Extracellular Hepatitis C Virus Core Protein Activates STAT3 in Human Monocytes/Macrophages/Dendritic Cells via an IL-6 Autocrine Pathway

Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2011; 286(12):10847-55. DOI: 10.1074/jbc.M110.217653
Source: PubMed


Hepatitis C virus (HCV) infection is highly efficient in the establishment of persistent infection, which leads to the development of chronic liver disease and hepatocellular carcinoma. Impaired T cell responses with reduced IFN-γ production have been reported to be associated with persistent HCV infection. Extracellular HCV core is a viral factor known to cause HCV-induced T cell impairment via its suppressive effect on the activation and induction of pro-inflammatory responses by antigen-presenting cells (APCs). The activation of STAT proteins has been reported to regulate the inflammatory responses and differentiation of APCs. To further characterize the molecular basis for the regulation of APC function by extracellular HCV core, we examined the ability of extracellular HCV core to activate STAT family members (STAT1, -2, -3, -5, and -6). In this study, we report the activation of STAT3 on human monocytes, macrophages, and dendritic cells following treatment with extracellular HCV core as well as treatment with a gC1qR agonistic monoclonal antibody. Importantly, HCV core-induced STAT3 activation is dependent on the activation of the PI3K/Akt pathway. In addition, the production of multifunctional cytokine IL-6 is essential for HCV core-induced STAT3 activation. These results suggest that HCV core-induced STAT3 activation plays a critical role in the alteration of inflammatory responses by APCs, leading to impaired anti-viral T cell responses during HCV infection.

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Available from: Young S Hahn, Dec 21, 2015
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    • "Interleukin-6 (IL6) is a multifunctional cytokine involved in oestrogen-regulated liver carcinogenesis [61]. Extracellular HCV core protein was suggested to impair antigen-presenting cells via the IL-6 pathway [62]. "
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    ABSTRACT: Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the identification of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies.
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    • "These evidences suggested that miR-125b may play a role in drug responsiveness. Gene regulation in PBMC has been associated with the pathogenesis of CHC progression and the immune-mediated response of hepatocyte apoptosis (Koziel, 1997; Nasir et al., 2000; Tacke et al., 2011). Increased expression levels of PBMC–miR-155 has been associated with chronic HCV infection, but not in those responded to antiviral therapy (Bala et al., 2012; Zhang et al., 2012). "
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    • "Cells were plated at 1×106 cells/mL and treated with 10 µg/mL rCore or β-galactosidase (Virogen) [26] for 24 hours, then washed twice in PBS and replated. "
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