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Sulfoglucuronosyl paragloboside promotes endothelial cell apoptosis in inflammation: elucidation of a novel glycosphingolipid‐signaling pathway
Author(s) -
Dasgupta Somsankar,
Wang Guanghu,
Yu Robert K.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07483.x
Subject(s) - microbiology and biotechnology , apoptosis , endothelial stem cell , transfection , inflammation , cytokine , signal transduction , biology , chemistry , immunology , cell culture , biochemistry , in vitro , genetics
J. Neurochem. (2011) 119 , 749–759. 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.