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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2389-2398
Salicylates Inhibit Adhesion and Transmigration of T Lymphocytes by
Preventing Integrin Activation Induced by Contact With Endothelial
Cells
Roberto Gerli,
Cristina Paolucci,
Paolo Gresele,
Onelia Bistoni,
Stefano Fiorucci,
Christopher Muscat,
Silvia Belia,
Alberto Bertotto, and
Vincenzo Costantini
From the Institute of Internal Medicine and Oncological Sciences,
Center for the Study of Rheumatic Diseases; Institute of Internal and
Vascular Medicine; Department of Clinical and Experimental Medicine,
Gastroenterology Section; Department of Cellular and Molecular Biology
and Institute of Pediatrics, University of Perugia, Perugia, Italy.
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- 2
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.
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