IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 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)-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.

• Authors: Stefan Fichtner-Feigl, Warren Strober, Koji Kawakami, Raj K Puri, Atsushi Kitani
• Journal: Nature medicine (Nat Med) Vol. 12 Issue 1 Pg. 99-106 (Jan 2006) ISSN: 1078-8956 [Print] United States
• PMID: 16327802 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Cytokines
• IL13RA1 protein, human
• Il13ra1 protein, mouse
• Immunoglobulin G
• Interleukin-13
• Interleukin-13 Receptor alpha1 Subunit
• NF-kappa B
• RNA, Small Interfering
• Receptors, Interleukin
• Receptors, Interleukin-13
• Receptors, Tumor Necrosis Factor
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transcription Factor AP-1
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• Bleomycin
• Oxazolone
• Collagen
• Luciferases
• Etanercept

Topics

• Animals
• Bleomycin (pharmacology)
• Blotting, Western
• Cell Lineage
• Colitis (metabolism, pathology)
• Collagen (metabolism)
• Cytokines (metabolism)
• Down-Regulation
• Enzyme-Linked Immunosorbent Assay
• Etanercept
• Fibrosis (metabolism)
• Flow Cytometry
• Gene Silencing
• Genetic Vectors
• Humans
• Immunoglobulin G (pharmacology)
• Inflammation
• Interleukin-13 (metabolism, physiology)
• Interleukin-13 Receptor alpha1 Subunit
• Luciferases (metabolism)
• Lung (pathology)
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Monocytes (metabolism)
• NF-kappa B (metabolism)
• Oxazolone (metabolism, pharmacology)
• Promoter Regions, Genetic
• RNA, Small Interfering (metabolism)
• Receptors, Interleukin (metabolism)
• Receptors, Interleukin-13
• Receptors, Tumor Necrosis Factor
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Time Factors
• Transcription Factor AP-1 (metabolism)
• Transforming Growth Factor beta (metabolism)
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation