Cyclosporine Inhibits Profibrotic Effects of Interleukin-4 and Transforming Growth Factor β on Human Intrahepatic Fibroblasts Cultured In Vitro

Background. Hepatic fibrosis, an outcome of chronic liver diseases, is characterized by an accumulation of collagen, which is produced by activated human intrahepatic fibroblasts (HIF). Transforming growth factor (TGF) beta is an important inducer of fibrogenesis, in collaboration with other cytokines, such as interleukin (IL) 4. IL-4 is overexpressed in severe recurrent hepatitis C after liver transplantation, exerting profibrotic effects. In contrast, cyclosporine (CsA) had been shown to decrease fibroblast activation and collagen production. We therefore investigated the effects of CsA on TGF-beta and IL-4 profibrotic activities on HIF in vitro. Methods. Isolated HIP were cultured without or with human TGF-beta, human IL-4, CsA, or combined TGF-beta+CsA or IL-4+CsA. We performed real-time polymerase chain reaction for collagen types I, III, and IV and alpha-SMA, a marker of fibroblast activation we also measured total collagen in supernates. TGF-beta and IL-4 increased the expressions of alpha smooth muscle action (SMA) collagen I, III, and IV mRNAs (P < .05 vs untreated cells) as well as the overall collagen level in the supernates (P < .01). CsA decreased the expression of mRNAs encoding alpha-SMA and collagens (P < .01). Expressions of alpha-SMA and collagens I, III, and IV mRNAs were significantly lower under combined treatments (TGF-beta vs TGF-beta+CsA [P < .01] and IL-4 vs IL-4+CsA [P < .01]). Collagen level was decreased by combined treatments (TGF-beta vs TGF-beta+CsA [P < .05] and IL-4 vs IL-4+CsA [P = .05]). Conclusion. CsA inhibited the profibrotic effects of TGF-beta and IL-4 by decreasing the activation and production of collagen by HIF. CsA may decrease fibroblast activation and collagen accumulation, exerting beneficial effects on fibrosis progression, particularly among patients with recurrent hepatitis C.