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)-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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Bleomycin / pharmacology
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Blotting, Western
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Cell Lineage
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Colitis / metabolism
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Colitis / pathology
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Collagen / metabolism
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Cytokines / metabolism
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Down-Regulation
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Enzyme-Linked Immunosorbent Assay
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Etanercept
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Fibrosis / metabolism
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Flow Cytometry
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Gene Silencing
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Genetic Vectors
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Humans
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Immunoglobulin G / pharmacology
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Inflammation
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Interleukin-13 / metabolism
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Interleukin-13 / physiology*
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Interleukin-13 Receptor alpha1 Subunit
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Luciferases / metabolism
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Lung / pathology
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Macrophages / metabolism*
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Mice
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Mice, Inbred C57BL
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Monocytes / metabolism
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NF-kappa B / metabolism
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Oxazolone / metabolism
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Oxazolone / pharmacology
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Promoter Regions, Genetic
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RNA, Small Interfering / metabolism
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Receptors, Interleukin / metabolism*
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Receptors, Interleukin-13
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Receptors, Tumor Necrosis Factor
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Time Factors
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Transcription Factor AP-1 / metabolism
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation
Substances
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Cytokines
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IL13RA1 protein, human
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Il13ra1 protein, mouse
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Immunoglobulin G
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Interleukin-13
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Interleukin-13 Receptor alpha1 Subunit
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NF-kappa B
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RNA, Small Interfering
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Receptors, Interleukin
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Receptors, Interleukin-13
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Receptors, Tumor Necrosis Factor
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Transcription Factor AP-1
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha
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Bleomycin
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Oxazolone
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Collagen
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Luciferases
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Etanercept