Cited by 288Proteoglycans and glycosaminoglycans researchCell Adhesion Molecules ResearchCarbohydrate Chemistry and Synthesis

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Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins

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Wang, Lianchun, Brown, Jillian R., Varki, Ajit, Esko, Jeffrey D.·2002·Journal of Clinical Investigation

DOI 10.1172/jci0214996

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Abstract

Heparin has been used clinically as an anticoagulant and antithrombotic agent for over 60 years.Here we show that the potent anti-inflammatory property of heparin results primarily from blockade of P-selectin and L-selectin.Unfractionated heparin and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis X and of cell adhesion to immobilized selectins or thrombin-activated endothelial cells.Compared with unfractionated heparin, the modified heparinoids had inhibitory activity in this general order: over-O-sulfated heparin > heparin > 2-O,3-O-desulfated ≥ N-desulfated/N-acetylated heparin ≥ carboxyl-reduced heparin ≥ N-,2-O,3-Odesulfated heparin >> 6-O-desulfated heparin.The heparinoids also showed similar differences in their ability to inhibit thioglycollate-induced peritonitis and oxazolone-induced delayed-type hypersensitivity.Mice deficient in P-or L-selectins showed impaired inflammation, which could be further reduced by heparin.However, heparin had no additional effect in mice deficient in both P-and L-selectins.We conclude that (a) heparin's anti-inflammatory effects are mainly mediated by blocking P-and L-selectin-initiated cell adhesion; (b) the sulfate groups at C6 on the glucosamine residues play a critical role in selectin inhibition; and (c) some non-anticoagulant forms of heparin retain anti-inflammatory activity.Such analogs may prove useful as therapeutically effective inhibitors of inflammation.

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Authors: Wang, L., Brown, J. R., Varki, A., & Esko, J. D.
Affiliations: University of California San Diego (US)
Corresponding author: Esko, Jeffrey D.
ORCID: Wang, Lianchun
Brown, Jillian R.
Varki, Ajit
Esko, Jeffrey D.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2002-07-01
Volume: 110
Issue: 1
Pages: 127-136
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci0214996
OpenAlex: W4250801983
Cited by: 288
References: 72
Citations by year: 2026: 9 · 2025: 5 · 2024: 9 · 2023: 6 · 2022: 3 · 2021: 11 · 2020: 11 · 2019: 9 · 2018: 14 · 2017: 11 · 2016: 16 · 2015: 15 · 2014: 11 · 2013: 15 · 2012: 12
FWCI: 5.35
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Funders: National Institutes of Health
University of California, San Diego
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
Keywords: heparin, anti-inflammatory activity, P-selectin, L-selectin, cell adhesion, sialyl Lewis X, heparinoids, peritonitis, delayed-type hypersensitivity, inflammation

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Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins

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