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Prepublished online as a Blood First Edition Paper on December 12, 2002; DOI 10.1182/blood-2002-07-2329.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3249-3256
PHAGOCYTES
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
Anne E. R. Hicks,
Sarah L. Nolan,
Victoria C. Ridger,
Paul G. Hellewell, and
Keith E. Norman
From the Cardiovascular Research Group, University of
Sheffield, Sheffield, United Kingdom.
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.
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