| First Author | Aumiller V | Year | 2013 |
| Journal | Am J Respir Cell Mol Biol | Volume | 49 |
| Issue | 1 | Pages | 96-104 |
| PubMed ID | 23526221 | Mgi Jnum | J:221774 |
| Mgi Id | MGI:5641467 | Doi | 10.1165/rcmb.2012-0524OC |
| Citation | Aumiller V, et al. (2013) WNT/beta-catenin signaling induces IL-1beta expression by alveolar epithelial cells in pulmonary fibrosis. Am J Respir Cell Mol Biol 49(1):96-104 |
| abstractText | 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-1beta 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-1beta 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-1beta 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-1beta 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-1beta 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-1beta 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. |
