WNT/β-catenin signaling induces IL-1β expression by alveolar epithelial cells in pulmonary fibrosis

Am J Respir Cell Mol Biol. 2013 Jul;49(1):96-104. doi: 10.1165/rcmb.2012-0524OC.


Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. It is characterized by alterations of the alveolar epithelium, myofibroblast activation, and increased extracellular matrix deposition. Recently, reactivation of the developmental WNT/β-catenin pathway has been linked with pulmonary fibrosis. The cell-specific mechanisms and mediators of WNT/β-catenin signaling in the lung, however, remain elusive. Here, we applied an unbiased gene expression screen to identify epithelial cell-specific mediators of WNT/β-catenin signaling. We found the proinflammatory cytokine IL-1β to be one of the most up-regulated genes in primary murine alveolar epithelial Type II (ATII) cells after WNT3a treatment. Increased transcript and protein expression of IL-1β upon WNT3a treatment was further detected in primary ATII cells by quantitative RT-PCR (log fold change, 2.0 ± 0.5) and ELISA (1.8-fold increase). We observed significant up-regulation of IL-1β and IL-6 in bronchoalveolar lavage fluid (BALF) in bleomycin-induced lung fibrosis in vivo. Importantly, primary fibrotic ATII cells isolated from lungs subjected to bleomycin secreted enhanced IL-1β and IL-6 in vitro. Furthermore, the orotracheal application of recombinant WNT protein in the Tcf optimal promoter (TOP)-β-galactosidase reporter animals led to WNT/β-catenin activation in epithelial cells, along with significant increases in IL-1β and IL-6 in vivo (2.7-fold and 6.0-fold increases, respectively). Finally, we found increased WNT3a protein in fibrotic alveolar epithelia, accompanied by enhanced IL-1β and IL-6 concentrations in BALF from patients with IPF. Taken together, our findings reveal that the alveolar epithelium is a relevant source of proinflammatory cytokines induced by active WNT/β-catenin in pulmonary fibrosis. Thus, WNT/interleukin signaling represents a novel link between developmental pathway reactivation and inflammation in the development of pulmonary fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / adverse effects
  • Bronchoalveolar Lavage Fluid / immunology
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Primary Cell Culture
  • Pulmonary Alveoli / immunology
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / immunology
  • Pulmonary Fibrosis / pathology
  • Recombinant Proteins / pharmacology
  • Up-Regulation
  • Wnt Signaling Pathway*
  • Wnt3A Protein / pharmacology


  • Interleukin-1beta
  • Recombinant Proteins
  • Wnt3A Protein
  • Bleomycin