Molecular mechanisms of cyclooxygenase(COX)-2-induction in human polymorphonucleocytes

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COX-2 was discovered as a TPA-induced sequence, TIS, in early 1990 at an iso-enzyme of cycloocxygenase. This newly discovered inducible enzyme has been considered to be involved in the pathogenesis of many inflammatory diseases such as rheumatic arthritis and deformed arthritis, because mRNA expression and amount of enzyme protein is increased in these inflammatory disease. We in vestigated the effect of LPS, a bacterial endtoxin, on mRNA expression, protein synthesis and activity of this enzyme in human RMNs. LPS dose-(max ; 100 ng/ml), and time-dependently max ; 6-8 hours) increased ionophore-stimulated TXB2 production in human PMNs. Messenger RNA expression measured by RT-PCR and protein synthesis measured by Wastern blotting were also time- and dose-dependently increased, indicating transcriptional up-regulation of COX-2 in human RMNs. We also found that mRNA expression of COX-2 was enhanced, and TXA2, final product of COX-pathway, in PMNs was sifnificantly increased in early phase of Kawasaki disease which was an acute febrile disease for infants. Ulinastatin, a PMN elastase inhibitor, that has been used for the treatment of Kawasaki disease, significantly inhibited mRNA-induction of COX-2 and the production of TXA2 in RMNs in the patients with Mawasaki disease. This is a novel pharmacological action of ulinastatin and is effective for the treatment of Kawasaki disease.