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Aumiller, V. ; Balsara, N.* ; Wilhelm, J.* ; Günther, A.* ; Königshoff, M.

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

Am. J. Respir. Cell Mol. Biol. 49, 96-104 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of yet unknown etiology. It is characterised by alterations of the alveolar epithelium, myofibroblast activation, and increased extracellular matrix deposition. Recently, reactivation of WNT/β-catenin signaling has been linked with IPF. 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 interleukin (IL) 1β as one of the most upregulated genes in primary murine alveolar epithelial type (AT) II cells after WNT3a treatment. Increased transcript and protein expression of IL-1β upon WNT3a treatment was further detected in primary ATII cells by qRT-PCR (log-fold change: 2.0 +/- 0.5) and ELISA (1.8 fold increase). We observed significant IL-1β and IL-6 upregulation in bronchoalveolar lavage fluid (BALF) in bleomycin induced lung fibrosis in vivo. Importantly, primary fibrotic ATII cells secreted enhanced IL-1β and IL-6 in vitro. Furthermore, orotracheal application of recombinant WNT protein in TOPGAL reporter animals led to WNT/β-catenin activation in epithelial cells along with a significant increase in IL-1β and IL-6 in vivo (2.7-fold and 6.0-fold, respectively). Finally, we found increased WNT3a protein in fibrotic alveolar epithelium accompanied by enhanced IL-1β and IL-6 level in BALF from IPF patients. Taken together, our findings revealed that the alveolar epithelium is a relevant source of proinflammatory cytokines induced by active WNT/β-catenin. Thus, WNT/interleukin signaling represents a novel link between developmental pathway reactivation and inflammation in the development of pulmonary fibrosis.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Lung fibrosis; Wnt signaling; Alveolar epithelial cells; Interleukin; Matrix-metalloproteinase Expression ; Interleukin-1 Receptor Antagonist ; Acute Lung Injury ; Beta-catenin ; In-vitro ; Mesenchymal Transition ; Articular Chondrocytes ; Rheumatoid-arthritis ; Systemic-sclerosis ; Tissue Inhibitor
ISSN (print) / ISBN 1044-1549
e-ISSN 1535-4989
Journal American Journal of Respiratory Cell and Molecular Biology
Quellenangaben Volume: 49, Issue: 1, Pages: 96-104 Article Number: , Supplement: ,
Publisher American Thoracic Society
Reviewing status Peer reviewed
Institute(s) German Center for Lung Research (DZL)
Institute of Lung Health and Immunity (LHI)