Ceramide kinase regulates TNF伪-stimulated NADPH oxidase activity and eicosanoid biosynthesis in neuroblastoma cells

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• 作者：Brian M. Barth^a ; ^b ; ^{bmb14@psu.edu} ; Sally J. Gustafson^a ; ¹ ; ^{sjbrown@alaska.edu} ; Jody L. Hankins^b ; ^{jlh59@psu.edu} ; James M. Kaiser^b ; ^{jmk39@psu.edu} ; Jeremy K. Haakenson^b ; ^{jkh190@psu.edu} ; Mark Kester^b ; ^{mxk38@psu.edu} ; Thomas B. Kuhn^a ; ^{tbkuhn@alaska.edu}
• 关键词：aSMase ; acid sphingomyelinase ; AA ; arachidonic acid ; BSA ; bovine serum albumin ; C1P ; ceramide-1-phosphate ; CerK ; ceramide kinase ; COX ; cyclooxygenase ; cPLA2 ; cytosolic phospholipase A2 ; DAPI ; 4 ; 6-diamidino-2-phynelindole ; DCF ; dichlorofluorescein ; DOPE ; 1
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：June, 2012
• 卷：24
• 期：6
• 页码：1126-1133
• 文件大小：698 K

摘要

A persistent inflammatory reaction is a hallmark of chronic and acute pathologies in the central nervous system (CNS) and greatly exacerbates neuronal degeneration. The proinflammatory cytokine tumor necrosis factor alpha (TNF伪) plays a pivotal role in the initiation and progression of inflammatory processes provoking oxidative stress, eicosanoid biosynthesis, and the production of bioactive lipids. We established in neuronal cells that TNF伪 exposure dramatically increased Mg²⁺-dependent neutral sphingomyelinase (nSMase) activity thus generating the bioactive lipid mediator ceramide essential for subsequent NADPH oxidase (NOX) activation and oxidative stress. Since many of the pleiotropic effects of ceramide are attributable to its metabolites, we examined whether ceramide kinase (CerK), converting ceramide to ceramide-1-phosphate, is implicated both in NOX activation and enhanced eicosanoid production in neuronal cells. In the present study, we demonstrated that TNF伪 exposure of human SH-SY5Y neuroblastoma caused a profound increase in CerK activity. Depleting CerK activity using either siRNA or pharmacology completely negated NOX activation and eicosanoid biosynthesis yet, more importantly, rescued neuronal viability in the presence of TNF伪. These findings provided evidence for a critical function of ceramide-1-phospate and thus CerK activity in directly linking sphingolipid metabolism to oxidative stress. This vital role of CerK in CNS inflammation could provide a novel therapeutic approach to intervene with the adverse consequences of a progressive CNS inflammation.