IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF- independent Smad signaling

Aims: Connective tissue growth factor (CTGF) plays a central role in stimulating extracellular matrix deposition in the liver, and hence is considered as a critical mediator of TGF-β dependent fibrogenesis. Hepatic stellate cells (HSCs) are known as the major source of CTGF. However, previous studies revealed that IL-13, rather than TGF-beta, represents the main inducer of CTGF expression in HSCs. Methods: We evaluate the effect of IL-13 on CTGF expression in primary cultured HSCs. We also investigated how IL-13 downstream signaling modulates CTGF expression in HSCs. Results: IL-13 induces a time- and dosage-dependent increase of CTGF in a TGF-beta independent manner. This process involves different Smad proteins and their upstream receptor kinases (ALKs). Smad1 and Smad2 were identified as key mediators for IL-13 dependent CTGF expression. Furthermore, IL-13 induces Stat6 phosphorylation in HSCs, but Stat6 was not involved in CTGF induction. Instead, the Erk1/2-MAPK pathway was responsible for IL-13 induced early Smad phosphorylation and CTGF production. Conclusion: We demonstrate that IL-13 induces CTGF expression in HSCs by activating TGF-beta independent ALK/Smad signaling via the Erk-MAPK pathway rather than via its canonical JAK/Stat6 pathway. These results may provide an improved new insight into the molecular mechanisms of pro-fibrotic IL-13 activity in the liver. Liver fibrosis - ALK - Stat6 - phosphor-Erk