Regulation of interleukin-8 via an airway epithelial signaling cascade
Regulation of interleukin-8 via an airway epithelial signaling cascade
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DOI：
10.1152/ajplung.00356.2006
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发表时间：
2007-05-01
影响因子：
4.9
通讯作者：
Shao, Matt X. G.
中科院分区：
文献类型：
--
作者：
Nakanaga, Takashi;Nadel, Jay A.;Shao, Matt X. G.
呼吸道作为先天免疫器官，对抗吸入并沉积在呼吸道中的空气传播的细菌。宿主防御的机制之一是将中性粒细胞招募到气道中以清除入侵者。气道上皮细胞产生中性粒细胞趋化因子白细胞介素（IL）-8对入侵的细菌作出反应。在这项研究中，我们显示了人气道上皮细胞NCI-H292细胞的血浆表面上的信号传导通路，其调节IL-8的产生以响应模型炎症刺激、佛波醇12-肉豆蔻酸酯13-乙酸酯和病理生理刺激、革兰氏阴性细菌脂多糖。首先，我们表明，表皮生长因子受体（EGFR）和MAP激酶ERK 1/2参与IL-8的表达，这些刺激。其次，我们发现EGFR配体转化生长因子（TGF）-α介导IL-8的产生。第三，我们发现肿瘤坏死因子-α-转化酶（TACE）是通过将EGFR前配体proTGF-α切割成可溶性TGF-α，激活EGFR来产生IL-8所必需的。最后，我们表明，双氧化酶1（Duox 1），气道中NADPH氧化酶的同源物，介导TACE激活和IL-8的表达，通过产生活性氧。总之，我们描述了气道上皮（NCI-H292）细胞表面的信号通路Duox 1-TACE-TGF-α-EGFR，其通过产生IL-8介导气道上皮防御细菌感染。该途径也调节人类气道中的粘蛋白产生，提供了杀死外来生物体及其清除的机制。
Airways function as an innate immune organ against airborne bacteria that are inhaled and deposited in airways. One of the mechanisms of host defense is to recruit neutrophils into airways to clear the invaders. Airway epithelial cells produce neutrophil chemoattractant interleukin (IL)-8 in response to invading bacteria. In this study we show a signaling pathway on the plasma surface of human airway epithelial NCI-H292 cells that regulate IL-8 production in response to a model inflammatory stimulus, phorbol 12-myristate 13-acetate, and a pathophysiological stimulus, gram-negative bacterial lipopolysaccharide. First, we show that EGF receptor (EGFR) and MAP kinase ERK1/2 are involved in IL-8 expression by these stimuli. Second, we show that EGFR ligand transforming growth factor (TGF)-alpha mediates IL-8 production. Third, we show that tumor necrosis factor-alpha-converting enzyme (TACE) is required for IL-8 production by cleaving EGFR proligand proTGF-alpha into soluble TGF-alpha, activating EGFR. Last, we show that dual oxidase 1 (Duox1), a homolog of NADPH oxidase in airways, mediates TACE activation and IL-8 expression via generation of reactive oxygen species. In summary, we describe a signaling pathway, Duox1-TACE-TGF-alpha-EGFR, on the surface of airway epithelial (NCI-H292) cells that mediates airway epithelial defense against bacterial infection by producing IL-8. This pathway, which also regulates mucin production in human airways, provides mechanisms for killing foreign organisms and for their clearance.