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Independent
* Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Biomedical Research Institute, Rockville, MD 20852;
Tropical Disease Research Unit, Department of Pathology, Veterans Affairs Medical Center, San Francisco, CA 94143; and
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892
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-
1 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- 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-1. 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-, studies were also performed with neutralizing anti-TGF- Abs, soluble antagonists (soluble TGF-R-Fc), and Tg mice (Smad3–/– and TGF-RII-Fc Tg) that have disruptions in all or part of the TGF- 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-1–/– 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-1 independent, illustrating the importance of targeting IL-13 directly in the treatment of infection-induced fibrosis.
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