Glycosulfopeptides modeled on P-selectin glycoprotein ligand 1 inhibit P-selectin-dependent leukocyte rolling in vivo.
Leukocytic inflammation can be limited by inhibiting selectin-dependent leukocyte rolling. In spite of intensive efforts to develop small molecule selectin inhibitors with defined structure-activity profiles, inhibition of P-selectin-dependent leukocyte rolling in vivo by such a compound has yet to be described. We recently reported that glycosulfopeptides (GSP), modeled on the high affinity selectin ligand PSGL-1, inhibit leukocyte binding to P-selectin in vitro. Here, we have used intravital microscopy to investigate whether GSP can inhibit P-selectin-dependent leukocyte rolling in vivo. Surgical preparation of the mouse cremaster muscle for intravital microscopy induced P-selectin-dependent leukocyte rolling. Baseline rolling was recorded for 1 min followed by i.v. injection of GSP. 2-GSP-6 and 4-GSP-6 substantially reversed P-selectin-dependent leukocyte rolling, whereas control GSP, which are not fully glycosylated, did not. Inhibition of leukocyte rolling by 2- and 4-GSP-6 lasted 2-4 min. Clearance studies with 125I-labeled 4-GSP-6 demonstrated rapid reduction in its circulating levels concurrent with accumulation in urine. These data represent the first demonstration that a precisely defined structure based on a natural P-selectin ligand can inhibit P-selectin-dependent leukocyte rolling in vivo.
Hicks
Anne E R
AE
Cardiovascular Research Group, Division of Clinical Sciences (North), University of Sheffield, Sheffield, UK.
Leppänen
Anne
A
Cummings
Richard D
RD
McEver
Rodger P
RP
Hellewell
Paul G
PG
Norman
Keith E
KE
D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006023:Glycoproteins / Q000494:pharmacology; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry*; D051379:Mice; D008954:Models, Biological; D019007:P-Selectin / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology*; D013455:Sulfur
D006023:Glycoproteins; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D010455:Peptides; D013455:Sulfur