title: Sulfoglucuronosyl paragloboside promotes endothelial cell apoptosis in inflammation: elucidation of a novel glycosphingolipid-signaling pathway.
abstract: Sulfoglucuronosyl paragloboside (SGPG), a minor glycosphingolipid of endothelial cells, is a ligand for L-selectin and has been implicated in neuro-inflammatory diseases, such as Guillian-Barré syndrome. Inflammatory cytokines, such as TNFα and IL-1β, up-regulate SGPG expression by stimulating gene expression for glucuronosyltransferases, both P and S forms (GlcATp and GlcATs), and the human natural killer antigen (HNK-1) sulfotransferase (HNK-1 ST). Transfection of a human cerebromicrovascular endothelial cell (SV-HCEC) line with HNK-1 ST siRNA down-regulated SGPG expression, inhibited cytokine-stimulated T-cell adhesion, and offered protection against apoptosis. However, the precise mechanisms of SGPG elevation in endothelial cell apoptosis and the maintenance of blood-brain or blood-nerve barrier integrity in inflammation have not been elucidated. Blocking SGPG expression inhibited cytokine-mediated stimulation of NF-κB activity but stimulated MAP kinase activity. Furthermore, elevation of SGPG by over-expression of GlcATp and GlcATs triggered endothelial cell apoptosis, with GlcATs being more potent than GlcATp. Although SGPG-mediated endothelial cell apoptosis was preceded by inhibiting the intracellular NF-κB activity, interfering with Akt and ERK activation and stimulating caspase 3 in SV-HCECs, HNK-1ST siRNA transfection also interfered with IκB phosphorylation but stimulated ERK activation. Our data indicate that SGPG is a critical regulatory molecule for maintaining endothelial cell survival and blood-brain or blood-nerve barrier function.
authors.affiliation: Institute of Molecular Medicine and Genetics and Institute of Neuroscience, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
authors.forename: Somsankar
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Guanghu
authors.initials: G
authors.lastname: Wang
authors.forename: Robert K
authors.initials: RK
authors.lastname: Yu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000033:anatomy & histology; D042783:Endothelial Cells / Q000187:drug effects*; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D005915:Globosides / Q000494:pharmacology*; D006028:Glycosphingolipids / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055806:Microvessels / Q000166:cytology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D005915:Globosides; D006028:Glycosphingolipids; D016328:NF-kappa B; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; C051917:sulfate-3-glucuronyl paragloboside; D049452:Green Fluorescent Proteins; C109318:HNK-1 sulfotransferase; D015238:Sulfotransferases; D020169:Caspases