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首页> 外文期刊>Life sciences >Metalloprotease-dependent amphiregulin release mediates tumor necrosis factor-alpha-induced IL-8 secretion in the human airway epithelial cell line NCI-H292
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Metalloprotease-dependent amphiregulin release mediates tumor necrosis factor-alpha-induced IL-8 secretion in the human airway epithelial cell line NCI-H292

机译：金属蛋白酶依赖性双调蛋白释放介导肿瘤坏死因子-α诱导人气道上皮细胞系NCI-H292中的IL-8分泌

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Tumor necrosis factor-alpha (TNF-alpha) is a potent multifunctional cytokine that plays a central role in the pathogenesis of many inflammatory diseases. Interleukin-8 (IL-8) is a principle neutrophil chemoattractant and activator in humans. The alveolar macrophage-derived TNF-alpha initiates lung inflammation through its ability to stimulate IL-8 synthesis in airway epithelial cells. Since recent studies demonstrated that the stimulation of epidermal growth factor receptor (EGFR) could induce IL-8 secretion, the involvement of EGFR in TNF-alpha-induced IL-8 secretion in airway epithelium-like NCl-H292 cells was investigated in this study. TNF-alpha and epidermal growth factor (EGF) stimulated IL-8 secretion in a time- and concentration-dependent manner. Inhibition of the EGFR by either an anti-EGFR neutralizing antibody or by its specific inhibitor AG1478 (1 mu M) blocked TNF-alpha-induced IL-8 secretion. In addition, TNF-alpha stimulated tyrosine phosphorylation of the EGFR within 5 min after stimulation. Further, TNF-alpha-induced IL-8 secretion was completely inhibited by the neutralizing antibody against amphiregulin (AR), an EGFR ligand, suggesting that TNF-alpha-induced IL-8 secretion was mediated by the AR-EGFR pathway. Furthermore, TNF-alpha stimulated the release of AR in a concentration-dependent manner. Finally, both AR and IL-8 release-induced by TNF-alpha were eliminated by pretreatment with either GM6001, a broad-spectrum inhibitor for metalloprotease, or TAPI-1, relatively selective inhibitor for TNF-alpha converting enzyme (TACE). These findings indicate that metalloprotease-mediated AR shedding and subsequent activation of EGFR play a critical role in TNF-alpha-induced IL-8 secretion from the human airway epithelium-like NCl-H292 cells, and that TACE is one of the most possible candidates for metalloprotease responsible for TNF-alpha-induced AR shedding. (c) 2005 Elsevier Inc. All rights reserved.
机译：肿瘤坏死因子-α（TNF-alpha）是一种有效的多功能细胞因子，在许多炎性疾病的发病机理中起着核心作用。白介素8（IL-8）是人类中性粒细胞的主要化学吸引剂和激活剂。肺泡巨噬细胞源性TNF-α通过刺激气道上皮细胞中IL-8合成的能力引发肺部炎症。由于最近的研究表明表皮生长因子受体（EGFR）的刺激可以诱导IL-8分泌，因此在这项研究中研究了EGFR参与TNF-α诱导的气道上皮样NCl-H292细胞的IL-8分泌。 。 TNF-α和表皮生长因子（EGF）以时间和浓度依赖性方式刺激IL-8分泌。用抗EGFR中和抗体或其特异性抑制剂AG1478（1μM）抑制EGFR可以阻断TNF-α诱导的IL-8分泌。另外，在刺激后5分钟内，TNF-α刺激了EGFR的酪氨酸磷酸化。此外，TNF-α诱导的IL-8分泌被抗EGFR配体amphiregulin（AR）的中和抗体完全抑制，表明TNF-α诱导的IL-8分泌是由AR-EGFR途径介导的。此外，TNF-α以浓度依赖性方式刺激AR的释放。最后，通过用金属蛋白酶的广谱抑制剂GM6001或TNF-α转化酶（TACE）的相对选择性抑制剂TAPI-1预处理，消除了由TNF-α诱导的AR和IL-8释放。这些发现表明，金属蛋白酶介导的AR脱落和EGFR的激活在人气道上皮样NCl-H292细胞的TNF-α诱导的IL-8分泌中起关键作用，并且TACE是最可能的候选药物之一负责TNF-α诱导的AR脱落的金属蛋白酶。 （c）2005 Elsevier Inc.保留所有权利。

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