Endothelial inflammation: the role of differential expression of N-deacetylase/N-sulphotransferase enzymes in alteration of the immunological properties of heparan sulphate

J Cell Sci. 2003 Sep 1;116(Pt 17):3591-600. doi: 10.1242/jcs.00662. Epub 2003 Jul 22.


Heparan sulphate N-deacetylase/N-sulphotransferase (NDST) enzymes catalyse the reaction that initiates sulphation and subsequent modification of the oligosaccharide, heparan sulphate (HS). The extent and distribution of sulphate substitution on HS plays a vital role in regulation of the binding of a range of proteins, including IFN-gamma, several interleukins and most chemokines. In this study, the expression of NDST transcripts was found to be non-uniform between a range of cell types, suggesting that different cells produce characteristic HS species. It was found that stimulation of the HMEC-1 microvascular endothelial cell line with the pro-inflammatory cytokines IFN-gamma and TNF-alpha caused a transient decrease in the level of NDST-1 and -2 transcripts after 4 hours (P < 0.05 and P < 0.01 respectively), but the expression of NDST-1 increased above control levels after 16 hours (P < 0.01). The change in NDST expression was concurrent with an increase in the abundance of sulphated HS epitopes on the cell surface; this was not caused by variation in the expression of proteoglycans or by changes in the rate of GAG turnover. Cytokine-stimulated endothelial cells also showed an increase in their potential to bind RANTES (CCL5); this was abrogated by chlorate blockade of sulphotransferase activity or by heparitinase cleavage of cell surface HS. Monolayers of cytokine-stimulated HMEC-1 also supported an enhanced leukocyte chemotactic response towards RANTES. This study demonstrated that pro-inflammatory cytokines can increase NDST expression leading to increased sulphation of HS and a corresponding increase in sequestration of functional RANTES at the apical surface of endothelial cells. This may enhance leukocyte extravasation at sites of inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / metabolism*
  • Animals
  • Cell Membrane / enzymology
  • Cells, Cultured
  • Chemokine CCL5 / metabolism
  • Chemotaxis / physiology
  • Endothelium, Vascular / metabolism*
  • Glycosaminoglycans / metabolism
  • Heparitin Sulfate / metabolism*
  • Humans
  • Interferon-gamma / metabolism
  • Leukocytes / metabolism
  • Polysaccharide-Lyases / metabolism
  • Proteoglycans / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfotransferases / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • Vasculitis / metabolism*


  • Chemokine CCL5
  • Glycosaminoglycans
  • Proteoglycans
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Heparitin Sulfate
  • NDST2 protein, human
  • Sulfotransferases
  • heparitin sulfotransferase
  • Amidohydrolases
  • Polysaccharide-Lyases
  • heparitinsulfate lyase