Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-κB transcription factors
Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-κB transcription factors
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DOI：
10.1093/jac/dkf008
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发表时间：
2002-05-01
影响因子：
5.2
通讯作者：
Nukiwa, T
中科院分区：
文献类型：
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作者：
Kikuchi, T;Hagiwara, K;Nukiwa, T
红霉素和其他大环内酯类药物可有效治疗慢性炎症性气道疾病，如弥漫性泛细支气管炎（DPB）和慢性鼻窦炎。大环内酯类药物在DPB中的作用被认为是抗炎而不是抗菌。我们使用人外周血单核细胞和人单核细胞白血病细胞系THP-1研究了克拉霉素对白细胞介素-8（IL-8）产生的影响。大肠杆菌、绿脓杆菌和幽门螺杆菌的细菌提取物，以及大肠杆菌。大肠杆菌衍生的脂多糖（LPS）诱导IL-8产生。克拉霉素在单核细胞和THP-1细胞中以剂量依赖性方式抑制这种产生（10 mg/L时抑制率为49.3-75.0%）。用含有连续缺失的IL-8启动子片段的质粒进行的荧光素酶报告基因测定表明，激活蛋白-1（AP-1）和/或核因子-κ B（NF-κ B）结合序列负责IL-8启动子的LPS和克拉霉素反应性。同样，在电迁移率变化试验中，LPS增加AP-1和NF-κ B的特异性结合，而克拉霉素抑制它。此外，LPS和克拉霉素调节其他三个启动子，无论是NF-κ B或AP-1结合序列：两个合成（pAP-1-Luc和pNF-κ B-Luc）和一个天然存在（ELAM-Luc）。我们的研究结果表明，克拉霉素通过抑制IL-8的产生来改变炎症，克拉霉素可能通过AP-1和NF-κ B影响其他基因的表达。大环内酯类药物的抗炎作用除了治疗气道疾病外，还可能有益于治疗其他炎症性疾病，如H.幽门。
Erythromycin and other macrolides are effective for the treatment of chronic inflammatory airway diseases such as diffuse panbronchiolitis (DPB) and chronic sinusitis. The effect of macrolides in DPB is suggested to be anti-inflammatory rather than antibacterial. We investigated the effects of clarithromycin on interleukin-8 (IL-8) production using human peripheral monocytes and the human monocytic leukaemia cell line, THP-1. Bacterial extracts from Escherichia coli, Pseudomonas aeruginosa and Helicobacter pylori, as well as E. coli-derived lipopolysaccharide (LPS), induced IL-8 production. Clarithromycin suppressed this production in a dose-dependent manner in both monocytes and THP-1 cells (49.3-75.0% inhibition at 10 mg/L). A luciferase reporter gene assay with plasmids containing a serially deleted IL-8 promoter fragment showed that both the activator protein-1 (AP-1) and/or the nuclear factor-kappaB (NF-kappaB) binding sequences were responsible for the LPS and clarithromycin responsiveness of the IL-8 promoter. Consistently, in an electromobility shift assay, LPS increased the specific binding of both AP-1 and NF-kappaB, whereas clarithromycin suppressed it. Moreover, LPS and clarithromycin regulated three other promoters that have either the NF-kappaB or the AP-1 binding sequences: two synthetic (pAP-1-Luc and pNF-kappaB-Luc) and one naturally occurring (ELAM-Luc). Our results indicate that clarithromycin modified inflammation by sup-pressing IL-8 production and that clarithromycin may affect the expression of other genes through AP-1 and NF-kappaB. In addition to treatment of airway diseases, the anti-inflammatory effect of macrolides may be beneficial for the treatment of other inflammatory diseases such as chronic gastritis caused by H. pylori.