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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Hypoxia transcriptionally induces macrophage-inflammatory protein-3alpha/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-kappaB.
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Hypoxia transcriptionally induces macrophage-inflammatory protein-3alpha/CCL-20 in primary human mononuclear phagocytes through nuclear factor (NF)-kappaB.

机译：缺氧通过核因子（NF）-κB在原代人单核吞噬细胞中转录诱导巨噬细胞炎性蛋白3alpha / CCL-20。

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摘要

Hypoxia, a condition of low oxygen tension, occurring in many pathological processes, modifies the mononuclear phagocyte transcriptional profile. Here, we demonstrate hypoxic up-regulation of the CCL20 chemokine in primary human monocytes (Mn) and macrophages. mRNA induction was paralleled by protein secretion and dependent on gene transcription activation. Functional studies of the CCL20 promoter using a series of 5'-deleted and mutated reporter constructs demonstrated the requirement for the NF-kappaB-binding site located at position -92/-82 for gene transactivation by hypoxia, as 1) transcription was abrogated by a 3-bp mutation of the NF-kappaB motif; 2) three copies of the wild-type NF-kappaB-binding site conferred hypoxia responsiveness to a minimal heterologous promoter; and 3) hypoxia increased specific NF-kappaB binding to this sequence. Furthermore, we provide evidence of the specific role of a single NF-kappaB family member, p50, in mediating CCL20 gene transcription in hypoxic Mn. p50 homodimers were the only detectable NF-kappaB complexes binding the cognate kappaB site on the CCL20 promoter upon hypoxia exposure, and NF-kappaBp50 knockdown by lentiviral-mediated short hairpin RNA interference resulted in complete binding inhibition. NF-kappaBp50 overexpression in transient cotransfection studies promoted CCL20 gene transactivation, which was abrogated by mutation of the -92/-82 kappaB site. Moreover, nuclear expression of the other NF-kappaB family members was inhibited in hypoxic Mn. In conclusion, this study characterizes a previously unrecognized role for hypoxia as a transcriptional inducer of CCL20 in human mononuclear phagocytes and highlights the importance of the NF-kappaB pathway in mediating this response, with potential implications for inflammatory disease and cancer pathogenesis.
机译：缺氧是许多病理过程中发生的一种低氧张力状态，可改变单核吞噬细胞的转录特性。在这里，我们证明原代人单核细胞（Mn）和巨噬细胞中CCL20趋化因子的低氧上调。 mRNA诱导与蛋白质分泌平行，并依赖于基因转录激活。使用一系列5'缺失和突变的报告基因构建体对CCL20启动子进行的功能研究表明，缺氧的基因反式激活需要位于-92 / -82位的NF-κB结合位点，因为1）转录被NF-κB基序的3bp突变; 2）三拷贝的野生型NF-κB结合位点赋予对最小异源启动子的低氧反应性; 3）低氧增加了特异性NF-κB与该序列的结合。此外，我们提供了单个NF-κB家族成员p50在介导缺氧Mn中CCL20基因转录中的特定作用的证据。 p50同二聚体是在缺氧暴露后结合CCL20启动子上同源kappaB位点的唯一可检测到的NF-kappaB复合物，慢病毒介导的短发夹RNA干扰导致的NF-kappaBp50敲低导致完全的结合抑制。在瞬时共转染研究中，NF-kappaBp50的过表达促进了CCL20基因的反式激活，这被-92 / -82 kappaB位点的突变所废除。此外，在低氧锰中其他NF-κB家族成员的核表达受到抑制。总而言之，这项研究表征了缺氧在人类单核吞噬细胞中作为CCL20转录诱导物的低氧作用，并突显了NF-κB通路在介导这种反应中的重要性，对炎性疾病和癌症发病机理具有潜在的影响。

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