Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/19072
Title: Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia
Authors: DEEPTI NAYAK
Keywords: Sphingosine kinase1, microglia, SiRNA, DMS, BV2, neuroinflammation,
Issue Date: 4-Jan-2010
Source: DEEPTI NAYAK (2010-01-04). Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. ScholarBank@NUS Repository.
Abstract: Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in the pathway leading to various neurodegenerative diseases including Alzheimer?s disease, Parkinson?s disease, prion diseases and HIV-dementia. Activation of microglial cells causes neurotoxicity through the release of a wide array of inflammatory mediators including proinflammatory cytokines, chemokines and reactive oxygen species. Microglial activation has been implicated as one of the causative factors for neuroinflammation in various neurodegenerative diseases. Therefore, suppression of microglia-mediated inflammation has been considered as an important therapeutic strategy for 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 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-a, IL-1?, and iNOS and release of TNF-a and nitric oxide (NO) in LPS-activated microglia. However, addition of sphingosine 1 phosphate (S1P), a breakdown product of sphingolipid metabolism, restored the increased expression levels of TNF-a and IL-1? and production of TNF-a and NO in activated microglia exposed to DMS or transfected with SphK1 siRNA. Hence, to summarize, suppression of SphK1 in activated microglia inhibits the production of proinflammatory cytokines and NO, and the addition of S1P to microglia reverses the suppressive effects. 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.
URI: http://scholarbank.nus.edu.sg/handle/10635/19072
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