Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins.
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 > or = N-desulfated/N-acetylated heparin > or = carboxyl-reduced heparin > or= N-,2-O,3-O-desulfated 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.
Wang
Lianchun
L
Department of Cellular and Molecular Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0687, USA.
Brown
Jillian R
JR
Varki
Ajit
A
Esko
Jeffrey D
JD
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy; D004195:Disease Models, Animal; D005944:Glucosamine / Q000737:chemistry*; D006493:Heparin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D019041:L-Selectin / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009844:Oligosaccharides / Q000378:metabolism; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D010538:Peritonitis / Q000188:drug therapy; D000080506:Sialyl Lewis X Antigen; D013431:Sulfates / Q000737:chemistry; D020298:U937 Cells
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009844:Oligosaccharides; D019007:P-Selectin; D000080506:Sialyl Lewis X Antigen; D013431:Sulfates; D019041:L-Selectin; D006493:Heparin; D005944:Glucosamine