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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Tumor necrosis factor α-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells
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Tumor necrosis factor α-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells

机译：肿瘤坏死因子α转化酶介导人气道上皮细胞中MUC5AC粘蛋白的表达

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Ectodomain shedding of epidermal growth factor receptor (EGFR) ligands [e.g., transforming growth factor type α (TGF-α)] and EGFR phosphorylation are implicated in mucin production in airway epithelial cells. Tumor necrosis factor α-converting enzyme (TACE) is reported to cleave precursor of TGF-α, with release of soluble mature TGF-α in various epithelial tissues. We hypothesized that TACE increases the shedding of TGF-α, resulting in EGFR phosphorylation and inducing mucin production in human airway epithelial (NCI-H292) cells. To examine this hypothesis, we stimulated NCI-H292 cells with phorbol 12-myristate 13-acetate (PMA, an activator of TACE) and pathophysiologic stimuli [lipopolysaccharide (LPS) and supernatant from the Gram-negative bacterium Pseudomonas aeruginosa (PA sup)]. PMA, PA sup, and LPS increased MUC5AC gene expression and mucin protein production, effects that were prevented by pretreatment with AG1478, a selective inhibitor of EGFR phosphorylation and by preincubation with an EGFR-neutralizing Ab or with a TGF-α-neutralizing Ab, implicating ligand (TGF-α)-dependent EGFR phosphorylation in mucin production. These stimuli induced release of soluble TGF-α, EGFR phosphorylation, and MUC5AC expression, which were blocked by the metalloprotease inhibitors tumor necrosis factor-α protease inhibitor-1 and tissue inhibitor of metalloprotease-3. We specifically knocked down the expression of metalloprotease TACE by using small interfering RNA for TACE. Knockdown of TACE inhibited PMA-, PA sup-, and LPS-induced TGF-α shedding, EGFR phosphorylation, and mucin production. From these results, we conclude that TACE plays a critical role in mucin production by airway epithelial cells by means of a TACE ligand–EGFR cascade in response to various stimuli.
机译：表皮生长因子受体（EGFR）配体[例如转化生长因子α（TGF-α）]的胞外域脱落和EGFR磷酸化与气道上皮细胞黏蛋白的产生有关。据报道，肿瘤坏死因子α转化酶（TACE）裂解TGF-α的前体，并在各种上皮组织中释放可溶性成熟的TGF-α。我们假设TACE增加了TGF-α的脱落，导致EGFR磷酸化并诱导人气道上皮（NCI-H292）细胞中的粘蛋白生成。为了检验这一假设，我们用佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA，TACE的活化剂）和病理生理刺激[脂多糖（LPS）和革兰氏阴性细菌铜绿假单胞菌（PA sup）]刺激了NCI-H292细胞。 。 PMA，PA sup和LPS会增加MUC5AC基因的表达和粘蛋白的产生，这种作用可通过用AG1478（一种选择性的EGFR磷酸化抑制剂）进行预处理以及通过与EGFR中和的Ab或与TGF-α中和的Ab的预孵育来预防，在粘蛋白生产中牵涉配体（TGF-α）依赖性EGFR磷酸化。这些刺激诱导可溶性TGF-α的释放，EGFR磷酸化和MUC5AC表达，这些被金属蛋白酶抑制剂肿瘤坏死因子-α蛋白酶抑制剂-1和金属蛋白酶-3的组织抑制剂所阻断。我们使用TACE的小分子干扰RNA特异性地敲低了金属蛋白酶TACE的表达。 TACE的抑制抑制PMA-，PA sup-和LPS诱导的TGF-α脱落，EGFR磷酸化和粘蛋白生成。根据这些结果，我们得出结论，TACE在TACE配体-EGFR级联反应中对多种刺激产生反应，在气道上皮细胞产生粘蛋白中起关键作用。

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