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

Y. Takada, L. Gresh, A. Bozec, E. Ikeda, K. Kamiya, Masazumi Watanabe, K. Kobayashi, K. Asano, Y. Toyama, E. F. Wagner, Koichi Matsuo

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13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3821-3832
Number of pages12
JournalOncogene
Volume30
Issue number36
DOIs
Publication statusPublished - 2011 Sep 8

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Keywords

  • AP-1
  • Fra-1
  • gefitinib
  • interstitial lung disease
  • MCP-1
  • TLR

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Takada, Y., Gresh, L., Bozec, A., Ikeda, E., Kamiya, K., Watanabe, M., Kobayashi, K., Asano, K., Toyama, Y., Wagner, E. F., & Matsuo, K. (2011). Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1. Oncogene, 30(36), 3821-3832. https://doi.org/10.1038/onc.2011.101