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 endothelium by preventing integrin activation induced by contact with endothelial cells. In the present study the effects of aspirin and sodium salicylate on the first steps of T cell adhesion have been analyzed in a nonstatic in vitro system. Salicylates partially reduced adhesion to activated endothelium and, in parallel, L-selectin expression on resting T cells by inducing shedding of the molecule without affecting its mRNA transcript. The role of L-selectin down-regulation in reducing T cell adhesion in this system was supported by the fact that aspirin inhibited T cell adhesion also on plastic-immobilized L-selectin ligand or when alpha(4) integrin-mediated adhesion to endothelium was blocked by specific mAbs. In addition, preincubation of T cells with inhibitors of L-selectin shedding prevented both functional and phenotypic inhibitory effects of salicylates. The decrease in T cell adhesion and L-selectin expression seems to be dependent on intracellular calcium increase and tyrosine kinase activation, because these effects could be reversed by preincubating salicylate-treated T cells with EGTA, genistein, or tyrphostin. Finally, the infusion of aspirin into healthy volunteers induced down-regulation of L-selectin on circulating T cells. These results suggest that salicylates interfere not only with integrin activation, but also with the L-selectin-mediated first steps of T cell binding to endothelium.
Gerli
R
R
Section of Internal Medicine, Center for the Study of Rheumatic Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Italy. gerlir@unipg.it
Gresele
P
P
Bistoni
O
O
Paolucci
C
C
Lanfrancone
L
L
Fiorucci
S
S
Muscat
C
C
Costantini
V
V
D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005732:Gangliosides / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007424:Intracellular Fluid / Q000187:drug effects / Q000276:immunology; D019169:Jurkat Cells; D019041:L-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007983:Lewis Blood Group Antigens / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D000080506:Sialyl Lewis X Antigen; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D012980:Sodium Salicylate / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology
D004151:Dipeptides; D004791:Enzyme Inhibitors; D005732:Gangliosides; D006877:Hydroxamic Acids; D007166:Immunosuppressive Agents; C099147:KD-IX 73-4; D007983:Lewis Blood Group Antigens; D011480:Protease Inhibitors; D012333:RNA, Messenger; C097661:Ro 31-9790; D000080506:Sialyl Lewis X Antigen; C094688:sialyl Lewis(x) ganglioside; D019041:L-Selectin; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D008666:Metalloendopeptidases; D001241:Aspirin; D012980:Sodium Salicylate