Different effects of telithromycin on MUC5AC production induced by human neutrophil peptide-1 or lipopolysaccharide in NCI-H292 cells compared with azithromycin and clarithromycin
Different effects of telithromycin on MUC5AC production induced by human neutrophil peptide-1 or lipopolysaccharide in NCI-H292 cells compared with azithromycin and clarithromycin
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DOI：
10.1093/jac/dkn427
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发表时间：
2009-01-01
影响因子：
5.2
通讯作者：
Kohno, Shigeru
中科院分区：
文献类型：
--
作者：
Ishimoto, Hiroshi;Mukae, Hiroshi;Kohno, Shigeru
粘液分泌过多是慢性呼吸道感染（如囊性纤维化和弥漫性泛细支气管炎）患者的显著特征，已有大环内酯类抗生素在这些患者中的临床疗效报告。由于人中性粒细胞肽-1（HNP-1），一种中性粒细胞中的抗微生物肽，在这些患者的气道液中以高浓度存在，我们使用NCI-H292细胞检测了HNP-1对MUC 5AC粘蛋白产生的直接影响。采用RT-PCR和ELISA检测MUC 5AC的合成。用HNP-1或铜绿假单胞菌的脂多糖（LPS）刺激细胞，可增加MUC 5AC mRNA和蛋白质的表达，HNP-1和LPS共同刺激时，两者的作用是相加的。阿奇霉素和克拉霉素对HNP-1或LPS刺激诱导的MUC 5AC过度产生有抑制作用。泰利霉素对LPS诱导的MUC 5AC的产生也有抑制作用，但对HNP-1的产生没有抑制作用。HNP-1或LPS刺激均可诱导ERK 1/2磷酸化，阿奇霉素、克拉霉素和泰利霉素对LPS诱导的ERK 1/2磷酸化有抑制作用，但对HNP-1无抑制作用。大环内酯类和酮内酯类抗生素通过干扰细胞内信号转导直接抑制这些作用。然而，泰利霉素抑制MUC 5AC合成的机制可能与阿奇霉素和克拉霉素诱导的反应不同。
Mucus hypersecretion is a prominent feature in patients with chronic respiratory tract infections such as cystic fibrosis and diffuse panbronchiolitis, and the clinical effectiveness of macrolide antibiotics has been reported in these patients. Because human neutrophil peptide-1 (HNP-1), an antimicrobial peptide in neutrophils, exists in high concentrations in the airway fluid of these patients, we examined the direct effect of HNP-1 on MUC5AC mucin production using NCI-H292 cells. The effects of macrolide antibiotics on the response were also examined.MUC5AC synthesis was assayed using RT-PCR and ELISA. Phosphorylation of ERK1/2 was determined by western blotting.Stimulation with HNP-1 or lipopolysaccharide (LPS) derived from Pseudomonas aeruginosa increases the production of MUC5AC mRNA and protein, and an additive effect was found upon co-stimulation with both HNP-1 and LPS. Azithromycin and clarithromycin had inhibitory effects on overproduction of MUC5AC induced by HNP-1 or LPS stimulation. Telithromycin also had an inhibitory effect on MUC5AC production induced by LPS, but not on production by HNP-1. Phosphorylation of ERK1/2 was induced by HNP-1 or LPS stimulation, and azithromycin, clarithromycin and telithromycin had inhibitory effects on ERK1/2 phosphorylation induced by LPS, but not by HNP-1.These findings suggest that neutrophil-derived defensins as bacterial components contribute to excessive mucus production in patients with respiratory tract infections, and that macrolide and ketolide antibiotics directly inhibit these actions by interfering with intracellular signal transduction. However, the mechanism of telithromycin inhibition of MUC5AC synthesis may differ from the response induced by azithromycin and clarithromycin.