Activation of hypoxia-inducible factor 1 during macrophage differentiation
Activation of hypoxia-inducible factor 1 during macrophage differentiation
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DOI：
10.1152/ajpcell.00614.2005
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发表时间：
2006-07-01
影响因子：
5.5
通讯作者：
Nohara, Ryuji
中科院分区：
文献类型：
--
作者：
Oda, Tomoyuki;Hirota, Kiichi;Nohara, Ryuji
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）是髓样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-1 α和HIF-1 α的表达增加，以及HIF-1转录活性增加，导致HIF-1靶基因的表达增加。在分化的THP-1细胞中增加的HIF-1活性是由增加的HIF-1 α mRNA水平和增加的HIF-1 α蛋白合成的组合作用引起的。分化诱导的HIF-1 α蛋白和mRNA和HIF-1依赖的基因表达被阻断与蛋白激酶C或MAP激酶信号通路的抑制剂处理细胞。THP-1细胞分化还与翻译调节蛋白p70 S6激酶、S6核糖体蛋白、真核起始因子4 E和4 E结合蛋白1的磷酸化增加相关，从而提供了调节HIF-1 α蛋白合成的可能机制。RNA干扰研究表明，HIF-1 α是巨噬细胞分化所必需的，但功能成熟所必需的。
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-1 alpha and HIF-1 alpha 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-1 alpha mRNA levels and increased HIF-1 alpha protein synthesis. Differentiation-induced HIF-1 alpha 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. THP-1 cell differentiation was also associated with increased phosphorylation of the translational regulatory proteins p70 S6 kinase, S6 ribosomal protein, eukaryotic initiation factor 4E, and 4E binding protein 1, thus providing a possible mechanism for the modulation of HIF-1 alpha protein synthesis. RNA interference studies demonstrated that HIF-1 alpha is dispensable for macrophage differentiation but is required for functional maturation.