Nature Medicine
- 12, 99 - 106 (2005)
Published online: 4 December 2005; | doi:10.1038/nm1332
IL-13 signaling through the IL-13 2 receptor is involved in induction of TGF- 1 production and fibrosisStefan Fichtner-Feigl1, 2, Warren Strober1, Koji Kawakami3, Raj K Puri3 & Atsushi Kitani11
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC 5W3864, 10 Center Drive, Bethesda, Maryland 20892, USA. 2
Department of Surgery, University of Regensburg Medical Center, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. 3
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Building 29B, 2NN10, 29 Lincoln Drive MSC 4555, Bethesda, Maryland 20892, USA.
Correspondence should be addressed to Warren Strober wstrober@niaid.nih.gov Interleukin (IL)-13 is a major inducer of fibrosis in many chronic infectious and autoimmune diseases. In studies of the mechanisms underlying such induction, we found that IL-13 induces transforming growth factor (TGF)- 1 in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13R 2. Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-. Second, it involves IL-13 signaling through IL-13R2 to activate an AP-1 variant containing c-jun and Fra-2, which then activates the TGFB1 promoter. In vivo, we found that prevention of IL-13R2 expression reduced production of TGF-1 in oxazolone-induced colitis and that prevention of IL-13R2 expression, Il13ra2 gene silencing or blockade of IL-13R2 signaling led to marked downregulation of TGF-1 production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13R2 signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-1–mediated fibrosis.
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