Opposite effects of two thiazolidinediones, ciglitazone and troglitazone, on proteinase-activated receptor-1-triggered prostaglandin E(2) release.
Thiazolidinediones, known as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, may modify prostaglandin formation and exert gastroprotective effects. Since activation of proteinase-activated receptor-1 (PAR1) reveals endogenous prostanoid-dependent gastroprotection, we investigated if two thiazolidinediones, ciglitazone and troglitazone, modulate the prostaglandin E(2) (PGE(2)) release caused by activation of PAR1 in normal rat gastric mucosal epithelial RGM1 cells. Ciglitazone dramatically facilitated the PAR1-triggered PGE(2) production and cyclooxygenase-2 (COX-2) upregulation, although it had no effect by itself. In contrast, troglitazone suppressed the PAR1-triggered PGE(2) production and COX-2 upregulation. Either effect of ciglitazone and troglitazone was resistant to GW9662, a PPARgamma antagonist. The facilitation of the PGE(2) release by ciglitazone was blocked by inhibitors of MEK, p38 MAP kinase (p38MAPK) and PI3-kinase (PI3K), but not JNK. Nonetheless, ciglitazone failed to enhance the PAR1-triggered phosphorylation of ERK and p38MAPK. In conclusion, ciglitazone and troglitazone, exert opposite effects on the PAR1-triggered PGE(2) production and COX-2 upregulation by targeting molecules other than PPARgamma.
Takaoka
Kaori
K
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
Sekiguchi
Fumiko
F
Shigi
Hidenori
H
Maeda
Yuma
Y
Nishikawa
Hiroyuki
H
Kawabata
Atsufumi
A
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D017931:DNA Primers; D015232:Dinoprostone / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D044463:Receptor, PAR-1 / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D017931:DNA Primers; D044463:Receptor, PAR-1; D045162:Thiazolidinediones; D000077288:Troglitazone; D015232:Dinoprostone; C039671:ciglitazone