IκB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells
IκB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells
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DOI：
10.1182/blood.v94.5.1711.417k20_1711_1716
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发表时间：
1999-09-01
期刊：
影响因子：
20.3
通讯作者：
Ballard, DW
中科院分区：
文献类型：
--
作者：
Hawiger, J;Veach, RA;Ballard, DW
内毒素脂多糖（LPS）是一种由革兰氏阴性菌产生的促炎激动剂，是美国医院每年记录的400，000例脓毒性休克病例中的大多数的原因。LPS的主要靶细胞是单核细胞和巨噬细胞。它们的反应包括大量产生促炎细胞因子、活性氧和氮中间体、促凝血剂和细胞粘附分子。反过来，这些LPS反应因子的表达导致循环系统的崩溃、弥散性血管内凝血和30%的死亡率。单核细胞和巨噬细胞中感染性休克基因表达的常见细胞内机制涉及NF-κ B的活化。该转录因子由结构相关的抑制剂家族调节，包括I kappa B α、I kappa B β和I kappa B β，其将NF-κ B捕获在细胞质中。在这份报告中，研究人员表明，来自不同革兰氏阴性菌的LPS激活了对精氨酸敏感的I κ B激酶，该激酶含有称为IKK α（IKK 1）和IKK β（IKK 2）的催化亚基。LPS刺激的人单核细胞中IKK α和IKK β活化的动力学与用肿瘤坏死因子-α刺激时记录的不同，从而暗示了不同的活化机制。LPS激活的IKK复合物磷酸化所有3种NF-κ B抑制剂：I κ B α、I κ B β和I κ B β。此外，相对于IKK α，LPS优先激活IKK β。因此，IKK复合物构成了LPS诱导的NF-κ B信号传导至人单核细胞核以激活引起败血性休克的基因的主要细胞内靶点。(C)1999年，美国血液学会。
Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-kappa B. This transcription factor is regulated by a family of structurally related inhibitors including I kappa B alpha, I kappa B beta, and I kappa B epsilon, which trap NF-KB in the cytoplasm. In this report, the investigators show that LPS derived from different gramnegative bacteria activates cytokine-responsive I kappa B kinases containing catalytic subunits termed IKK alpha (IKK1) and IKK beta (IKK2). The kinetics of IKK alpha and IKK beta activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-alpha, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-kappa B: I kappa B alpha, I kappa B beta, and I kappa B epsilon. Moreover, LPS activates IKK beta preferentially, relative to IKK alpha. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappa B signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock. (C) 1999 by The American Society of Hematology.