Lactosylceramide: a lipid second messenger in neuroinflammatory disease

Authors

  • Je-Seong Won,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
    2. Department of Pediatrics, Charles P. Darby Children’s Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA
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  • Avtar K. Singh,

    1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
    2. Laboratory Medicine Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina, USA
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  • Inderjit Singh

    1. Department of Pediatrics, Charles P. Darby Children’s Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA
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Address correspondence and reprint requests to Inderjit Singh, Department of Pediatrics, 173 Ashley Ave, Children’s Research Institute, 516, Charleston, SC 29425-5799, USA. E-mail: singhi@musc.edu

Abstract

Inflammatory disease plays a critical role in the pathogenesis of many neurological disorders. Astrogliosis and induction of pro-inflammatory mediators such as chemokines, cytokines and inducible nitric oxide synthase (iNOS) are the ‘hallmarks’ of inflammatory disease. Increased activity of lactosylceramide (LacCer) synthase and increased synthesis of LacCer during glial proliferation, and induction of pro-inflammatory cytokines and iNOS suggests a role for LacCer in these cellular signaling pathways. Studies using complementary techniques of inhibitors and antisense reported that inhibition of LacCer synthesis inhibits glial proliferation, as well as the induction of pro-inflammatory mediators (cytokines and iNOS). This inhibition was bypassed by exogenous LacCer, but not by other related lipids (e.g. glucosylceramide, galactocerebroside, GD1, GM1), indicating a role for LacCer in inflammatory signaling pathways. Furthermore, inhibition of glial proliferation and induction of inflammatory mediators by antisense to Ras GTPase, PI3Kinase and inhibitors of mitogen-activated protein kinase indicate the participation of the phosphoinositide 3-kinase (PI3Kinas)/Ras/mitogen-activated protein kinase/nuclear factor-κB (NF-κB) signaling pathways in LacCer-mediated inflammatory events thus exposing additional targets for therapeutics for inflammatory disease conditions.

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