Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia

• Published in: Neuroscience 2010-03, Vol.166 (1), p.132-144
• Main Authors: Nayak, D, Huo, Y, Kwang, W.X.T, Pushparaj, P.N, Kumar, S.D, Ling, E.-A, Dheen, S.T
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line; cytokines; Cytokines - metabolism; Encephalitis - enzymology; Encephalitis - physiopathology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Gliosis - enzymology; Gliosis - physiopathology; inflammation; Interleukin-1beta - metabolism; Lipopolysaccharides; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; Mice; microglia; Microglia - drug effects; Microglia - enzymology; Neurology; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; RNA Interference - physiology; RNA, Messenger - metabolism; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine - pharmacology; sphingosine kinase 1; sphingosine-1-phosphate; Tumor Necrosis Factor-alpha - metabolism; Up-Regulation - drug effects; Up-Regulation - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2009.12.020

Abstract Microglial activation has been implicated as one of the causative factors for neuroinflammation in various neurodegenerative diseases. The sphingolipid metabolic pathway plays an important role in inflammation, cell proliferation, survival, chemotaxis, and immunity in peripheral macrophages. In this study, we demonstrate that sphingosine kinase1 (SphK1), a key enzyme of the sphingolipid metabolic pathway, and its receptors are expressed in the mouse BV2 microglial cells and SphK1 alters the expression and production of proinflammatory cytokines and nitric oxide in microglia treated with lipopolysaccharide (LPS). LPS treatment increased the SphK1 mRNA and protein expression in microglia as revealed by the RT–PCR, Western blot and immunofluorescence. Suppression of SphK1 by its inhibitor, N, N Dimethylsphingosine (DMS), or siRNA resulted in decreased mRNA expression of TNF-α, IL-1β, and iNOS and release of TNF-α and nitric oxide (NO) in LPS-activated microglia. Moreover, addition of sphingosine 1 phosphate (S1P), a breakdown product of sphingolipid metabolism, increased the expression levels of TNF-α, IL-1β and iNOS and production of TNF-α and NO in activated microglia. Hence to summarize, suppression of SphK1 in activated microglia inhibits the production of proinflammatory cytokines and NO and the addition of exogenous S1P to activated microglia enhances their inflammatory responses. Since the chronic proinflammatory cytokine production by microglia has been implicated in neuroinflammation, modulation of SphK1 and S1P in microglia could be looked upon as a future potential therapeutic method in the control of neuroinflammation in neurodegenerative diseases.