IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-β Independent

作者：Mallika Kaviratne, Matthias Hesse, Mary Leusink, Allen W. Cheever, Stephen J. A. Davies, James Hobson McKerrow, Lalage M. Wakefield, John J. Letterio, Thomas A. Wynn · 发表于：The Journal of Immunology · 年份：2004 · DOI：10.4049/jimmunol.173.6.4020 · 被引用次数：373 · 研究领域：TGF-β signaling in diseases、Liver physiology and pathology、Protease and Inhibitor Mechanisms

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, i...