Dual receptors and distinct pathways mediate interleukin-1 receptor-associated kinase degradation in response to lipopolysaccharide -: Involvement of CD14/TLR4, CR3, and phosphatidylinositol 3-kinase
Dual receptors and distinct pathways mediate interleukin-1 receptor-associated kinase degradation in response to lipopolysaccharide -: Involvement of CD14/TLR4, CR3, and phosphatidylinositol 3-kinase
复制标题
DOI：
10.1074/jbc.m312431200
复制
发表时间：
2004-06-11
影响因子：
4.8
通讯作者：
Reiner, NE
中科院分区：
文献类型：
--
作者：
Sanaâ, N;Hmama, Z;Reiner, NE
单核吞噬细胞中导致核因子κ b激活的脂多糖（LPS）信号涉及白细胞介素-1受体相关激酶（IRAK），该激酶在暴露于激动剂后迅速激活。虽然已知IRAK在LPS作用下也会经历快速失活/降解，提供负反馈导致LPS耐受，但控制IRAK降解的机制尚不完全清楚。在本研究中，对LPS信号的检测表明，IRAK的降解是双峰的，涉及双受体和不同的途径。暴露于激动剂30分钟内，IRAK的快速降解通过CD14/TLR4信号传导，并受磷脂酰肌醇3-激酶调节。暴露于LPS 2小时后，第二波延迟的IRAK降解发生，并由独立于磷脂酰肌醇3-激酶的CR3介导。因此，多种独立的机制已经进化到调节IRAK降解，可能反映了限制细胞对LPS反应的重要性。识别导致IRAK降解的cr3依赖、CD14/ tlr4独立的途径，有助于理解具有重要免疫调节功能的细胞（如CD14（-）的树突状细胞）对LPS反应的调节。
Lipopolysaccharide (LPS) signaling leading to nuclear factor-kappaB activation in mononuclear phagocytes involves interleukin-1 receptor-associated kinase ( IRAK), which is rapidly activated after exposure to agonist. Although it is known that IRAK also undergoes rapid inactivation/degradation in response to LPS, providing negative feedback leading to LPS tolerance, mechanisms governing IRAK degradation are not fully understood. In the present study, examination of LPS signaling showed that IRAK degradation was bimodal and involved dual receptors and distinct pathways. Rapid degradation of IRAK, occurring within 30 min of exposure to agonist, was shown to signal through CD14/TLR4 and was regulated by phosphatidylinositol 3-kinase. A second delayed wave of IRAK degradation occurred 2 h after exposure to LPS and was mediated by CR3 independently of phosphatidylinositol 3-kinase. Thus, multiple independent mechanisms have evolved to regulate IRAK degradation, likely reflecting the importance of limiting cellular responses to LPS. Recognition of a CR3-dependent, CD14/TLR4-independent pathway leading to IRAK degradation has implications for understanding modulation of LPS responses by cells with important immunoregulatory function such as dendritic cells that are CD14(-).