title: Salicylates inhibit adhesion and transmigration of T lymphocytes by preventing integrin activation induced by contact with endothelial cells.
abstract: The inhibition of cyclooxygenase does not fully account for the spectrum 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 migration 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 the expression of integrins on T cells, they blunted the increased adherence induced by the anti-beta2 monoclonal antibody (MoAb) KIM127 and prevented the appearance of an activation-dependent epitope of the CD11/CD18 complex, recognized by the MoAb 24, induced by contact with endothelial cells. Salicylates also induced an increase of intracellular calcium ([Ca2+]i) and activation of protein kinase C (PKC) in T cells, but not cell proliferation and interleukin (IL)-2 synthesis. The reduction 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 an increase in [Ca2+]i similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by salicylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the antiinflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lymphocytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites.
authors.affiliation: Institute of Internal Medicine and Oncological Sciences, Center for the Study of Rheumatic Diseases, Perugia, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gerli
authors.forename: C
authors.initials: C
authors.lastname: Paolucci
authors.forename: P
authors.initials: P
authors.lastname: Gresele
authors.forename: O
authors.initials: O
authors.lastname: Bistoni
authors.forename: S
authors.initials: S
authors.lastname: Fiorucci
authors.forename: C
authors.initials: C
authors.lastname: Muscat
authors.forename: S
authors.initials: S
authors.lastname: Belia
authors.forename: A
authors.initials: A
authors.lastname: Bertotto
authors.forename: V
authors.initials: V
authors.lastname: Costantini
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D018845:CD11 Antigens / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003094:Collagen; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D003864:Depression, Chemical; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D017136:Ion Transport; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D046911:Macromolecular Substances; D012980:Sodium Salicylate / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014471:Umbilical Veins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018845:CD11 Antigens; D018821:CD18 Antigens; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D019012:Integrin beta1; D007376:Interleukin-2; D007476:Ionophores; D046911:Macromolecular Substances; D015759:Ionomycin; D003094:Collagen; D001241:Aspirin; D002118:Calcium; D012980:Sodium Salicylate