Divergence of bacterial lipopolysaccharide pro-apoptotic signaling downstream of IRAK-1
Divergence of bacterial lipopolysaccharide pro-apoptotic signaling downstream of IRAK-1
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DOI：
10.1074/jbc.m111249200
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发表时间：
2002-03-08
影响因子：
4.8
通讯作者：
Harlan, JM
中科院分区：
文献类型：
--
作者：
Bannerman, DD;Tupper, JC;Harlan, JM
血管内皮是循环细菌脂多糖（LPS）的关键靶点。LPS引起广泛的内皮反应，包括细胞因子、粘附分子和组织因子的上调，其中许多依赖于NF-κ B活化。此外，LPS已被证明在体外和体内诱导内皮细胞凋亡。虽然LPS激活NF-κ B的机制已被很好地阐明，但LPS诱导的细胞凋亡中涉及的信号通路仍不清楚。使用各种显性负性构建体，我们已经确定了MyD 88和白细胞介素-1受体相关激酶-1（IRAK-1）在人内皮细胞中介导LPS促凋亡信号传导中的作用。我们还证明了LPS诱导的内皮NF-κ B活化和凋亡的发生是相互独立的。总之，这些数据表明，参与LPS诱导的NF-κ B活化的近端信号分子在LPS诱导的细胞凋亡中具有必要的参与，并且导致NF-κ B活化和细胞凋亡的途径在IRAK-1下游发散。
The vascular endothelium is a key target of circulating bacterial lipopolysaccharide (LPS). LPS elicits a wide array of endothelial responses, including the up-regulation of cytokines, adhesion molecules, and tissue factor, many of which are dependent on NF-kappaB activation. In addition, LPS has been demonstrated to induce endothelial apoptosis both in vitro and in vivo. Although the mechanism by which LPS activates NF-kappaB has been well elucidated, the signaling pathway(s) involved in LPS-induced apoptosis remains unknown. Using a variety of dominant negative constructs, we have identified a role for MyD88 and interleukin-1 receptor-associated kinase-1 (IRAK-1) in mediating LPS pro-apoptotic signaling in human endothelial cells. We also demonstrate that LPS-induced endothelial NF-kappaB activation and apoptosis occur independent of one another. Together, these data suggest that the proximal signaling molecules involved in LPS-induced NF-kappaB activation have a requisite involvement in LPS-induced apoptosis and that the pathways leading to NF-kappaB activation and apoptosis diverge downstream of IRAK-1.