Thiazolidinediones increase arachidonic acid release and subsequent prostanoid production in a peroxisome proliferator-activated receptor gamma-independent manner.
Thiazolidinedione, peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has been used as an anti-diabetic drug and as an useful tool to elucidate multiple PPARgamma functions by in vitro and in vivo studies. We investigated the effects of thiazolidinediones on prostanoid production in lipopolysaccharide-stimulated cells. The high concentrations (>10 microM) of rosiglitazone and pioglitazone significantly increased lipopolysaccharide-stimulated prostanoid production such as thromboxane A2 and prostaglandin E2. However, PPARgamma antagonist could not inhibit them. In PPARgamma-deficient cells, thiazolidinediones increased prostaglandin E2 production. Thiazolidinediones increased arachidonic acid (AA) release from the cell membrane by not stimulating AA releasing process involving several phospholipase A2s but inhibiting AA reuptaking process. The expression of cyclooxygenase-1 and cyclooxygenase-2 were not affected by thiazolidinediones. In this study, we demonstrated that high concentrations of TZDs increased AA release by the inhibition of AA reuptaking process, leading to subsequent increase in the prostanoid production in a PPARgamma-independent manner. This mechanism provides useful information for the elucidation of multiple PPARgamma functions and diabetic drug therapy.
Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Hiroki
H
Tsukamoto
Takanori
T
Hishinuma
Naoto
N
Suzuki
Risa
R
Tayama
Masahiro
M
Hiratsuka
Tomioka
T
Yoshihisa
Michinao
M
Mizugaki
Junichi
J
Goto
D000818:Animals; D016718:Arachidonic Acid / Q000096:biosynthesis*; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D010741:Phospholipases A / Q000378:metabolism; D010766:Phosphorylation; D000077205:Pioglitazone; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000096:biosynthesis*; D020298:U937 Cells
D008070:Lipopolysaccharides; D008565:Membrane Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016718:Arachidonic Acid; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D010741:Phospholipases A; D015232:Dinoprostone; D000077205:Pioglitazone