Cyclooxygenase-2 expression in lipopolysaccharide-stimulated human monocytes is modulated by cyclic AMP, prostaglandin E2, and nonsteroidal anti-inflammatory drugs
Cyclooxygenase-2 expression in lipopolysaccharide-stimulated human monocytes is modulated by cyclic AMP, prostaglandin E2, and nonsteroidal anti-inflammatory drugs
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DOI：
10.1006/bbrc.2000.3885
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发表时间：
2000-11-30
影响因子：
3.1
通讯作者：
Pahl, A
中科院分区：
文献类型：
--
作者：
Hinz, B;Brune, K;Pahl, A
本研究采用人血单核细胞（用于RT-PCR测定环氧化酶-2（考克斯-2）mRNA）和人全血（用于前列腺素测定），研究第二信使cAMP对脂多糖（LPS）诱导的考克斯-2表达的影响，特别强调前列腺素E-2（PGE（2））在此过程中的作用。用细胞可渗透的cAMP类似物（二丁酰cAMP）、腺苷酸环化酶激活剂（霍乱毒素）或磷酸二酯酶抑制剂（3-异丁基-1-甲基黄嘌呤）升高细胞内cAMP可显著增强LPS诱导的PGE（2）形成和考克斯-2 mRNA表达，但不改变考克斯-2酶活性。此外，PGE（2）、布他前列素（腺苷酸环化酶偶联EP 2受体的选择性激动剂）和II-脱氧PGE（1）（EP 2/EP 4激动剂）引起LPS诱导的考克斯-2表达上调，而硫前列酮（EP 3/EP 1激动剂）使考克斯-2表达不变。用选择性考克斯-2抑制剂NS-398消除LPS诱导的PGE（2）合成，导致考克斯-2 mRNA水平下降，外源性PGE（2）可恢复该水平，S（S）-氟比洛芬和酮洛芬可模拟该水平。总之，这些结果表明cAMP在调节考克斯-2表达中的调节作用。PGE（2）是考克斯-2通路的最终产物，可通过正反馈机制自动调节人单核细胞中考克斯-2的表达。(C)北京大学出版社.
Using human blood monocytes (for determination of cyclooxygenase-2 (COX-2) mRNA by RT-PCR) and human whole blood (for prostanoid determination), the present study investigates the influence of the second messenger cAMP on Lipopolysaccharide (LPS)-induced COX-2 expression with particular emphasis on the role of prostaglandin E-2 (PGE(2)) in this process. Elevation of intracellular cAMP with a cell-permeable cAMP analogue (dibutyryl cAMP), an adenylyl cyclase activator (cholera toxin), or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) substantially enhanced LPS-induced PGE(2) formation and COX-2 mRNA expression, but did not modify COX-2 enzyme activity. Moreover, up-regulation of LPS-induced COX-2 expression was caused by PGE(2), butaprost (selective agonist of the adenylyl cyclase-coupled EP2 receptor) and Il-deoxy PGE(1) (EP2/EP4 agonist), whereas sulprostone (EP3/EP1 agonist) left COX-2 expression unaltered. Abrogation of LPS-induced PGE(2) synthesis with the selective COX-2 inhibitor NS-398 caused a decrease in COX-2 mRNA levels that was restored by exogenous PGE(2) and mimicked by S(S)-flurbiprofen and ketoprofen. Overall, these results indicate a modulatory role of cAMP in the regulation of COX-2 expression. PGE(2), a cAMP-elevating final product of the COX-2 pathway, may autoregulate COX-2 expression in human monocytes via a positive feedback mechanism. (C) 2000 Academic Press.