Interstitial lung disease induced by gefitinib and toll-like receptor ligands is mediated by Fra-1

Oncogene. 2011 Sep 8;30(36):3821-32. doi: 10.1038/onc.2011.101. Epub 2011 Apr 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL2 / metabolism
  • Female
  • Gefitinib
  • Humans
  • Ligands*
  • Lipopolysaccharides / metabolism
  • Lung Diseases, Interstitial / chemically induced*
  • Macrophages, Alveolar / cytology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Quinazolines / adverse effects*
  • Toll-Like Receptors / metabolism*


  • CCL2 protein, human
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Ligands
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-fos
  • Quinazolines
  • Toll-Like Receptors
  • fos-related antigen 1
  • Gefitinib