INHIBITION OF NEUTROPHIL ADHESION BY ADENOSINE AND AN ADENOSINE KINASE INHIBITOR - THE ROLE OF SELECTINS

Adenosine and adenosine analogues exhibit anti-inflammatory effects in vitro and in vivo, but their usefulness is limited by profound cardio vascular side effects. Therefore, we synthesized inhibitors of an enzy me involved in adenosine metabolism, adenosine kinase (AK) (EC 2.7.1.2 0), to enhance endogenous adenosine concentrations at sites of inflamm ation. GP-1-515 ribofuranosyl)-3-bromo-pyrazolo[3,4-d]pyrimidine), a n ovel AK inhibitor, decreased adhesion of activated human neutrophils t o cultured endothelial cell monolayers by increasing local adenosine l evels. The mechanism of inhibition in this assay seemed to involve sel ectin blockade and was independent of the beta 2 integrins. GP-1-515 a nd 2-chloroadenosine (a nonmetabolizable adenosine analogue) had no ef fect on the surface expression or shedding of adhesion molecules. An a gent that disrupts the cytoskeleton, cytochalasin B, mimicked the effe ct of adenosine on cell adhesion. Interactions between L-selectin and the neutrophil cytoskeleton might be altered by adenosine and could co ntribute to adenosine-mediated adhesion inhibition.