IL-13 Signaling Through the IL-13alpha2 Receptor Is Involved in Induction of TGF-beta1 Production and Fibrosis

Nat Med. 2006 Jan;12(1):99-106. doi: 10.1038/nm1332. Epub 2005 Dec 4.

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

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Bleomycin / pharmacology
  • Blotting, Western
  • Cell Lineage
  • Colitis / metabolism
  • Colitis / 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
  • Interleukin-13 / physiology*
  • Interleukin-13 Receptor alpha1 Subunit
  • Luciferases / metabolism
  • Lung / pathology
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism
  • NF-kappa B / metabolism
  • Oxazolone / metabolism
  • Oxazolone / 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

Substances

  • 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