IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent

J Immunol. 2004 Sep 15;173(6):4020-9. doi: 10.4049/jimmunol.173.6.4020.


Fibrosis is a characteristic feature in the pathogenesis of a wide spectrum of diseases. Recently, it was suggested that IL-13-dependent fibrosis develops through a TGF-beta1 and matrix metalloproteinase-9-dependent (MMP-9) mechanism. However, the significance of this pathway in a natural disorder of fibrosis was not investigated. In this study, we examined the role of TGF-beta in IL-13-dependent liver fibrosis caused by Schistosoma mansoni infection. Infected IL-13-/- mice showed an almost complete abrogation of fibrosis despite continued and undiminished production of TGF-beta1. Although MMP-9 activity was implicated in the IL-13 pathway, MMP-9-/- mice displayed no reduction in fibrosis, even when chronically infected. To directly test the requirement for TGF-beta, studies were also performed with neutralizing anti-TGF-beta Abs, soluble antagonists (soluble TGF-betaR-Fc), and Tg mice (Smad3-/- and TGF-betaRII-Fc Tg) that have disruptions in all or part of the TGF-beta signaling cascade. In all cases, fibrosis developed normally and with kinetics similar to wild-type mice. Production of IL-13 was also unaffected. Finally, several genes, including interstitial collagens, several MMPs, and tissue inhibitors of metalloprotease-1 were up-regulated in TGF-beta1-/- mice by IL-13, demonstrating that IL-13 activates the fibrogenic machinery directly. Together, these studies provide unequivocal evidence of a pathway of fibrogenesis that is IL-13 dependent but TGF-beta1 independent, illustrating the importance of targeting IL-13 directly in the treatment of infection-induced fibrosis.

MeSH terms

  • Animals
  • Cells, Cultured
  • Chronic Disease
  • DNA-Binding Proteins / physiology
  • Extracellular Matrix / genetics
  • Extracellular Matrix / immunology
  • Extracellular Matrix / metabolism
  • Female
  • Fibrosis
  • Gene Expression Regulation / immunology
  • Interleukin-13 / deficiency
  • Interleukin-13 / genetics
  • Interleukin-13 / physiology*
  • Liver / enzymology
  • Liver / immunology
  • Liver / parasitology
  • Liver / pathology*
  • Liver Cirrhosis / enzymology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / parasitology
  • Matrix Metalloproteinase 9 / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Schistosomiasis mansoni / enzymology
  • Schistosomiasis mansoni / genetics
  • Schistosomiasis mansoni / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Smad3 Protein
  • Trans-Activators / physiology
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / deficiency
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1
  • Wound Healing / genetics
  • Wound Healing / immunology


  • DNA-Binding Proteins
  • Interleukin-13
  • Smad3 Protein
  • Smad3 protein, mouse
  • Tgfb1 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Matrix Metalloproteinase 9