Cutting edge:: Essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis
Cutting edge:: Essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis
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DOI：
10.4049/jimmunol.178.12.7516
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Nizet, Victor
中科院分区：
文献类型：
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作者：
Peyssonnaux, Carole;Cejudo-Martin, Pilar;Nizet, Victor
脓毒症是重症监护病房死亡的主要原因，反映了细菌或LPS作为免疫细胞（包括单核细胞和巨噬细胞）的有效激活剂对感染的有害宿主反应。在本报告中，我们发现LPS提高巨噬细胞中转录调节因子缺氧诱导因子-1 α (HIF-1 α)的水平，以tlr4依赖的方式增加HIF-1 α并减少脯氨酸羟化酶mRNA的产生。利用小鼠条件基因靶向HIF-1 α在骨髓谱系，我们证明HIF-1 α是脓毒症表型的关键决定因素。HIF-1 α促进炎性细胞因子的产生，包括tnf - α、IL-1、IL-4、IL-6和IL-12，这些因子在早期败血症时在宿主体内达到有害水平。巨噬细胞中的HIF-1 α缺失对lps诱导的死亡具有保护作用，并阻止低血压和低体温等临床标志物的发展。因此，抑制HIF-1 α活性可能是lps诱导脓毒症的新治疗靶点。
Sepsis, the leading cause of death in intensive care units, reflects a detrimental host response to infection in which bacteria or LPS act as potent activators of immune cells, including monocytes and macrophages. In this report, we show that LPS raises the level of the transcriptional regulator hypoxia-inducible factor-1 alpha (HIF-1 alpha) in macrophages, increasing HIF-1 alpha and decreasingprolyl hydroxylase mRNA production in a TLR4-dependent fashion. Using murine conditional gene targeting, of HIF-1 alpha in the myeloid lineage, we demonstrate that HIF-1 alpha is a critical determinant of the sepsis phenotype. HIF-1 alpha promotes the production of inflammatory cytokines, including TNF-alpha, IL-1, IL-4, IL-6, and IL-12, that reach harmful levels in the host during early sepsis. HIF-1 alpha deletion in macrophages is protective against LPS-induced mortality and blocks the development of clinical markers including hypotension and hypothermia. Inhibition of HIF-1 alpha activity may thus represent a novel therapeutic target for LPS-induced sepsis.