Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium
Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium
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DOI：
10.1152/ajplung.00025.2008
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发表时间：
2008-06-01
影响因子：
4.9
通讯作者：
Nadel, Jay A.
中科院分区：
文献类型：
--
作者：
Koff, Jonathan L.;Shao, Matt X. G.;Nadel, Jay A.
Toll样受体（TLR）对于识别存款在气道上皮表面上的吸入病原体是关键的。上皮细胞对病原体的反应包括激活EGF受体（EGFR）的信号级联。我们假设TLR通过上皮信号传导与EGFR沟通，以产生某些先天免疫应答。气道上皮表达最高水平的TLR 2、TLR 3、TLR 5和TLR 6，并且在此我们发现这些TLRs的配体增加正常人支气管上皮细胞中IL-8和VEGF的产生。这些作用可通过EGFR磷酸化选择性抑制剂（AG-1478）、金属蛋白酶（MP）抑制剂、活性氧（ROS）清除剂和NADPH氧化酶抑制剂治疗来预防。在气道上皮细胞系（NCI-H292）中，使用TNF-α转化酶（TACE）小干扰RNA（siRNA）确认TACE是参与TLR配体诱导的IL-8和VEGF产生的MP。我们表明，转化生长因子（TGF）-α是EGFR配体在这个信号级联反应中，通过使用TGF-α中和抗体，并通过显示，上皮细胞产生的TGF-α发生在TLR配体。使用双氧化酶1（Duox 1）siRNA来确认Duox 1是参与TLR配体诱导的IL-8和VEGF产生的NADPH氧化酶。我们得出结论，多种TLR配体通过Duox 1-> ROS -> TACE -> TGF-α-> EGFR磷酸化途径诱导气道上皮细胞产生IL-8和VEGF。这些结果首次表明，气道上皮细胞中的多种TLR通过上皮细胞信号级联激活EGFR产生先天性免疫应答。
Toll-like receptors (TLRs) are critical for the recognition of inhaled pathogens that deposit on the airway epithelial surface. The epithelial response to pathogens includes signaling cascades that activate the EGF receptor (EGFR). We hypothesized that TLRs communicate with EGFR via epithelial signaling to produce certain innate immune responses. Airway epithelium expresses the highest levels of TLR2, TLR3, TLR5, and TLR6, and here we found that ligands for these TLRs increased IL-8 and VEGF production in normal human bronchial epithelial cells. These effects were prevented by treatment with a selective inhibitor of EGFR phosphorylation (AG-1478), a metalloprotease (MP) inhibitor, a reactive oxygen species (ROS) scavenger, and an NADPH oxidase inhibitor. In an airway epithelial cell line (NCI-H292), TNF-alpha-converting enzyme (TACE) small interfering RNA (siRNA) was used to confirm that TACE is the MP involved in TLR ligand-induced IL-8 and VEGF production. We show that transforming growth factor (TGF)-alpha is the EGFR ligand in this signaling cascade by using TGF-alpha neutralizing antibody and by showing that epithelial production of TGF-alpha occurs in response to TLR ligands. Dual oxidase 1 (Duox1) siRNA was used to confirm that Duox1 is the NADPH oxidase involved in TLR ligand-induced IL-8 and VEGF production. We conclude that multiple TLR ligands induce airway epithelial cell production of IL-8 and VEGF via a Duox1 -> ROS -> TACE -> TGF-alpha -> EGFR phosphorylation pathway. These results show for the first time that multiple TLRs in airway epithelial cells produce innate immune responses by activating EGFR via an epithelial cell signaling cascade.