Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1β-rich microparticles.
Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1β-rich microparticles.
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DOI：
10.4049/jimmunol.1001623
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发表时间：
2011-05-01
期刊：
影响因子：
--
通讯作者：
McIntyre TM
中科院分区：
文献类型：
--
作者：
Brown GT;McIntyre TM
血小板含有未剪接的异源IL-1β RNA，其在活化后快速剪接和翻译。LPS是这种非典型血小板反应的上级激动剂，但LPS如何诱导缺乏NF-κB的无核细胞产生促炎细胞因子尚不清楚。血小板表达功能性TLR 4，经caspase-1加工后，LPS刺激诱导IL-1β快速剪接、翻译和分泌。LPS刺激微粒脱落，分泌的IL-1β仅存在于这些微粒中。LPS刺激的血小板微粒诱导培养的人内皮细胞产生VCAM-1，用IL-1受体拮抗剂阻断内皮细胞IL-1β受体可完全抑制内皮细胞活化。剪接是转录后的，因为SR激酶抑制剂TG 003阻断血小板产生IL-1β RNA，但不阻断单核细胞产生IL-1β RNA，并且剪接依赖于血小板的外源性CD 14- a特性。我们使用小分子抑制剂、细胞穿透嵌合肽抑制剂和基因靶向动物的组合来显示剪接所需的MyD 88和TIRAP以及IRAK 1/4、AKT和JNK磷酸化和激活。TRAF 6将MyD 88与AKT通路偶联，并且值得注意的是，TRAF 6相互作用肽-触角足嵌合体在刺激IL-1β剪接方面比LPS更有效。然而，TRAF 6嵌合体不刺激微粒脱落，也不释放IL-1β。我们得出结论，LPS诱导的激酶级联反应足以改变细胞反应，三个信号来自血小板TLR 4，AKT和JNK激活足以启动转录后剪接，而另一个事件夫妇微粒脱落TLR 4激活。血小板通过产生促进内皮细胞活化的微粒而促进对LPS的炎症反应。
Platelets contain unspliced heteronuclear IL-1β RNA, which is rapidly spliced and translated upon activation. LPS is a superior agonist for this atypical platelet response, but how LPS induces proinflammatory cytokine production in anucleate cells lacking NF-κB is unknown. Platelets express functional TLR4, and stimulation by LPS induced rapid splicing, translation and secretion of mature IL-1β after caspase-1 processing. LPS stimulated microparticle shedding, and secreted IL-1β was exclusively present in these particles. Microparticles from LPS-stimulated platelets induced VCAM-1 production by cultured human endothelial cells, and blockade of endothelial IL-1β receptor with IL-1 receptor antagonist completely suppressed endothelial activation. Splicing was post-transcriptional as the SR kinase inhibitor TG003 blocked IL-1β RNA production by platelets, but not by monocytes, and was dependent on exogenous CD14 - a property of platelets. We used a combination of small molecule inhibitors, cell-penetrating chimeric peptide inhibitors, and gene-targeted animals to show splicing required MyD88 and TIRAP, and IRAK1/4, AKT and JNK phosphorylation and activation. TRAF6 couples MyD88 to the AKT pathway and, remarkably, a TRAF6 interacting peptide-antennapedia chimera was more effective than LPS in stimulating IL-1β splicing. The TRAF6 chimera did not, however, stimulate microparticle shedding, nor was IL-1β released. We conclude LPS-induced kinase cascades are sufficient to alter cellular responses, that three signals emanate from platelet TLR4, and that AKT and JNK activation are sufficient to initiate post-transcriptional splicing while another event couples microparticle shedding to TLR4 activation. Platelets contribute to the inflammatory response to LPS through production of microparticles that promote endothelial cell activation.
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