 cells incubated with conditioned medium (CM) collected from HCV-infected cells transfected with siTGF-b1, siTSP-1, or sifurin (Fig. 7C)
Induction of profibrogenic molecules such as transforming growth factor-beta 1 (TGF-b1) has been shown to play an important role in the pathogenesis of HCV, little is understood about the mechanism of HCV-mediated liver fibrosis [10,12]
Summary
HCV infection causes chronic hepatitis in a significant number of infected individuals, which may gradually progress to liver fibrosis, cirrhosis and subsequently to hepatocellular carcinoma (HCC) [1]. HCV is an enveloped, single-stranded, positive-sense RNA virus which is approximately 9.6 kb in length, contains both 59 and 39 untranslated regions (UTRs), and encodes a single polyprotein of about 3000 amino acids [2]. The 59 UTR contains the internal ribosome entry site (IRES) which is required for capindependent translation of the polyprotein. Until 2005, the studies of molecular mechanisms of HCV replication and pathogenesis had been hampered by the lack of an efficient cell culture system or a suitable small-animal model. The development of a productive HCV (genotype 2a) infection system provided a major breakthrough which allows the production of infectious virions in cell culture [4,5,6]
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