IL-13 induces liver fibrosis via TGF-β-dependent and independent pathways

IL-13 is now well recognized as a crucial pro-fibrogenic cytokine, especially in Schistosomiasis associated chronic liver disease. However, the molecular/cellular mechanism of IL-13 in liver fibrosis is unknown. We hypothesized that IL-13 may exert its pro-fibrogenic effects through both, TGF-b-dependent and independent pathways in liver. IL-13, but not TGF-b treatment remarkably induced connective tissue growth factor (CTGF) protein expression in quiescent and activated rat hepatic stellate cells (HSCs), the key cells for collagen production during liver fibrogenesis. The data suggest that IL-13 induces pro-fibrogenic protein independent of TGF-b in HSCs. Alone, IL-13 treatment does not induce CTGF protein expression, however, IL-13 enhances TGF-b-induced CTGF expression in CFSC-2G, a cell line from CCl₄-induced cirrhotic rat HSCs. Both, IL-13 and TGF-b induce a-smooth muscle actin (a-SMA) protein expression in CFSC-2G cells. However, IL-13-dependent a-SMA protein expression is completely abrogated with SB431542, a specific TGF-b receptor I (ALK5) inhibitor, suggesting that IL-13-induced a-SMA expression is TGF-b-dependent. Furthermore, IL-13 treatment directly up-regulated TGF-b protein expression STAT6-independent in CFSC-2G cells.

Conclusions: Our data demonstrate a TGF-b dependent/independent pro-fibrogenic mechanism in IL-13 associated liver fibrosis.