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

人多形核细胞环氧合酶（COX）-2诱导的分子机制

• 批准号: 11670767
• 负责人: MIYAZAKI Sumio
• 金额: $ 1.09万
• 依托单位: Saga Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670767/
• 关键词: COX-2 ; cyclooxygenase; TXA_2 ; Hexambaxane A_2; Kawasaki Disease; polymorphonucleocyte; ulinastatin; COX-2;cyclooxygenase-2; TXA2;thromboxane A2; cytosolic PLA_2(phospholipase2); TXA_2:thromboxane A2; 好中球

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.

考克斯-2是在1990年早期在环氧合酶的同工酶中发现的TPA诱导序列TIS。这种新发现的诱导酶被认为参与了许多炎症性疾病如风湿性关节炎和变形性关节炎的发病机制，因为在这些炎症性疾病中酶蛋白的mRNA表达和量增加。我们研究了细菌内毒素LPS对人RMNs中该酶的mRNA表达、蛋白质合成和活性的影响。LPS剂量-（最大; 100 ng/ml）和时间依赖性最大; 6-8小时）增加人PMN中离子载体刺激的TXB 2产生。RT-PCR测量的信使RNA表达和Wastern印迹测量的蛋白质合成也呈时间和剂量依赖性增加，表明人RMNs中考克斯-2的转录上调。川崎病早期PMN中考克斯-2 mRNA表达增强，COX通路终产物TXA 2明显升高。乌司他丁是一种PMN弹性蛋白酶抑制剂，已用于治疗川崎病，可显著抑制川崎病患者RMN中考克斯-2的mRNA诱导和TXA 2的产生。这是乌司他丁的一种新的药理作用，对治疗川崎有效。

项目成果

Zaitsu M etal: "Induction of cytosolic phospholipase A2 and prostaglandin H2 synthase-2 by lipopolysaccharide in human PMN leukayte"Eur.J.Haematol.. 63. 94-102 (1999)

Zaitsu M等人：“通过人PMN白细胞中的脂多糖诱导胞质磷脂酶A2和前列腺素H2合酶-2”Eur.J.Haematol.. 63. 94-102 (1999)

Zaitsu M, et al.: "Induction of cytosolic phospholipase A2 and prostaglandin H2 synthase-2 by lipopolysaccharide in human polymorphonuclear leukocytes"Eur H Haemotol. 63. 94-102 (1999)

Zaitsu M 等：“人多形核白细胞中脂多糖诱导胞质磷脂酶 A2 和前列腺素 H2 合酶-2”Eur H Haemotol。

Zaitsu M, et al.: "Effect of dexamethasone on leukotriene synthesis in DMSO-stimulated HL-60 cells"Prostaglandin Leukotriene Essent Fatty Acid. 59. 385-393 (1998)

Zaitsu M 等人：“地塞米松对 DMSO 刺激的 HL-60 细胞中白三烯合成的影响”前列腺素白三烯精华脂肪酸。

Zaitsu M, et al.: "Ulinastatin, an elastase inhibitor, inhibits the increased mRNA expression of prostaglandin H2 synthase type-2 in Kawasaki disease"J.Infect Dis. 181. 1101-1109 (2000)

Zaitsu M 等人：“乌司他丁是一种弹性蛋白酶抑制剂，可抑制川崎病中前列腺素 H2 合酶 2 型 mRNA 表达的增加”J.Infect Dis。

Zaitsu M. et al: "Induction of cytosolic phospholipase A_2 and Prostaglandin H_2 Synthase-2 by lipoPolysaccharide in human PMN leukocytes"Eur.J.Haematol.. 63. 94-102 (1999)

Zaitsu M.等：“在人PMN白细胞中通过脂多糖诱导胞质磷脂酶A_2和前列腺素H_2合成酶-2”Eur.J.Haematol.. 63. 94-102 (1999)