Characterization of a human and murine mPGES-1 inhibitor and comparison to mPGES-1 genetic deletion in mouse models of inflammation

被引：61

作者：

Leclerc, Patrick ^{[1
]}

Idborg, Helena ^{[1
,2
,3
]}

Spahiu, Linda ^{[4
]}

Larsson, Charlotte ^{[2
,3
]}

Nekhotiaeva, Natalia ^{[2
,3
]}

Wannberg, Johan ^{[2
,3
]}

Stenberg, Patric ^{[2
,3
]}

Korotkova, Marina ^{[1
]}

Jakobsson, Per-Johan ^{[1
]}

机构：

[1] Karolinska Inst, Dept Med, Rheumatol Res Unit, S-17177 Stockholm, Sweden

[2] KDev Exploratory AB, S-17165 Solna, Sweden

[3] NovaSAID AB, S-17165 Solna, Sweden

[4] Karolinska Inst, Inst Environm Med, Div Biochem Toxicol, SE-17177 Stockholm, Sweden

来源：

PROSTAGLANDINS & OTHER LIPID MEDIATORS | 2013年 / 107卷

基金：

瑞典研究理事会;

关键词：

mPGES-1; Inflammation; Mouse; PGE2; Macrophages; Air pouch model; PROSTAGLANDIN-E SYNTHASE-1; MICE LACKING; IN-VIVO; EXPRESSION; TISSUE; PAIN; IDENTIFICATION; LEUKOTRIENE; PLATELETS; RECEPTOR;

D O I：

10.1016/j.prostaglandins.2013.09.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Microsomal prostaglandin E synthase-1 (mPGES-1) inhibition has been suggested as an alternative to cyclooxygenase (COX) inhibition in the treatment of pain and inflammation. We characterized a selective inhibitor of mPGES-1 activity (compound III) and studied its impact on the prostanoid profile in various models of inflammation. Compound III is a benzoimidazole, which has a submicromolar IC50 in both human and rat recombinant mPGES-1. In cellular assays, it reduced PGE(2) production in A549 cells, mouse macrophages and blood, causing a shunt to the prostacyclin pathway in the former two systems. Lastly, we assayed compound III in the air pouch model to verify its impact on the prostanoid profile and compare it to the profile obtained in mPGES-1 k.o. mice. As opposed to mPGES-1 genetic deletion, which attenuated PGE2 production and caused a shunt to the thromboxane pathway, mPGES-1 inhibition with compound III reduced PGE2 production and tended to decrease the levels of other prostanoids. (C) 2013 Elsevier Inc. All rights reserved.

引用

页码：26 / 34

页数：9

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