15-Deoxy-delta12,14-prostaglandin-J(2) up-regulates cyclooxygenase-2 but inhibits prostaglandin-E(2) production through a thiol antioxidant-sensitive mechanism.
15-Deoxy-delta12,14-prostaglandin-J(2) (15d-PGJ(2)) has potent anti-inflammatory effects including the inhibition of interleukin-1beta (IL-1beta)-induced expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) production in several cell types. 15d-PGJ(2) contains an alpha,beta-unsaturated electrophilic ketone and several evidences suggest that thiol reducing agents prevent or revert the cellular effects of 15d-PGJ(2). The present study was devoted to analyze the effect of 15d-PGJ(2) on COX-2 expression in cultured human mesangial cells (HMC). 15d-PGJ(2) induced an increase in the reduced glutathione (GSH) content and up-regulated COX-2 protein expression, but not COX-1, in a manner which was unaffected by selective peroxisome proliferator-activated receptor gamma (PPARgamma) blockade nor mimicked by ciglitazone, a PPARgamma agonist. N-acetylcysteine (NAC), a thiol reducing agent, but not reactive oxygen species scavengers, prevented 15d-PGJ(2)-induced COX-2 up-regulation. Depletion of GSH by buthionine sulfoximine, which diminishes thiol antioxidant activity, cooperated with 15d-PGJ(2) to accumulate COX-2. Therefore, 15d-PGJ(2) up-regulated COX-2 through a thiol antioxidant-sensitive mechanism. Interestingly, NAC did not inhibit the COX-2 expression induced by the electrophilic alpha,beta-unsaturated compound PGA(2). Up-regulation of COX-2 by 15d-PGJ(2) did not result in increased PGE(2) production. Furthermore, preincubation with 15d-PGJ(2) inhibited IL-1beta-induced PGE(2) production although IL-1beta-induced COX-2 expression remained unaffected by the treatment with 15d-PGJ(2). On the contrary, PGA(2) elicited an increase in PGE(2) production and it acted synergistically with IL-1beta to enhance PGE(2) production. These results indicate for the first time that 15d-PGJ(2) inhibits PGE(2) production independently of its effect on COX-2 expression.
Reyes-Martin
Patricia
P
Department of Physiology, University of Alcala, Alcala de Henares, Madrid 28871, Spain.
Ramirez-Rubio
Sara
S
Parra-Cid
Trinidad
T
Bienes-Martínez
Raquel
R
Lucio-Cazana
Javier
J
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011454:Prostaglandins A / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C477819:15-deoxyprostaglandin J2; D000975:Antioxidants; D016166:Free Radical Scavengers; D047495:PPAR gamma; D011454:Prostaglandins A; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D019328:Buthionine Sulfoximine; D051546:Cyclooxygenase 2; D005978:Glutathione; C100008:prostaglandin A2; D015232:Dinoprostone; D015230:Prostaglandin D2; D000111:Acetylcysteine