Ceramide kinase mediates cytokine- and calcium ionophore-induced arachidonic acid release
Ceramide kinase mediates cytokine- and calcium ionophore-induced arachidonic acid release
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DOI：
10.1074/jbc.m304816200
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发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Chalfant, CE
中科院分区：
文献类型：
--
作者：
Pettus, BJ;Bielawska, A;Chalfant, CE
尽管前列腺素很重要，但对前列腺素类合成的调节（接近胞浆磷脂酶A的激活，即最初的限速步骤）知之甚少（2）。在这项研究中，1-磷酸神经酰胺（C-1-P）被证明是细胞中花生四烯酸（AA）和前列腺素类合成的特异性且有效的诱导剂。这项研究还表明，两个公认的激活剂AA释放和前列腺素合成，细胞因子，白细胞介素-1 β（IL-1 β），和钙离子载体，A23187，诱导增加C-1-P水平在相关的时间范围内AA释放。此外，在哺乳动物细胞中负责产生C-1-P的酶，神经酰胺激酶，响应于IL-1 β和A23187而被激活。针对神经酰胺激酶的RNA干扰特异性下调了神经酰胺激酶的mRNA和活性，同时减少了响应IL-1 β和A23187的AA释放。神经酰胺激酶的下调对外源性C-1-P诱导的AA释放没有影响。总之，这些结果表明，神经酰胺激酶通过形成C-1-P，是磷脂酶A（2）激活的上游调节剂。这项研究确定了神经酰胺激酶及其产物C-1-P在AA释放和类花生酸产生中的未知作用，并为阻断炎症反应的潜在新靶点提供了线索。
Despite the importance of prostaglandins, little is known about the regulation of prostanoid synthesis proximal to the activation of cytosolic phospholipase A(2), the initial rate-limiting step. In this study, ceramide-1-phosphate (C-1-P) was shown to be a specific and potent inducer of arachidonic acid (AA) and prostanoid synthesis in cells. This study also demonstrates that two well established activators of AA release and prostanoid synthesis, the cytokine, interleukin-1beta (IL-1beta), and the calcium ionophore, A23187, induce an increase in C-1-P levels within the relevant time-frame of AA release. Furthermore, the enzyme responsible for the production of C-1-P in mammalian cells, ceramide kinase, was activated in response to IL-1beta and A23187. RNA interference targeted to ceramide kinase specifically down-regulated ceramide kinase mRNA and activity with a concomitant decrease of AA release in response to IL-1beta and A23187. Down-regulation of ceramide kinase had no effect on AA release induced by exogenous C-1-P. Collectively, these results indicate that ceramide kinase, via the formation of C-1-P, is an upstream modulator of phospholipase A(2) activation. This study identifies previously unknown roles for ceramide kinase and its product, C-1-P, in AA release and production of eicosanoids and provides clues for potential new targets to block inflammatory responses.