SALICYLATES INHIBIT ADHESION AND TRANSMIGRATION OF T-LYMPHOCYTES BY PREVENTING INTEGRIN ACTIVATION-INDUCED BY CONTACT WITH ENDOTHELIAL-CELLS

The inhibition of cyclooxygenase does not fully account for the spectr um of activities of nonsteroidal antiinflammatory drugs. It is evident , indeed, that regulation of inflammatory cell function may contribute in explaining some of the effects of these drugs. Tissue recruitment of T cells plays a key role in the development of chronic inflammation . Therefore, the effects of salicylates on T-cell adhesion to and migr ation through endothelial cell monolayers on collagen were analyzed in an in vitro static system. Aspirin and sodium salicylate reduced the ability of unstimulated T cells to adhere to and transmigrate through cytokine-activated endothelium. Although salicylates did not modify th e expression of integrins on T cells, they blunted the increased adher ence induced by the anti-Pa monoclonal antibody (MoAb) KIM127 and prev ented the appearance of an activation-dependent epitope of the CD11/CD 18 complex, recognized by the MoAb 24, induced by contact with endothe lial cells. Salicylates also induced an increase of intracellular calc ium ([Ca2+](i)) and activation of protein kinase C (PKC) in T cells, b ut not cell proliferation and interleukin (IL)-2 synthesis. The reduct ion of T-cell adhesiveness appears to be dependent on the increase in [Ca2+](i) levels, as it could be reversed by blocking Ca2+ influx, but not by inhibiting PKC. Moreover, ionomycin at concentrations giving a n increase in [Ca2+](i) similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by sa licylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the anti inflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lympho cytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites. (C) 1998 by The American Society of Hematology.