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Study on the regulatory role of hypoxia sensor or hypoxia-inducible factor 1 system in inflammation

缺氧传感器或缺氧诱导因子1系统在炎症中的调节作用研究

基本信息

批准号：
16591576
负责人：
HIROTA Kiichi
金额：
$ 2.3万
依托单位：
Kyoto University (2005)Tazuke Kofukai Medical Research Institute (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591576/
关键词：
hypoxia macrophage differentiation hypoxia sensor inflammation HIF-1

项目摘要

Monocytes/macrophages of the myeloid lineage are the main cellular effectors of innate immunity. Hypoxia inducible factor-1 (HIF-1) is essential for myeloid cell activation in response to inflammatory stimuli. However, it has not been established whether HIF-1 activity is induced during differentiation from monocyte to macrophage. We demonstrate that macrophage differentiation of THP-1 cells or monocytes from peripheral blood induces increased expression of both HIF-1a and HIF-1b as well as increased HIF-1 transcriptional activity leading to increased expression of HIF-1 target genes. The increased HIF-1 activity in differentiated THP-1 cells resulted from the combined effect of increased HIF-1a mRNA levels and increased HIF-1a protein synthesis. Differentiation-induced HIF-1a protein and mRNA and HIF-1-dependent gene expression was blocked by treating cells with an inhibitor of the protein kinase C or MAP kinase signaling pathway. We also demonstrate that lipopolysaccharide induces HIF-1 activation by enhancing both HIF-1a protein expression through a translation-dependent pathway and HIF-1a transcriptional activity in THP-1 cells that have undergone macrophage differentiation, but not in undifferentiated monocytic THP-1 cells, via a pathway that requires the generation of reactive oxygen species.

骨髓系的单核细胞/巨噬细胞是先天免疫的主要细胞效应子。缺氧诱导因子-1（HIF-1）是髓系细胞活化所必需的炎症刺激。然而，尚未确定HIF-1活性是否在从单核细胞分化为巨噬细胞期间被诱导。我们证明，THP-1细胞或外周血单核细胞的巨噬细胞分化诱导HIF-1a和HIF-1b的表达增加，以及HIF-1的转录活性增加，导致HIF-1靶基因的表达增加。在分化的THP-1细胞中HIF-1活性的增加是由于HIF-1a mRNA水平增加和HIF-1a蛋白合成增加的综合作用。用蛋白激酶C或MAP激酶信号通路抑制剂处理细胞，可阻断分化诱导的HIF-1a蛋白和mRNA以及HIF-1依赖性基因表达。我们还表明，脂多糖诱导HIF-1激活，通过增强HIF-1a蛋白的表达，通过一个依赖于抑制的途径和HIF-1a的转录活性在THP-1细胞，已经历巨噬细胞分化，但不是在未分化的单核细胞THP-1细胞，通过一个途径，需要产生活性氧。