Salicylates inhibit T cell adhesion on endothelium under nonstatic conditions: Induction of L-selectin shedding by a tyrosine kinase-dependent mechanism

Salicylates inhibit T cell adhesion to and transmigration through endotheli um by preventing integrin activation induced by contact with endothelial ce lls. In the present study the effects of aspirin and sodium salicylate on t he first steps of T cell adhesion have been analyzed in a nonstatic in vitr o system. Salicylates partially reduced adhesion to activated endothelium a nd, in parallel, L-selectin expression on resting T cells by inducing shedd ing of the molecule without affecting its mRNA transcript. The role of L-se lectin down-regulation in reducing T cell adhesion in this system was suppo rted by the fact that aspirin inhibited T cell adhesion also on plastic-imm obilized L-selectin ligand or when alpha (4) integrin-mediated adhesion to endothelium was blocked by specific mAbs. In addition, preincubation of T c ells with inhibitors of L-selectin shedding prevented both functional and p henotypic inhibitory effects of salicylates. The decrease in T cell adhesio n and L-selectin expression seems to be dependent on intracellular calcium increase and tyrosine kinase activation, because these effects could be rev ersed by preincubating salicylate-treated T cells with EGTA, genistein, or tyrphostin. Finally, the infusion of aspirin into healthy volunteers induce d down-regulation of L-selectin on circulating T cells. These results sugge st that salicylates interfere not only with integrin activation, but also w ith the L-selectin-mediated first steps of T cell binding to endothelium.