| First Author | Takada Y | Year | 2011 |
| Journal | Oncogene | Volume | 30 |
| Issue | 36 | Pages | 3821-32 |
| PubMed ID | 21460858 | Mgi Jnum | J:175585 |
| Mgi Id | MGI:5286047 | Doi | 10.1038/onc.2011.101 |
| Citation | Takada Y, et al. (2011) Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1. Oncogene 30(36):3821-32 |
| abstractText | The role of the AP-1 transcription factor Fra-1 (encoded by Fosl1) in inflammatory responses associated with lung disease is largely unknown. Here, we show that Fra-1 overexpression in mice reduced proinflammatory cytokine production in response to injection of lipopolysaccharide (LPS), a Toll-like receptor (TLR)-ligand. Unexpectedly, Fra-1 transgenic mice died rapidly following LPS treatment, showing severe interstitial lung disease and displaying massive accumulation of macrophages and overproduction of several chemokines, including macrophage chemoattractant protein-1 (MCP-1, encoded by Ccl2). To assess the clinical relevance of Fra-1 in lung pathology, mice were treated with the anticancer drug gefitinib (Iressa), which can lead to interstitial lung disease in patients. Gefitinib-treated mice showed increased Fosl1 and Ccl2 expression and developed interstitial lung disease in response to LPS, endogenous TLR ligands and chemotherapy. Moreover, deletion of Fra-1 or blocking MCP-1 receptor signaling in mice attenuated gefitinib-enhanced lethality in response to LPS. Importantly, human alveolar macrophages showed enhanced LPS-induced FOSL1 and CCL2 expression after gefitinib treatment. These results indicate that Fra-1 is an important mediator of interstitial lung disease following gefitinib treatment. |
