Cysteinyl leukotriene-receptor-1 antagonists interfere with PGE₂ synthesis by inhibiting mPGES-1 activity

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• 作者：Astrid Stefanie Kahnt^a ; ^{kahnt@pharmchem.uni-frankfurt.de} ; Florian Rö ; rsch^b ; ^{florianroersch@gmx.de} ; Olaf Diehl^a ; ^{diehl@pharmchem.uni-frankfurt.de} ; Bettina Hofmann^a ; ^{hofmann@pharmchem.uni-frankfurt.de} ; Christoph Lehmann^a ; ^c ; ^{lehmann@pharmchem.uni-frankfurt.de} ; Svenja Dorothea Steinbrink^a ; ^{steinbrink@em.uni-frankfurt.de} ; Carlo Angioni^b ; ^{angioni@em.uni-frankfurt.de} ; Gerd Geisslinger^b ; ^{geisslinger@em.uni-frankfurt.de} ; Sabine Grö ; sch^b ; ^{groesch@em.uni-frankfurt.de} ; Dieter Steinhilber^a ; ^{steinhilber@em.uni-frankfurt.de} ; Thorsten Jü ; rgen Maier^a ; ^{maier@pharmchem.uni-frankfurt.de}
• 关键词：AA ; arachidonic acid ; AR ; allergic rhinitis ; BMI ; body mass index ; COX ; cyclooxygenase ; cPLA2¦Á ; cytosolic phospholipase A2¦Á ; CSS ; Churg-Strauss syndrome ; CysLT ; Cysteinyl leukotriene ; DC ; dendritic cell ; FCS ; fetal calf serum ; GC ; glucocorticoid ; GI ; ga
• 刊名：Biochemical Pharmacology
• 出版年：2013
• 出版时间：15 July, 2013
• 年：2013
• 卷：86
• 期：2
• 页码：286-296
• 全文大小：1327 K

文摘

Because of their favourable safety profile and beneficial anti-inflammatory properties, the CysLT₁ receptor antagonists (LTRA), montelukast, zafirlukast and pranlukast are approved for the treatment of asthma and are frequently prescribed as add-on therapeutics to reduce the amount of inhaled glucocorticoids and ¦Â₂-agonists. There is evidence that some of these anti-inflammatory properties might be of a secondary nature and therefore, unrelated to the CysLT₁ antagonism. Here, we show that LTRA inhibit PGE₂ formation in cytokine-stimulated Hela and A549 carcinoma cells and in lipopolysaccharide (LPS)-stimulated human leukocyte preparations (IC₅₀ ¡« 20 ¦ÌM). Neither expression of enzymes involved in PGE₂ synthesis nor arachidonic acid release and COX activities were inhibited by the compounds. In contrast, mPGES-1 activity was suppressed at low micromolar levels (IC₅₀ between 2 and 4 ¦ÌM). This suppression was specific for PGE₂ synthesis, since PGD₂ and PGI₂ levels in LPS-stimulated leukocyte preparations were not negatively affected. PGF_2¦Á levels were concomitantly inhibited, probably due to its direct synthesis from PGE₂. Several major conclusions can be drawn from this study: (A) clinical trials investigating elevated doses of the compounds are helpful to confirm suppression of PGE₂ synthesis in vivo; (B) studies investigating the role of CysLTs in cell culture or animal models of inflammation and cancer have to be reassessed carefully, if higher doses of LTRA were applied or serum levels in cell culture assays were low; and (C) LTRA may serve as new scaffolds for the development of potent, selective and well tolerated mPGES-1 inhibitors.