Recombinant P-selectin glycoprotein ligand-1 directly inhibits leukocyte rolling by all 3 selectins in vivo: complete inhibition of rolling is not required for anti-inflammatory effect.
Selectin-dependent leukocyte rolling is one of the earliest steps of an acute inflammatory response and, as such, contributes to many inflammatory diseases. Although inhibiting leukocyte rolling with selectin antagonists is a strategy that promises far-reaching clinical benefit, the perceived value of this strategy has been limited by studies using inactive, weak, or poorly characterized antagonists. Recombinant P-selectin glycoprotein ligand-1-immunoglobulin (rPSGL-Ig) is a recombinant form of the best-characterized selectin ligand (PSGL-1) fused to IgG, and is one of the best prospects in the search for effective selectin antagonists. We have used intravital microscopy to investigate the ability of rPSGL-Ig to influence leukocyte rolling in living blood vessels and find that it can reduce rolling dependent on each of the selectins in vivo. Interestingly, doses of rPSGL-Ig required to reverse pre-existing leukocyte rolling are 30-fold higher than those required to limit inflammation, suggesting additional properties of this molecule. In support of this, we find that rPSGL-Ig can bind the murine chemokine KC and inhibit neutrophil migration toward this chemoattractant in vitro.
Hicks
Anne E R
AE
Cardiovascular Research Group, University of Sheffield, Sheffield, United Kingdom.
Nolan
Sarah L
SL
Ridger
Victoria C
VC
Hellewell
Paul G
PG
Norman
Keith E
KE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001024:Aortic Valve Stenosis / Q000150:complications / Q000473:pathology; D054360:Chemokine CXCL1; D018925:Chemokines / Q000037:antagonists & inhibitors*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors*; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D007511:Ischemia / Q000209:etiology / Q000473:pathology; D019041:L-Selectin / Q000502:physiology*; D036904:Leukocyte Rolling / Q000187:drug effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects; D019007:P-Selectin / Q000502:physiology*; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000473:pathology; D013864:Thioglycolates / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D019040:E-Selectin; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011993:Recombinant Fusion Proteins; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin