title: Interstitial lung disease induced by gefitinib and toll-like receptor ligands is mediated by Fra-1.
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.
authors: Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan.
authors: Y
authors: Y
authors: Takada
authors: L
authors: L
authors: Gresh
authors: A
authors: A
authors: Bozec
authors: E
authors: E
authors: Ikeda
authors: K
authors: K
authors: Kamiya
authors: M
authors: M
authors: Watanabe
authors: K
authors: K
authors: Kobayashi
authors: K
authors: K
authors: Asano
authors: Y
authors: Y
authors: Toyama
authors: E F
authors: EF
authors: Wagner
authors: K
authors: K
authors: Matsuo
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000139:chemically induced*; D016676:Macrophages, Alveolar / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011799:Quinazolines / Q000009:adverse effects*; D051193:Toll-Like Receptors / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D018932:Chemokine CCL2; D000077156:Gefitinib; D008024:Ligands; D008070:Lipopolysaccharides; D016760:Proto-Oncogene Proteins c-fos; D011799:Quinazolines; D051193:Toll-Like Receptors; D000099169:Fos-Related Antigen 1; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse