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

Mallika Kaviratne, Matthias Hesse, Mary Leusink, Allen W. Cheever, Stephen J. Davies, James H. McKerrow, Lalage M. Wakefield, John J. Letterio, Thomas A. Wynn*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

323 Scopus citations

Abstract

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-β1 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-β 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-β1. 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-β, studies were also performed with neutralizing anti-TGF-β Abs, soluble antagonists (soluble TGF-βR-Fc), and Tg mice (Smad3-/- and TGF-βRII-Fc Tg) that have disruptions in all or part of the TGF-β 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-β1-/- 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-β1 independent, illustrating the importance of targeting IL-13 directly in the treatment of infection-induced fibrosis.

Original languageEnglish
Pages (from-to)4020-4029
Number of pages10
JournalJournal of Immunology
Volume173
Issue number6
DOIs
StatePublished - 15 Sep 2004

Fingerprint

Dive into the research topics of 'IL-13 activates a mechanism of tissue fibrosis that is completely TGF-β independent'. Together they form a unique fingerprint.

Cite this