Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C†

Hepatitis C virus (HCV) infects ~120 million people worldwide. In the United States, with nearly 5 million people infected, HCV is the most common cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (1–3). However, the progression of hepatic fibrosis varies considerably among chronic HCV-infected patients. Consequently, some patients will have no appreciable fibrosis after decades of viral infection while others rapidly progress to end stage liver disease (2, 4, 5). Although the mechanisms leading to liver cell injury in chronic HCV infection are incompletely understood, the immune response is thought to be an important determinant of the rate of hepatic fibrogenesis (6, 7). Intrahepatic inflammation has been shown to be one of the most important predictors of fibrosis progression in chronic HCV-infected patients (4, 8–10). Consequently, the degree of inflammatory activity is an important factor in disease assessment and may even have value in the decision to initiate therapy. Chemokines, small chemotactic cytokines that attract leukocytes to inflammatory sites, are important determinants of the development of intrahepatic inflammation in chronic HCV infection. They have been divided into four subfamilies, CC, CXC, CX3C and C, based on the relative position of two conserved N-terminal cysteine residues. CXC chemokines have been further divided into two groups depending on the presence of the ELR (Glu-Leu-Arg) motif preceding the first cysteine: the ELR CXC and non-ELR CXC chemokines (11, 12). The non-ELR CXC chemokines, interferon (IFN) γ–inducible protein 10 (IP-10/CXCL10), monokine induced by IFN γ (Mig/CXCL9) and IFN-inducible T cell α chemoattractant (I-TAC/CXCL11), appear to be important in HCV pathogenesis. In chronic HCV-infected patients, peripheral blood and intrahepatic levels of these three chemokines are elevated compared to uninfected individuals. Their common receptor, CXCR3, has been detected on the majority of intrahepatic lymphocytes (13, 14). The CXCR3 receptor is preferentially expressed on T-helper 1 lymphocytes (15, 16), cells that are characterized by IFN γ and interleukin-2 secretion, and that predominate in the liver of chronic HCV-infected patients. Consequently, through the attraction of CXCR3+ lymphocytes, CXCL10, CXCL9, and CXCL11 may foster ongoing intrahepatic inflammation that may subsequently promote the development of liver cell injury and fibrogenesis. In this study, we evaluated the expression level and intrahepatic localization of CXCL10, CXCL9 and CXCL11 in a total of 118 chronic HCV-infected patients. Our primary goal was to evaluate the role of these chemokines in the development of intrahepatic inflammation and fibrosis in chronic HCV infection. Intrahepatic mRNA expression levels of these chemokines were measured in liver biopsies obtained from 106 patients with different degrees of liver inflammation and fibrosis as well as in uninfected controls. Additionally, we determined the intrahepatic chemokine producer cells, their intrahepatic localization, and the number of CXCR3+ lymphocytes in 20 liver samples from virally-infected individuals.