Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages.
Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages.
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DOI：
10.1002/eji.201142079
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发表时间：
2012-03
影响因子：
5.4
通讯作者：
Brough, David
中科院分区：
文献类型：
--
作者：
Luheshi, Nadia M.;Giles, James A.;Lopez-Castejon, Gloria;Brough, David
白细胞介素-1 β（IL-1β）是一种促炎细胞因子，调节对损伤和感染的炎症反应。IL-1β分泌需要蛋白酶caspase-1，其在募集到炎性小体后被激活。从坏死细胞释放的内源性凋亡相关分子模式（DAMP）通过NLRP 3-炎性体激活caspase-1。在这里，我们表明内源性脂质代谢物鞘氨醇（Sph）通过诱导巨噬细胞NLRP 3-炎性体依赖性IL-1β分泌而起DAMP作用。这一过程依赖于丝氨酸/苏氨酸蛋白磷酸酶，因为PP 1/PP 2A抑制剂冈田酸和calyculin A抑制Sph-induced IL-1β的释放。除NLRC 4和AIM 2炎性体激活剂外，由其他充分表征的NLRP 3炎性体激活剂（如ATP和尿酸晶体）诱导的IL-1β释放也被这些抑制剂阻断。因此，我们提出了一个新的DAMP，和丝氨酸/苏氨酸磷酸酶（PP 1/PP 2A）依赖的信号是中央的内源性宿主机制，通过不同的刺激调节炎性小体激活。
Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that regulates inflammatory responses to injury and infection. IL-1β secretion requires the protease caspase-1, which is activated following recruitment to inflammasomes. Endogenous danger-associated molecular patterns (DAMPs) released from necrotic cells activate caspase-1 through an NLRP3-inflammasome. Here, we show that the endogenous lipid metabolite sphingosine (Sph) acts as a DAMP by inducing the NLRP3-inflammasome-dependent secretion of IL-1β from macrophages. This process was dependent upon serine/threonine protein phosphatases since the PP1/PP2A inhibitors okadaic acid and calyculin A inhibited Sph-induced IL-1β release. IL-1β release induced by other well-characterized NLRP3-inflammasome activators, such as ATP and uric acid crystals, in addition to NLRC4 and AIM2 inflammasome activators was also blocked by these inhibitors. Thus, we propose Sph as a new DAMP, and that a serine/threonine phosphatase (PP1/PP2A)-dependent signal is central to the endogenous host mechanism through which diverse stimuli regulate inflammasome activation.
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