Hypoxia modifies the transcriptome of primary human monocytes: Modulation of novel immune-related genes and identification of CC-chemokine ligand 20 as a new hypoxia-inducible gene
Hypoxia modifies the transcriptome of primary human monocytes: Modulation of novel immune-related genes and identification of CC-chemokine ligand 20 as a new hypoxia-inducible gene
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DOI：
10.4049/jimmunol.177.3.1941
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发表时间：
2006-08-01
影响因子：
4.4
通讯作者：
Varesio, Luigi
中科院分区：
文献类型：
--
作者：
Bosco, Maria Carla;Puppo, Maura;Varesio, Luigi
外周血单核细胞迁移到炎症和肿瘤病变的缺氧区并积聚。为了表征低氧微环境中单核细胞功能的分子基础，我们使用高密度寡核苷酸微阵列研究了低氧诱导的原代人类单核细胞的转录谱。暴露于1%O-2 16h后，基因表达谱发生了深刻的变化，分别有536条和677条序列至少增加和减少了1.5倍。通过定量RT-PCR确认所选基因的表达差异，验证了该分析的有效性。在调节基因中，74个是已知的低氧反应基因，而大多数是以前没有描述过的对低氧反应的新基因。低氧转录组的特征是与免疫学相关的一组重要基因的调节。这些受体包括清道夫受体(CD163、STAB1、C1qR1、MSR1、MARCO、TLR7)、免疫调节、共刺激和黏附分子(CD32、CD64、CD69、CD89、CMRF-35H、ITGB5、LAIR1、LIR9)、趋化因子/细胞因子和受体(CCL23、CCL15、CCL8、CCR1、CCR2、RDC1、IL-23A、IL-6S7)。此外，我们提供了CCL20低氧诱导的确凿证据，CCL20是一种对未成熟树突状细胞、激活/记忆T淋巴细胞和幼稚B细胞的趋化诱导剂。CCL20mRNA的上调与蛋白表达和分泌的增加是平行的。这项研究是首次对缺氧的原代人类单核细胞进行转录组分析，这为研究缺血/缺氧组织中单核细胞的功能行为提供了新的见解。低氧上调CCL20可能是促进特定白细胞亚群在病理部位募集的重要机制，并可能在慢性炎症性疾病的发病机制中发挥作用。
Peripheral blood monocytes migrate to and accumulate in hypoxic areas of inflammatory and tumor lesions. To characterize the molecular bases underlying monocyte functions within a hypoxic microenvironment, we investigated the transcriptional profile induced by hypoxia in primary human monocytes using high-density oligonucleotide microarrays. Profound changes in the gene expression pattern were detected following 16 h exposure to 1% O-2, with 536 and 677 sequences showing at least a 1.5-fold increase and decrease, respectively. Validation of this analysis was provided by quantitative RT-PCR confirmation of expression differences of selected genes. Among modulated genes, 74 were known hypoxia-responsive genes, whereas the majority were new genes whose responsiveness to hypoxia had not been previously described. The hypoxic transcriptome was characterized by the modulation of a significant cluster of genes with immunological relevance. These included scavenger receptors (CD163, STAB1, C1qR1, MSR1, MARCO, TLR7), immunoregulatory, costimulatory, and adhesion molecules (CD32, CD64, CD69, CD89, CMRF-35H, ITGB5, LAIR1, LIR9), chemokines/cytokines and receptors (CCL23, CCL15, CCL8, CCR1, CCR2, RDC1, IL-23A, IL-6S7). Furthermore, we provided conclusive evidence of hypoxic induction of CCL20, a chemoattractant for immature dendritic cells, activated/memory T lymphocytes, and naive B cells. CCL20 mRNA up-regulation was paralleled by increased protein expression and secretion. This study represents the first transcriptome analysis of hypoxic primary human monocytes, which provides novel insights into monocyte functional behavior within ischemic/hypoxic tissues. CCL20 up-regulation by hypoxia may constitute an important mechanism to promote recruitment of specific leukocyte subsets at pathological sites and may have implications for the pathogenesis of chronic inflammatory diseases.