Inhibition of β2 Integrin–mediated Leukocyte Cell Adhesion

Abstract

Many integrins mediate cell attachment to the extracellular matrix by recognizing short tripeptide sequences such as arginine–glycine–aspartic acid and leucine–aspartate–valine. Using phage display, we have now found that the leukocyte-specific b2 integrins bind sequences containing a leucine–leucine–glycine (LLG) tripeptide motif. An LLG motif is present on intercellular adhesion molecule (ICAM)-1, the major b2 integrin ligand, but also on several matrix proteins, including von Willebrand factor. We developed a novel b2 integrin antagonist peptide CPCFLLGCC (called LLG-C4), the structure of which was determined by nuclear magnetic resonance. The LLG-C4 peptide inhibited leukocyte adhesion to ICAM-1, and, interestingly, also to von Willebrand factor. When immobilized on plastic, the LLG-C4 sequence supported the b2 integrin–mediated leukocyte adhesion, but not b1 or b3 integrin–mediated cell adhesion. These results suggest that LLG sequences exposed on ICAM-1 and on von Willebrand factor at sites of vascular injury play a role in the binding of leukocytes, and LLG-C4 and peptidomimetics derived from it could provide a therapeutic approach to inflammatory reactions.