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.

Gefitinib, but Not Erlotinib, is a Possible Inducer of Fra-1-mediated Interstitial Lung Disease

“…11 We therefore examined whether erlotinib combined with bleomycin could modulate Ccl2 and Fosl1 mRNA levels in the lungs of wild-type mice in a similar way to that of gefitinib. Three weeks after bleomycin administration, neither erlotinib nor gefitinib treatments significantly affected Tnf expression, and both increased Ccl2 expression (Fig.…”

“…In Fra-1 transgenic mice, which show preexisting pulmonary fibrosis, LPS treatment alone results in severe lung injury associated with reduced inflammatory cytokine production and increased chemokine production. 11 The observation of increased chemokine production in Fra-1 transgenic mice was not anticipated, since these mice show reduced inflammatory responses in bone and the intestinal tract. 13,14 That Fra-1 differentially modulates Tnfa and Ccl2 expression is further supported by the observation that mice lacking Fra-1 do not show skewed expression of cytokines and chemokines and are resistant to gefitinib/LPS-induced lung injury.…”

“…13,14 That Fra-1 differentially modulates Tnfa and Ccl2 expression is further supported by the observation that mice lacking Fra-1 do not show skewed expression of cytokines and chemokines and are resistant to gefitinib/LPS-induced lung injury. 11 In addition, inhibition of MCP-1 by neutralizing antibody or a small-molecule inhibitor against its receptor partially prevents lung injury. These and other observations suggest that gefitinib, in the presence of chemotherapy-induced tissue destruction, induces lung injury through transcriptional activation of Fra-1 and its downstream targets.…”

“…9, 10 We recently reported that gefitinib administration to mice along with the exogenous TLR ligand lipopolysaccharide (LPS) or various endogenous ligands induces interstitial lung disease. 11 Mice treated with gefitinib and LPS showed elevated expression of the transcription factor Fos-related antigen-1 (Fra-1, encoded by Fosl1) in lung tissues. Fra-1, a member of the activator protein 1 (AP-1) (Fos/Jun) transcription factor family, activates and/or represses various target genes by heterodimerizing with a Jun family protein, such as cJun, JunB or JunD.…”

“…These and other observations suggest that gefitinib, in the presence of chemotherapy-induced tissue destruction, induces lung injury through transcriptional activation of Fra-1 and its downstream targets. 11 In this study, we used both cultured macrophages and bleomycin-induced lung injury experiments to determine whether EGFR inhibitors such as gefitinib and erlotinib act similarly to induce interstitial lung disease. We report that gefitinib is distinct from other EGFR inhibitors in that it activates the interstitial lung disease-causing signaling cascade by an off-target effect.…”