Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction Of β2 integrin gene expression
Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction Of β2 integrin gene expression
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DOI：
10.1073/pnas.0401339101
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发表时间：
2004-07-13
影响因子：
11.1
通讯作者：
Shelley, CS
中科院分区：
文献类型：
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作者：
Kong, TQ;Eltzschig, HK;Shelley, CS
炎症反应与组织代谢的显著变化有关。特别是，炎症期间的代谢变化可导致显著的组织缺氧，从而诱导缺氧反应基因。鉴于这种关联，我们假设白细胞功能反应受到缺氧的影响。最初的实验表明，暴露于缺氧的促红细胞系U937导致活化内皮的粘附增加。这种增加是转录依赖的，并被针对β(2)的抗体阻断，而不是β(1)，整合素。对U937细胞中92个整合素mRNA和蛋白的分析显示，缺氧时其含量增加5 ~ 6倍。将这一分析扩展到缺氧的人全血中，发现92种整合素mRNA和蛋白在体外有明显的诱导作用。此外，小鼠O-2整合素mRNA在体内缺氧时被显著诱导。随后的研究在CD18基因中发现了含氧因子1 （HIF-1）的结合位点。该基因编码四种已知β蛋白共有的亚基(2)。整合素异质二聚体。在体内证明了HIF-1的结合，CD18启动子内HIF-11位点的突变分析导致缺氧诱导能力的丧失。综上所述，这些结果表明，缺氧通过依赖于HIF-1的转录机制诱导白细胞β(2)整合素的表达和功能。
Inflammatory responses are associated with significant changes in tissue metabolism. In particular, metabolic shifts during inflammation can result in significant tissue hypoxia, with resultant induction of hypoxia-responsive genes. Given this association, we hypothesized that leukocyte functional responses are influenced by hypoxia. Initial experiments revealed that exposure of the promonocytic cell line U937 to hypoxia resulted in increased adhesion to activated endothelia. Such increases were transcription-dependent and were blocked by antibodies directed against beta(2), but not beta(1), integrins. Analysis Of 92 integrin mRNA and protein in U937 cells revealed a 5 to 6-fold increase with hypoxia. Extension of this analysis to hypoxic human whole blood revealed prominent induction Of 92 integrin mRNA and protein ex vivo. Furthermore, murine O-2 integrin mRNA was found to be significantly induced during hypoxia in vivo. Subsequent studies identified a binding site for hypoxia-inclucible factor 1 (HIF-1) in the CD18 gene. This gene encodes the subunit common to all four known types of beta(2). integrin heterodimer. HIF-1 binding was demonstrated in vivo, and mutational analysis of the HIF-11 site within the CD18 promoter resulted in a loss of hypoxia inducibility. Taken together, these results demonstrate that hypoxia induces leukocyte beta(2) integrin expression and function by transcriptional mechanisms dependent upon HIF-1.