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Backgroud & Aims: Chronic hepatitis C is both a virological and progressive fibrotic disease.Recent studies demonstrated that IL-22 and IL-20, cytokine expressed by immune cells and hepatocytes, respectively, both exacerbate liver fibrosis in patients with hepatitis C by activating hepatic stellate cells.The aims of this study were to evaluate whether IL-22 and IL-20 are related to disease progression and to explore the possible mechanisms.Methods: The levels of IL-22, IL-20, IL-17 and TNF-α in plasma were analyzed in a cohort of HCV-infected patients including 25 with chronic hepatitis C (CHC), 28 with HCV-associated liver cirrhosis (LC), and 15 healthy subjects as controls.The distribution of IL-20+ cells in situ in liver tissues was observed by immunohistochemistry.IL-20 response to recombinant IL-22 in human hepatic cells was studied by flow cytometry, ELISA and Western blot.Results: Patients with CHC and especially LC disclosed significant increases in IL-22, IL-20, IL-17 and TNF-α plasma levels.IL-22 up-regulation correlated significantly with plasma IL-20 levels.Furthermore, longitudinal analyses indicated that the plasma concentrations of IL-22,IL-20, IL-17 and TNF-α decreased in CHC patients with sustained virological responses,and their levels were elevated in LC patients.Meanwhile, liver infiltrating IL-20 positive cells were largely increased in HCV-infected patients with LC, compared to those without LC or healthy controls.As previously shown for IL-22, the increased intrahepatic IL-20+ cells were positively correlated with fibrotic staging scores and clinical progression from CHC to cirrhosis.Moreover, IL-20 was more highly expressed in the hepatocytes of patients with liver fibrosis, liver cirrhosis than in the liver tissue of healthy controls.In vitro, administration of IL-22 was accompanied with increased expression of IL-20 in LO-2 cells by activating STAT3.IL-20 activated HSCs and up-regulated TGF-β1.Conclusions: The serum level of IL-22 can be used as a indicator for the severity of disease progression and may contribute to the fibrogenesis of HCV-associated liver fibrosis by up-regulating IL-20.These findings demonstrate that an immune cell mediator induces a tissue cell cytokine and therefore suggests a novel type of pathogenetic cascade of fibrogenesis.