title: WNT/β-catenin signaling induces IL-1β expression by alveolar epithelial cells in pulmonary fibrosis.
abstract: 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.
authors.affiliation: Comprehensive Pneumology Center, Ludwig Maximilians University, University Hospital Grosshadern, and Helmholtz Zentrum München, Munich, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Aumiller
authors.forename: Nisha
authors.initials: N
authors.lastname: Balsara
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D011994:Recombinant Proteins; D060509:Wnt3A Protein; D001761:Bleomycin