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

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.