Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1
Interstitial lung disease induced by gefitinib and Toll-like receptor ligands is mediated by Fra-1
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DOI：
10.1038/onc.2011.101
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发表时间：
2011-09
期刊：
影响因子：
8
通讯作者：
Y. Takada;L. Gresh;A. Bozec;E. Ikeda;K. Kamiya;M. Watanabe;K. Kobayashi;K. Asano;Y. Toyama;E. Wagner;K. Matsuo
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文献类型：
--
作者：
Y. Takada;L. Gresh;A. Bozec;E. Ikeda;K. Kamiya;M. Watanabe;K. Kobayashi;K. Asano;Y. Toyama;E. Wagner;K. Matsuo
AP-1转录因子Fra-1(由Fosl1编码)在与肺部疾病相关的炎症反应中的作用在很大程度上尚不清楚。在这里，我们发现在注射Toll样受体(TLR)配体--脂多糖(LPS)时，小鼠体内FrA-1的过度表达减少了促炎细胞因子的产生。出乎意料的是，在脂多糖治疗后，Fra-1转基因小鼠迅速死亡，表现出严重的间质性肺部疾病，并表现出巨噬细胞的大量聚集和几种趋化因子的过度产生，包括CCL2编码的巨噬细胞趋化蛋白-1(MCP-1)。为了评估Fra-1在肺部病理中的临床相关性，用抗癌药物Gefitinib(易瑞沙)治疗小鼠，这种药物可能导致患者的间质性肺疾病。Gefitinib治疗的小鼠表现出Fosl1和CCL2表达增加，并出现间质性肺疾病，以响应内毒素、内源性TLR配体和化疗。此外，缺失Fra-1或阻断小鼠的MCP-1受体信号可减弱吉非替尼对脂多糖的致死率。重要的是，经吉非替尼治疗后，人肺泡巨噬细胞显示内毒素诱导的FOSL1和CCL2表达增强。这些结果表明，FrA-1是吉非替尼治疗后间质性肺疾病的重要介质。
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.