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

Research output: Contribution to journalArticle

12 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

Fingerprint

Toll-Like Receptors
Interstitial Lung Diseases
Lipopolysaccharides
Ligands
CCR2 Receptors
Macrophages
Chemotactic Factors
Transcription Factor AP-1
Alveolar Macrophages
Chemokines
Transgenic Mice
Lung Diseases
gefitinib
Therapeutics
Pathology
Cytokines
Drug Therapy
Lung
Injections
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1. / Takada, Y.; Gresh, L.; Bozec, A.; Ikeda, E.; Kamiya, K.; Watanabe, Masazumi; Kobayashi, K.; Asano, K.; Toyama, Y.; Wagner, E. F.; Matsuo, Koichi.

In: Oncogene, Vol. 30, No. 36, 08.09.2011, p. 3821-3832.

Research output: Contribution to journalArticle

Takada, Y, Gresh, L, Bozec, A, Ikeda, E, Kamiya, K, Watanabe, M, Kobayashi, K, Asano, K, Toyama, Y, Wagner, EF & Matsuo, K 2011, 'Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1', Oncogene, vol. 30, no. 36, pp. 3821-3832. https://doi.org/10.1038/onc.2011.101
Takada Y, Gresh L, Bozec A, Ikeda E, Kamiya K, Watanabe M et al. Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1. Oncogene. 2011 Sep 8;30(36):3821-3832. https://doi.org/10.1038/onc.2011.101
Takada, Y. ; Gresh, L. ; Bozec, A. ; Ikeda, E. ; Kamiya, K. ; Watanabe, Masazumi ; Kobayashi, K. ; Asano, K. ; Toyama, Y. ; Wagner, E. F. ; Matsuo, Koichi. / Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1. In: Oncogene. 2011 ; Vol. 30, No. 36. pp. 3821-3832.
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