IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis

S Fichtner-Feigl, W Strober, K Kawakami, RK Puri… - Nature medicine, 2006 - nature.com
S Fichtner-Feigl, W Strober, K Kawakami, RK Puri, A Kitani
Nature medicine, 2006nature.com
Abstract 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)-β1 in macrophages through a two-stage
process involving, first, the induction of a receptor formerly considered to function only as a
decoy receptor, IL-13Rα2. Such induction requires IL-13 (or IL-4) and tumor necrosis factor
(TNF)-α. Second, it involves IL-13 signaling through IL-13Rα2 to activate an AP-1 variant …
Abstract
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)-β1 in macrophages through a two-stage process involving, first, the induction of a receptor formerly considered to function only as a decoy receptor, IL-13Rα2. Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-α. Second, it involves IL-13 signaling through IL-13Rα2 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-13Rα2 expression reduced production of TGF-β1 in oxazolone-induced colitis and that prevention of IL-13Rα2 expression, Il13ra2 gene silencing or blockade of IL-13Rα2 signaling led to marked downregulation of TGF-β1 production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Rα2 signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-β1–mediated fibrosis.
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