A HOOKWORM GLYCOPROTEIN THAT INHIBITS NEUTROPHIL FUNCTION IS A LIGANDOF THE INTEGRIN CD11B CD18

The chronic survival of many endoparasites is dependent on the ability of these organisms to escape the host immune response. Identification of the molecular mechanisms by which these organisms evade this respo nse may yield novel approaches in the development of anti-inflammatory agents. We describe here the discovery and characterization of a nove l 41-kilodalton glycoprotein from the canine hookworm (Ancylostoma can inum) that potently inhibits CD11/CD18-dependent neutrophil function i n vitro. Neutrophil inhibitory factor (NIF) blocks the adhesion of act ivated human neutrophils to vascular endothelial cells as well as the release of H2O2 from activated neutrophils, over a similar concentrati on range (IC50 10-20 nM). Studies aimed at determining the nature of t he NIF binding site on neutrophils revealed selective, high affinity b inding of this protein to the integrin CD11b/CD18. A cDNA encoding NIF was isolated from a canine hookworm cDNA library. NIF comprises a mat ure polypeptide of 257 amino acids, preceded by a 17-amino acid leader . The mature protein has 10 cysteines and has seven potential N-linked glycosylation sites. NIF has no significant sequence homologies to an y previously reported protein. As such, NIF represents a prototype of a novel class of leukocyte function inhibitors.