Salicylates inhibit I kappa B-alpha phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration.
The expression of leukocyte adhesion molecules on endothelial cells is induced by TNF-alpha and other inflammatory cytokines. This induction of endothelial-leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 requires the transcription factor nuclear factor-kappa B (NF-kappa B). Recent work has suggested that some nonsteroidal anti-inflammatory agents, including sodium salicylate and aspirin, can inhibit NF-kappa B-dependent gene activation. We studied the effects of salicylates on expression of adhesion molecules in HUVECs. We found that sodium salicylate inhibited activation of NF-kappa B (p50/p65 and p65/p65) by preventing phosphorylation and subsequent degradation of the inhibitor 1 kappa B-alpha. Salicylate treatment had no effect on TNF-alpha-induced phosphorylation of the transcription factor ATF-2. Salicylate blocked the TNF-alpha-induced increase in mRNA levels of adhesion molecules and gave a dose-dependent inhibition of TNF-alpha-induced surface expression of vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 with higher doses required to inhibit endothelial-leukocyte adhesion molecule-1 expression. Indomethacin, a nonsalicylate cyclooxygenase inhibitor, had no effect on surface expression of adhesion molecules, suggesting that the effects were not due to inhibition of cyclooxygenase. Treatment of endothelial cell monolayers with sodium salicylate inhibited transendothelial migration of neutrophils but had no significant effect on neutrophil adhesion under flow conditions. The clinical importance of high-dose salicylates in inflammation may be due, in part, to the ability to prevent expression of inducible adhesion molecules and recruitment of leukocytes.
Pierce
J W
JW
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Read
M A
MA
Ding
H
H
Luscinskas
F W
FW
Collins
T
T
D001483:Base Sequence; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019040:E-Selectin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020672:I-kappa B Proteins; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012980:Sodium Salicylate / Q000494:pharmacology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D004268:DNA-Binding Proteins; D019040:E-Selectin; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D012980:Sodium Salicylate