Abstract: BACKGROUND: Obese subjects with chronic hepatitis C virus (HCV) infection have more rapidly progressive liver disease. OBJECTIVE: We aimed to compare the intrahepatic cytokine and chemokine profiles in obese and lean subjects with chronic HCV infection using qRT-PCR and immunohistochemistry. METHODS: Liver biopsies from 55 subjects were studied, including 20 with chronic hepatitis C (CHC), 25 with non-alcoholic fatty liver disease (NAFLD) and 10 non-diseased liver. RESULTS: Compared to the control groups, the liver injury in CHC was characterized by increased expression of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha, and chemokines such as RANTES, IP-10 and MCP-1. In comparison with lean -HCV infected subjects, obese-HCV infected subjects had increased hepatic expression of IFN-gammap=0.004) and TNF-alpha(p<0.001) as well as increased expression of IP-10 (p=0.009) and MCP-1 (p<0.001). Localization of these inflammatory chemokines revealed that in comparison to lean-HCV subjects, HCV infected liver from obese subjects exhibited increased expression of IP-10 (p<0.001) and MCP-1 (p=0.02) in the inflammatory infiltrate of the portal tracts. In parallel, there was increased CD3+ T cell infiltration in the liver of obese-HCV subjects. CONCLUSIONS: The data provide important mechanistic information on the cause of hepatic injury in obese-HCV subjects including: 1) enhanced TH-1 cytokine response-to promote hepatocellular injury; 2) increased expression of the chemokines IP-10 and MCP-1 at both the mRNA and protein levels-to enhance inflammatory cell recruitment; 3) differing localization of these chemokines within the liver of obese-HCV versus lean-HCV subjects and; 4) increased CD3+ cells expression in the liver of obese-HCV subject.

Abstract: Adipose tissue releases pro-inflammatory and anti-inflammatory mediators, including adiponectin, which elicit a broad range of metabolic and immunological effects. The study aim was to determine in subjects infected with chronic hepatitis C virus (HCV) the effects of total adiponectin and its high-molecular-weight (HMW) and low-molecular-weight isoforms on HCV-specific immune responses. Serum levels of total adiponectin and its isoforms were determined by immunoassay. The ex vivo effect of adiponectin on the HCV-specific T-cell response was examined by interferon gamma (IFN-gamma) enzyme-linked immunosorbent spot and enzyme-linked immunosorbent assay cytokine assays. The role of the mitogen-activated protein kinase (MAPK) signaling pathway in mediating the adiponectin effect on T cells was also evaluated. We found that serum levels of total and HMW adiponectin were significantly decreased in subjects with chronic HCV and increased body mass index (BMI) compared with HCV-infected lean subjects. The presence of an anti-HCV specific immune response was strongly associated with lower BMI (P = 0.004) and higher serum total (P = 0.01) and HMW (P = 0.02) adiponectin. In ex vivo assays, total adiponectin and the HMW adiponectin isoform enhanced HCV-specific IFN-gamma production (P = 0.02 and 0.03, respectively). Adiponectin-R1 receptors were expressed on T cells and monocytes. In depletion experiments, the IFN-gamma response to adiponectin was entirely dependent on the simultaneous presence of both CD4 and CD8 T cells, and to a lesser extent, natural killer cells. Selective inhibition of p38MAPK activity by SB203580 abrogated the IFN-gamma response to adiponectin, whereas extracellular signal-regulated kinase 1/2 inhibition by PD98059 did not affect the response. Conclusion: In chronic HCV, a reciprocal association exists between BMI, adiponectin, and the anti-HCV immune responses, emphasizing the important role played by adiposity in regulating the immune response in HCV infection.