目的 支气管平滑肌对气道收缩剂的高反应性是哮喘的主要病理表现,但这种现象背后的分子机制尚未明确.肿瘤坏死因子-α(TNF-α)和白细胞介素-1β(IL-1β)的释放对气道高反应性的发生起重要作用.研究旨在考察促炎性细胞因子 TNF-α和IL-1β对缓激肽、内皮素-1和血栓素A2的G蛋白偶联受体(GPCR)在人支气管平滑肌细胞(HBSMCs)中mRNA水平的影响.方法 将HBSMCs与炎性细胞因子 TNF-α,IL-1β,IL-6,IL-13以及MAPK信号通路抑制剂共同培养后,检测缓激肽受体B1和B2、内皮素B受体、血栓素A2受体和β2肾上腺素受体mRNA水平的变化.结果 TNF-α增加了HBSMCs中缓激肽B1和B2受体的mRNA水平,IL-1β增加了 HBSMCs中的内皮素B受体的 mRNA水平.P38 MAPK 抑制剂 SB203580和 JNK 抑制剂SP600125降低了TNF-α上调的缓激肽受体mRNA水平,MEK1/2抑制剂U0126和IκB激酶抑制剂TPCA-1消除了由IL-1β引起的内皮素B受体的mRNA水平增加.结论 TNF-α通过p38 MAPK和JNK信号通路在转录水平上调缓激肽B1和B2受体,IL-1β通过MEK1/2和下游NF-κB通路在转录水平上调HBSMCs中内皮素B受体.%Objective The molecular mechanisms behind airway-hyperresponsiveness to bronchoconstrictor are not fully understood. Release of tumor necrosis factor-alpha(TNF-α)and interleukin-1beta(IL-1β)during the inflammatory process is believed to play an important role in airway hyperresponsiveness.In the present study,the effects of pro-inflammatory cytokines TNF-αand IL-1β on the G-protein coupled receptors(GPCRs)mRNA for bradykinin,endothelin-1 and thromboxane A2in human airway smooth muscle cells(HBSMCs)were investigated.Methods Human bronchial smooth muscle cells(HBSMCs)were treated with TNF-α, IL-1β,IL-6,IL-13 and MAPK signaling pathway inhibitors,then bradykinin receptor B1 and B2,endothelin type B receptor,throm-boxane A2receptor and β2-adrenoceptor mRNA was investigated.Results Bradykinin B1 and B2 receptor mRNA was increased by TNF-αand endothelin type B receptor mRNA was increased by IL-1βin HBSMCs.P38 MAPK inhibitor SB203580 and JNK inhibi-tor SP600125 attenuated the TNF-αenhanced bradykinin receptors mRNA and MEK1/2 inhibitor U0126 and IκB kinase inhibitor TPCA-1 abrogated the IL-1βenhanced endothelin type B receptor mRNA.Conclusion TNF-αtranscriptionally upregulates bradyki-nin B1 and B2 receptors via p38 MAPK and JNK signaling pathway and IL-1βtranscriptionally upregulates the endothelin receptor type B via MEK1/2 and the downstream NF-κB pathway in HBSMCs.
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