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

Abstract

Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-␥ (IFN-␥)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-␥ (Mig/CXCL9), and interferon-inducible T cell ␣ chemoattractant (I-TAC/ CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR. The intrahepatic localization of chemokine producer cells and CXCR3 ؉ lymphocytes was determined in selected patients by immunohistochemistry. We found elevated intrahepatic mRNA expression of all three chemokines, most markedly CXCL10, in chronic HCV-infected patients with higher necroinflammation and fibrosis. By multivariable multivariate analysis, intrahepatic CXCL10 mRNA expression levels were significantly associated with lobular necroinflammatory grade and HCV genotype 1. In the lobular region, CXCL10-expressing and CXCL9-expressing hepatocytes predominated in areas with necroinflammation. Strong CXCL11 expression was observed in almost all portal tracts, whereas CXCL9 expression varied considerably among portal tracts in the same individual. Most intrahepatic lymphocytes express the CXCR3 receptor, and the number of CXCR3 ؉ lymphocytes was increased in patients with advanced necroinflammation. Conclusion: These findings suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the development of necroinflammation and fibrosis in the liver parenchyma in chronic HCV infection.

Hepatic Serum Amyloid A1 Aggravates T Cell-mediated Hepatitis by Inducing Chemokines via Toll-like Receptor 2 in Mice

“…The function of CCR5, a MIP-1␣ and MIP-1␤ receptor, has been reported in hepatitis (18,31). The function of CXCR3, an IP-10 receptor, has also been reported in hepatitis (32)(33)(34). Further studies are needed to examine the relationship between chemokine receptors and chemokine induction by SAA1.…”

Liver fibrosis: mechanisms of immune-mediated liver injury

“…Moreover, expression of chemokines interacting with CXCR3 and particularly CXCL10, is upregulated in patients with advanced inflammation and fibrosis. 35 In patients with primary biliary cirrhosis, expression of CCR7 is upregulated and immunostaining for its ligand, CCL21, is detected around inflammatory lymphoid follicles. 36 Involvement in the fibrogenic process was indicated by the observation that activation of CCR7 on cultured HSCs stimulates cell migration and accelerates wound healing.…”

Identifying Molecular Factors That Contribute to Resolution of Liver Fibrosis

“…14 The implication of the CXCL9/CXCR3 axis in promoting liver fibrosis has been recently suggested in human diseases. [15][16][17] Therefore, both molecules seem to be "good guys" in fibrosis resolution, but "bad guys" during liver fibrogenesis. This dual biological behavior can hamper their potential use as therapeutic targets, because patients may alternate between periods of disease progression and regression.…”