Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance (Retracted Article)
Hypoxia-Inducible Factor (HIF) 1α Accumulation and HIF Target Gene Expression Are Impaired after Induction of Endotoxin Tolerance (Retracted Article)
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DOI：
10.4049/jimmunol.0802378
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发表时间：
2009-05-15
影响因子：
4.4
通讯作者：
Fandrey, Joachim
中科院分区：
文献类型：
--
作者：
Frede, Stilla;Stockmann, Christian;Fandrey, Joachim
氧敏感性转录因子缺氧诱导因子1（hypoxia-inducible factor 1，HIF-1）是缺氧诱导基因表达的关键调节因子。除缺氧外，内毒素如细菌LPS以及促炎细胞因子已显示诱导HIF-1，表明HIF-1在缺氧和炎症条件下的整合作用。细胞可以通过反复暴露于LPS而变得对内毒素耐受。在此，我们研究了内毒素耐受对人单核细胞和原代小鼠腹腔巨噬细胞中HIF-1 α积累和HIF靶基因表达的影响。耐受细胞在缺氧条件下具有降低的HIF-1 α水平，这是由于HIF-1 α mRNA水平降低。HIF-1 α表达受NF-κ B B控制，在耐受细胞中发现NF-κ B B的p52亚基的DNA结合增加。敲低p52可消除内毒素耐受对HIF-1 α表达的影响，这表明p52在内毒素耐受期间对HIF-1 α转录具有负调节作用。内毒素耐受细胞显示HIF靶基因磷酸甘油酸激酶1和肾上腺髓质素的表达减少，在缺氧条件下生存能力降低，以及侵袭力显著降低。来自内毒素耐受小鼠的腹膜巨噬细胞显示出显着降低的HIF-1 α蛋白积累和随后的HIF靶基因表达。我们的结论是，内毒素耐受性损害HIF-1 α诱导，从而降低单核细胞在缺氧条件下的生存和功能的能力。免疫学杂志，2009，182：6470-6476.
The oxygen-sensitive transcription factor hypoxia-inducible factor 1 (HIF-1) is known as the key regulator of hypoxia-induced gene expression. In addition to hypoxia, endotoxins such as bacterial LPS as well as proinflammatory cytokines have been shown to induce HIF-1, suggesting an integrative role for HIF-1 in conditions of hypoxia and inflammation. Cells can become tolerant to endotoxins by repetitive exposure to LPS. Herein, we studied the effect of endotoxin tolerance on HIF-1 alpha accumulation and expression of HIF target genes in human monocytic cells and primary mouse peritoneal macrophages. Tolerant cells had reduced levels of HIF-1 alpha under hypoxia, which was due to lowered levels of HIF-1 alpha mRNA. HIF-1 alpha expression is under control of NF-kappa B and increased DNA binding of the p52 subunit of NF-kappa B was found in tolerant cells. Knock down of p52 abolished the effects of endotoxin tolerance on HIF-1 alpha expression, which suggest a negative regulatory role of p52 on HIF-1 alpha transcription during endotoxin tolerance. Endotoxin tolerant cells showed diminished expression of the HIF target genes phosphoglycerate kinase 1 and adrenomedullin and reduced viability under hypoxic conditions, as well as a significantly reduced invasion. Peritoneal macrophages from endotoxin-tolerant mice made showed significantly reduced HIF-1 alpha protein accumulation and subsequent HIF target gene expression. We conclude that endotoxin tolerance impairs HIF-1 alpha induction which reduces the ability of monocytic cells to survive and function under hypoxic conditions. The Journal of Immunology, 2009, 182: 6470-6476.