IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis.
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)-beta(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-13Ralpha(2). Such induction requires IL-13 (or IL-4) and tumor necrosis factor (TNF)-alpha. Second, it involves IL-13 signaling through IL-13Ralpha(2) 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-13Ralpha(2) expression reduced production of TGF-beta(1) in oxazolone-induced colitis and that prevention of IL-13Ralpha(2) expression, Il13ra2 gene silencing or blockade of IL-13Ralpha(2) signaling led to marked downregulation of TGF-beta(1) production and collagen deposition in bleomycin-induced lung fibrosis. These data suggest that IL-13Ralpha(2) signaling during prolonged inflammation is an important therapeutic target for the prevention of TGF-beta(1)-mediated fibrosis.
Fichtner-Feigl
Stefan
S
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.
Strober
Warren
W
Kawakami
Koji
K
Puri
Raj K
RK
Kitani
Atsushi
A
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D019070:Cell Lineage; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005355:Fibrosis / Q000378:metabolism; D005434:Flow Cytometry; D020868:Gene Silencing; D005822:Genetic Vectors; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism / Q000502:physiology*; D053661:Interleukin-13 Receptor alpha1 Subunit; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010081:Oxazolone / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D018124:Receptors, Tumor Necrosis Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D016207:Cytokines; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D007074:Immunoglobulin G; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D018124:Receptors, Tumor Necrosis Factor; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D010081:Oxazolone; D003094:Collagen; D008156:Luciferases; D000068800:Etanercept