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首页> 外文期刊>Clinical and experimental allergy : >Montelukast inhibits tumour necrosis factor-α-mediated interleukin-8 expression through inhibition of nuclear factor-κB p65-associated histone acetyltransferase activity
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Montelukast inhibits tumour necrosis factor-α-mediated interleukin-8 expression through inhibition of nuclear factor-κB p65-associated histone acetyltransferase activity

机译：孟鲁司特通过抑制核因子-κBp65相关的组蛋白乙酰转移酶活性来抑制肿瘤坏死因子-α介导的白介素8表达

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Background: Montelukast is a potent cysteinyl leukotriene-1 receptor antagonist possessing some anti-inflammatory effects although the molecular mechanism of these anti-inflammatory effects is unknown. In this study, we aimed to investigate the effect of montelukast on nuclear factor (NF)-築- associated histone acetylation activity in phorbol myristate acetate (PMA)-differentiated U937 cells. Methods: We examined the inhibitory effects of montelukast on TNF-?-induced IL-8 production in PMA-differentiated U-937 cells. U-937 cells were exposed to PMA (50 ng/mL) for 48 h to allow differentiation to macrophages. Macrophages were then exposed to TNF-? (10 ng/mL) in the presence or absence of montelukast (0.01-10 糾) for 24 h. After this time, the concentration of IL-8 in the culture supernatant was measured by sandwich-type ELISA kit. The effect of signalling pathways on TNF-?-induced IL-8 release was examined pharmacologically using selective NF-築/IKK2 (AS602868, 3 糾), (PD98059, 10 糾) and p38 mitogen activated protein kinase (MAPK) (SB203580, 1 糾) inhibitors. NF-築 DNA binding activity was measured by a DNA-binding ELISA-based assay. NF-築-p65-associated histone acetyltransferase (HAT) activity was measured by immunoprecipitation linked to commercial flourescent HAT. Results: TNF-?-induced IL-8 release was suppressed by an NF-築 inhibitor but not by MEK or p38 MAPK inhibitors. Montelukast induced a concentration-dependent inhibition of TNF-?-induced IL-8 release and mRNA expression that reached a plateau at 0.1 糾 without affecting cell viability. Montelukast did not affect NF-築 p65 activation as measured by DNA binding but suppressed NF-築 p65-associated HAT activity. Conclusion: Montelukast inhibits TNF-?-stimulated IL-8 expression through changes in NF-築 p65-associated HAT activity. Drugs targeting these enzymes may enhance the anti-inflammatory actions of montelukast.
机译：背景：孟鲁司特是一种有效的半胱氨酸白三烯-1受体拮抗剂，具有一些抗炎作用，尽管这些抗炎作用的分子机理尚不清楚。在这项研究中，我们旨在研究孟鲁司特对佛波醇肉豆蔻酸酯乙酸（PMA）分化的U937细胞中核因子（NF）-筑相关组蛋白乙酰化活性的影响。方法：我们检查了孟鲁司特对TNF-α诱导的PMA分化的U-937细胞中IL-8产生的抑制作用。将U-937细胞暴露于PMA（50 ng / mL）48小时，以使其分化为巨噬细胞。然后将巨噬细胞暴露于TNF-α。 （10 ng / mL）在存在或不存在孟鲁司特（0.01-10扭曲）的情况下持续24小时。此后，通过夹心型ELISA试剂盒测量培养上清液中IL-8的浓度。使用选择性NF-筑/ IKK2（AS602868，3纠偏），（PD98059，10纠偏）和p38丝裂原活化蛋白激酶（MAPK）（SB203580，药理学）检验了信号通路对TNF-α诱导的IL-8释放的影响。 1纠）抑制剂。通过基于DNA结合ELISA的测定法测量NF-筑DNA结合活性。 NF-筑-p65相关的组蛋白乙酰转移酶（HAT）活性是通过与商业荧光HAT相连的免疫沉淀来测量的。结果：TNF-α诱导的IL-8释放被NF-筑抑制剂抑制，但未被MEK或p38 MAPK抑制剂抑制。孟鲁司特诱导TNF-α诱导的IL-8释放和mRNA表达的浓度依赖性抑制，在0.1方向达到稳定水平，而不影响细胞活力。如通过DNA结合所测量的，孟鲁司特不影响NF-构筑p65的活化，但是抑制了NF-构筑p65相关的HAT活性。结论：孟鲁司特通过改变与NF-筑p65相关的HAT活性来抑制TNF-α刺激的IL-8表达。靶向这些酶的药物可能会增强孟鲁司特的抗炎作用。

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