LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species - Dependent manner
LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species - Dependent manner
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DOI：
10.1089/ars.2007.1825
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发表时间：
2008-05-01
影响因子：
6.6
通讯作者：
Hirota, Kiichi
中科院分区：
文献类型：
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作者：
Nishi, Kenichiro;Oda, Tomoyuki;Hirota, Kiichi
各种发炎和患病组织的一个突出特征是存在低氧张力（缺氧）。先天免疫系统的效应细胞必须在缺氧微环境中维持其活力和生理功能。在血流中循环的单核细胞分化成巨噬细胞。在此过程中，细胞获得在炎症缺氧部位发挥作用的能力。转录因子缺氧诱导因子1（HIF-1）介导的适应性反应，减少氧气供应。在这项研究中，我们证明，脂多糖（LPS）诱导HIF-1激活，通过增强HIF-1 α蛋白表达，通过一个依赖性的途径和HIF-1 α转录活性在THP-1人髓样细胞，经历了巨噬细胞分化，但不是在未分化的单核细胞THP-1细胞。LPS诱导的HIF-1活化被抗氧化剂（N-乙酰半胱氨酸或硫氧还蛋白-1）、NADPH氧化酶抑制剂（diphenyleneiodonium）阻断，表明响应LPS产生的活性氧在此过程中是必不可少的。LPS介导的HIF-1的活化不依赖于NF-κ B活性。LPS诱导的ROS产生和HIF-1激活需要Toll样受体4或髓样分化因子（MyD）88的表达，从而为在分化的THP-1细胞中选择性激活HIF-1提供了分子基础。
A prominent feature of various inflamed and diseased tissue is the presence of low oxygen tension (hypoxia). Effector cells of the innate immune system must maintain their viability and physiologic functions in a hypoxic microenvironment. Monocytes circulating in the bloodstream differentiate into macrophages. During this process, cells acquire the ability to exert effects at hypoxic sites of inflammation. The transcription factor hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability. In this study, we demonstrated that lipopolysaccharide (LPS) induces HIF-1 activation by enhancing both HIF-1 alpha protein expression through a translation-dependent pathway and HIF-1 alpha transcriptional activity in THP-1 human myeloid cells that have undergone macrophage differentiation but not in undifferentiated monocytic THP-1 cells. LPS-induced HIF-1 activation was blocked by treatment with antioxidant (N-acetylcysteine or thioredoxin-1), NADPH oxidase inhibitor (diphenyleneiodonium), indicating that reactive oxygen species generated in response to LPS are essential in this process. LPS-mediated activation of HIF-1 was independent of NF-kappa B activity. LPS-induced ROS generation and HIF-1 activation required the expression of Toll-like receptor 4 or myeloid differentiation factor (MyD) 88, thus providing a molecular basis for the selective activation of HIF-1 in differentiated THP-1 cells.