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First published online 22 July 2003
doi: 10.1242/jcs.00662

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

¹ Applied Immunobiology Research Group, Department of Surgery, University of Newcastle, The Medical School, Newcastle upon Tyne NE2 4HH, UK
² Institute of Pharmacy, Chemistry and Biomedical Science, University of Sunderland, Sunderland SR1 3SD, UK

^* Author for correspondence (e-mail: j.a.kirby{at}ncl.ac.uk)

Accepted 12 May 2003

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-, 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- and TNF- 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.

Key words: Heparan sulphate, Inflammation, Chemokine, IFN-, TNF-, RANTES

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