F. Diazgonzalez et al., PREVENTION OF IN-VITRO NEUTROPHIL-ENDOTHELIAL ATTACHMENT THROUGH SHEDDING OF L-SELECTIN BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS, The Journal of clinical investigation, 95(4), 1995, pp. 1756-1765
The activation of the endothelial cells by extravascular stimuli is th
e key event in the extravasation of circulating leukocytes to target t
issues. L-selectin, a member of the selectin family, is constitutively
expressed by white cells, and is the molecule involved in the initial
binding of leukocytes to activated endothelium. After activation, leu
kocytes rapidly release L-selectin from the cell surface, suggesting t
hat the functional activity of this molecule is controlled in large pa
rt by its appearance and disappearance from cell surface. We have stud
ied in a neutrophil-activated endothelial cell binding assay, the effe
ct of different antiinflammatory drugs (steroidal and nonsteroidal) in
the L-selectin-mediated interaction of neutrophils with activated end
othelial cells. Some nonsteroidal antiinflammatory drugs (NSAIDs), suc
h as indomethacin, diclofenac, ketoprofen, and aspirin, but not steroi
ds, strongly inhibited the neutrophil-endothelial cell attachment. Fur
thermore, we also investigated the underlying mechanism of this functi
onal effect. The expression of L-selectin on the neutrophil surface ra
pidly decreased in the presence of different NSAIDs, in a dose- and ti
me-dependent manner, whereas no changes in the expression of other adh
esion molecules such as CD11a, CD11b, CD31, or ICAM-3 (CD50) were obse
rved. Interestingly, studies in vivo on healthy volunteers treated wit
h physiological doses of indomethacin showed a significant decrease of
L-selectin neutrophil expression. Only diclofenac induced an upregula
tion of CDllb expression, suggesting an activating effect on neutrophi
ls. No enzyme release was observed upon treatment of neutrophils with
different NSAIDs, indicating a lack of degranulatory activity of NSAID
s, with the exception of diclofenac. The downregulation of L-selectin
expression was due to the rapid cleavage and shedding of the membrane
L-selectin, as determined by both immunoprecipitation from I-125-label
ed neutrophils, and quantitative estimation in cell-free supernatants.
These results suggest that NSAIDs exert a specific action on adhesion
receptor expression in neutrophils, which might account, at least in
part, for the antiinflammatory activities of NSAIDs.