Microsomal prostaglandin E synthase-1 is a major terminal synthase that is selectively up-regulated during cyclooxygenase-2-dependent prostaglandin E2 production in the rat adjuvant-induced arthritis model
Microsomal prostaglandin E synthase-1 is a major terminal synthase that is selectively up-regulated during cyclooxygenase-2-dependent prostaglandin E2 production in the rat adjuvant-induced arthritis model
复制标题
DOI：
10.4049/jimmunol.170.9.4738
复制
发表时间：
2003-05-01
影响因子：
4.4
通讯作者：
Mancini, JA
中科院分区：
文献类型：
--
作者：
Claveau, D;Sirinyan, M;Mancini, JA
为了更好地确定各种前列腺素合成酶在佐剂性关节炎（AIA）模型中的作用，我们测定了诱导型PGE合成酶（mPGES-1）、mPGES-2、胞浆型PGES （cPGES/p23）和前列腺环素合成酶的时间表达，并与环氧化酶-1 （COX-1）和COX-2进行了比较。通过RNA和蛋白分析，mPGES-1在初代足跖的诱导谱与COX-2相似（50 ~ 80倍）。定量PCR分析表明，第15天mPGES-1的诱导量是COX-2的2倍以内。炎症爪膜制剂中PGES活性升高，MK-886对PGES活性的抑制率大于或等于90%，效价与重组大鼠mPGES-1相似（IC50=2.4 muM）。新描述的mPGES-2的RNA在佐剂后第1天至第15天在初级爪子中减少了2至3倍。在AIA过程中，cPGES/p23和COX-1均被诱导表达，但表达量远低于mPGES-1（2- 6倍），且cPGES/p23的表达高峰晚于COX-2和PGE的表达高峰。第1天前列环素（以6-酮- pgf （1α）测量）短暂升高，第3天前列环素合成酶在RNA水平下调，提示前列环素在大鼠AIA慢性炎症维持中的作用减弱。这些结果表明，在AIA的整个发展过程中，mPGES-1被上调，这表明它在该模型中PGE的产生升高中起主要作用(2)。
To better define the role of the various prostanoid synthases in the adjuvant-induced arthritis (AIA) model, we have determined the temporal expression of the inducible PGE synthase (mPGES-1), mPGES-2, the cytosolic PGES (cPGES/p23), and prostacyclin synthase, and compared with that of cyclooxygenase-1 (COX-1) and COX-2. The profile of induction of mPGES-1 (50- to 80-fold) in the primary paw was similar to that of COX-2 by both RNA and protein analysis. Quantitative PCR analysis indicated that induction of mPGES-1 at day 15 was within 2-fold that of COX-2. Increased PGES activity was measurable in membrane preparations of inflamed paws, and the activity was inhibitable by MK-886 to greater than or equal to90% with a potency similar to that of recombinant rat mPGES-1 (IC50=2.4 muM). The RNA of the newly described mPGES-2 decreased by 2- to 3-fold in primary paws between days 1 and 15 postadjuvant. The cPGES/p23 and COX-1 were induced during AIA, but at much lower levels (2- to 6-fold) than mPGES-1, with the peak of cPGES/p23 expression occurring later than that of COX-2 and PGE, production. Prostacyclin (measured as 6-keto-PGF(1alpha)) was transiently elevated on day 1, and prostacyclin synthase was down-regulated at the RNA level after day 3, suggesting a diminished role of prostacyclin during the maintenance of chronic inflammation in the rat AIA. These results show that mPGES-1 is up-regulated throughout the development of AIA and suggest that it plays a major role in the elevated production of PGE(2) in this model.