Journal article

Publication year: 2013

Pages: 96-104

Journal: American Journal of Respiratory Cell and Molecular Biology

Volume number: 49

Issue number: 1

ISSN: 1044-1549

eISSN: 1535-4989

DOI Link: https://doi.org/10.1165/rcmb.2012-0524OC

Publisher: American Thoracic Society

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/beta-catenin pathway has been linked with pulmonary fibrosis. The cell-specific mechanisms and mediators of WNT/beta-catenin signaling in the lung, however, remain elusive. Here, we applied an unbiased gene expression screen to identify epithelial cell-specific mediators of WNT/beta-catenin signaling. We found the proinflammatory cytokine IL-1 beta 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-1 beta 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-1 beta 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-1 beta and IL-6 in vitro. Furthermore, the orotracheal application of recombinant WNT protein in the Tcf optimal promoter (TOP)-beta-galactosidase reporter animals led to WNT/beta-catenin activation in epithelial cells, along with significant increases in IL-1 beta 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-1 beta 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/beta-catenin in pulmonary fibrosis. Thus, WNT/interleukin signaling represents a novel link between developmental pathway reactivation and inflammation in the development of pulmonary fibrosis.

Harvard Citation style: Aumiller, V., Balsara, N., Wilhelm, J., Guenther, A. and Koenigshoff, M. (2013) WNT/β-Catenin Signaling Induces IL-1β Expression by Alveolar Epithelial Cells in Pulmonary Fibrosis, American Journal of Respiratory Cell and Molecular Biology, 49(1), pp. 96-104. https://doi.org/10.1165/rcmb.2012-0524OC

APA Citation style: Aumiller, V., Balsara, N., Wilhelm, J., Guenther, A., & Koenigshoff, M. (2013). WNT/β-Catenin Signaling Induces IL-1β Expression by Alveolar Epithelial Cells in Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology. 49(1), 96-104. https://doi.org/10.1165/rcmb.2012-0524OC