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

J Immunol. 2011 Sep 1;187(5):2814-23. doi: 10.4049/jimmunol.1003260. Epub 2011 Jul 29.


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-β-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-β, 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-β-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-β-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Connective Tissue Growth Factor / biosynthesis*
  • Gene Expression Regulation / physiology
  • Gene Knockdown Techniques
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Interleukin-13 / metabolism*
  • Liver Cirrhosis / metabolism*
  • RNA, Small Interfering
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Smad1 Protein / metabolism*
  • Smad2 Protein / metabolism*
  • Transforming Growth Factor beta / metabolism


  • Interleukin-13
  • RNA, Small Interfering
  • Smad1 Protein
  • Smad1 protein, rat
  • Smad2 Protein
  • Smad2 protein, rat
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor