Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB
Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB
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DOI：
10.1042/bj20051839
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发表时间：
2006-06-15
影响因子：
4.1
通讯作者：
Fandrey, Joachim
中科院分区：
文献类型：
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作者：
Frede, Stilla;Stockmann, Christian;Fandrey, Joachim
炎症介质激活转录复合体HIF-1(低氧诱导因子-1)，它是低氧诱导基因表达的关键调节因子。本文报道了细菌脂多糖在常氧条件下诱导人单核细胞以及人单核细胞系THP-1未分化和分化细胞中HIF-1αmRNA表达和HIF-1α蛋白积聚。脂多糖和低氧协同激活HIF-1。而内毒素通过激活HIF-1α基因启动子中的核因子kappa B(核因子kappa B)位点来增加HIF-1αmRNA的表达，而低氧翻译后稳定HIF-1α蛋白。HIF-1α激活后，编码ADM(肾上腺髓质素)的HIF-1靶基因表达增加。RNA干扰抑制HIF-1α可显著降低ADM的表达，说明HIF-1在常氧条件下脂多糖诱导的ADM表达中的重要性。在HIF-1激活的同时，经内毒素孵育后，p44/42MAPK(丝裂原活化蛋白激酶)的磷酸化水平增加。在p44/42MAPK抑制剂PD 98059或针对p44/42MAPK的RNA干扰处理的细胞中，内毒素诱导的HIF-1α积聚和ADM表达显著减少。根据这些结果，我们认为内毒素在HIF-1的激活中起关键作用，p44/42MAPK和NF-kappa B通路是内毒素诱导ADM表达的重要转录因子。
Inflammatory mediators activate the transcriptional complex HIF-1 (hypoxia-inducible factor-1), the key regulator of hypoxia-induced gene expression. Here we report that bacterial LPS (lipopolysaccharide) induces HIF-1 alpha mRNA expression and HIF-1 alpha protein accumulation in human monocytes as well as in non-differentiated and differentiated cells of the human monocytic cell line THP-1 under normoxic conditions. LPS and hypoxia synergistically activated HIF-1. Whereas LPS increased HIF-1 alpha mRNA expression through activation of a NF-kappa B (nuclear factor kappa B) site in the promoter of the HIF-1 alpha gene, hypoxia post-translationally stabilized HIF-1 alpha protein. HIF-1 alpha activation was followed by increased expression of the HIF-1 target gene encoding ADM (adrenomedullin). Knocking down HIF-1 alpha by RNA interference significantly decreased ADM expression, which underlines the importance of HIF-1 for the LPS-induced ADM expression in normoxia. Simultaneously with HIF-1 activation, an increase in p44/42 MAPK (mitogen-activated protein kinase) phosphorylation was observed after incubation with LPS. In cells pretreated with the p44/42 MAPK inhibitor PD 98059 or with RNAi (interfering RNA) directed against p44/42 MAPK, LPS-induced HIF-1 alpha accumulation and ADM expression were significantly decreased. From these results we conclude that LPS critically involves the p44/42 MAPK and NF-kappa B pathway in the activation of HIF-1, which is an important transcription factor for LPS-induced ADM expression.