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

Oncogene volume 30, pages 3821–3832 (2011)Cite this article

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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.

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Acknowledgements

We thank A Oide, M Asakawa and S Fukuse for technical support; T Yamaguchi for Fra-1 mouse maintenance; A Dent, A Ueda and M Busslinger for plasmids; H Daub for AX14596; and H Handa, S Sakamoto, K Maruyama, T Mitsudomi and L Bakiri for helpful input. We thank the Core Instrumentation Facility, Keio University School of Medicine, for technical assistance. This work was funded by a grant-in-aid from the global COE program, a grant-in-aid for Scientific Research (B) from MEXT of Japan (21390425), and a grant-in-aid for Scientific Research on Priority Areas and the Naito Foundation (YT). LG was funded by an EMBO Long-Term Fellowship. IMP is funded by Boehringer Ingelheim.

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Author notes

  1. L Gresh

    Present address: Current address: Biosciences Department, Council for Scientific and Industrial Research (CSIR), Pretoria 0001, South Africa.,

  2. E Ikeda

    Present address: Current address: Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.,

Authors and Affiliations

  1. Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan

    Y Takada & K Matsuo

  2. Research Institute for Molecular Pathology (IMP), Vienna, Austria

    L Gresh

  3. Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    A Bozec & E F Wagner

  4. Department of Pathology, School of Medicine, Keio University, Tokyo, Japan

    E Ikeda

  5. Department of Surgery, School of Medicine, Keio University, Tokyo, Japan

    K Kamiya, M Watanabe & K Kobayashi

  6. Department of Medicine, School of Medicine, Keio University, Tokyo, Japan

    K Asano

  7. Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan

    Y Toyama

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Correspondence to K Matsuo.

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Takada, Y., Gresh, L., Bozec, A. et al. Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1. Oncogene 30, 3821–3832 (2011). https://doi.org/10.1038/onc.2011.101

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