Sulfoglucuronosyl paragloboside promotes endothelial cell apoptosis in inflammation: Elucidation of a novel glycosphingolipid-signaling pathway

Somsankar Dasgupta, Guanghu Wang, Robert K. Yu

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)749-759
Number of pages11
JournalJournal of Neurochemistry
Volume119
Issue number4
DOIs
StatePublished - Nov 1 2011

Keywords

  • apoptosis
  • cell signaling
  • endothelial cells
  • glycosphingolipid
  • inflammation
  • sulfoglucuronosyl paragloboside

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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