IL-13 Induces Connective Tissue Growth Factor in Rat Hepatic Stellate Cells via TGF-β-Independent Smad Signaling

Connective tissue growth factor (CTGF) plays a central role in stimulating extracellular matrix deposition in the liver, and hence is considered a critical mediator of TGF-beta-dependent fibrogenesis. Hepatic stellate cells (HSCs) are known as the major source of CTGF in damaged liver. However, previous studies revealed that IL-13, rather than TGF-beta, represents the predominant inducer of CTGF expression in HSCs. We now dissected IL-13 downstream signaling that modulates CTGF expression in HSCs. IL-13 induces a time-and dosage-dependent increase of CTGF in a TGF-beta-independent manner. This process requires participation of different Smad proteins and their upstream receptor kinases (activin receptor-like kinases). Smad1 and Smad2 were identified as the key mediators of 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 found to be responsible for IL-13-induced early Smad phosphorylation and CTGF synthesis. We demonstrate that IL-13 induces CTGF expression in HSCs by activating TGF-beta-independent activin receptor-like kinase/Smad signaling via the Erk-MAPK pathway rather than via its canonical JAK/Stat6 pathway. These results provide an improved new insight into the molecular mechanisms of profibrotic IL-13 activities in the liver. The Journal of Immunology, 2011, 187: 2814-2823.