RT Journal Article
SR Electronic
T1 Inhibition of Prostaglandin Synthesis Up-Regulates Cyclooxygenase-2 Induced by Lipopolysaccharide and Peroxisomal Proliferators
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1235
OP 1241
VO 288
IS 3
A1 Nuria A. Callejas
A1 Antonio Castrillo
A1 Lisardo Boscá
A1 Paloma Martı́n-Sanz
YR 1999
UL http://jpet.aspetjournals.org/content/288/3/1235.abstract
AB Primary cultures of fetal hepatocytes expressed cyclooxygenase-2 (COX-2) upon stimulation with bacterial lipopolysaccharide (LPS) or peroxisomal proliferators. This enzyme was active and a good correlation between the mRNA levels, the amount of protein, and the synthesis of prostaglandin E2 was observed. However, when cells were incubated in the presence of indomethacin or the COX-2-specific inhibitor NS398, the amount of COX-2 protein increased 5-fold after activation with LPS and 2-fold after treatment with clofibrate. This up-regulation of COX-2 was not observed at the mRNA level. The mechanism of protein accumulation might involve either a direct stabilization of the enzyme by the inhibitors or the absence of prostaglandins involved in the regulation of its turnover. Among the prostaglandins assayed, only 15-deoxy-Prostaglandin J2 exerted a statistically significant decrease in the COX-2 levels in cells stimulated with LPS or LPS plus NS398. The accumulation of COX-2 in the presence of inhibitors was also observed in peritoneal macrophages treated under identical conditions. These results indicate that COX-2 protein accumulates after enzyme inhibition, and because removal of the inhibitors restored the enzyme activity, suppression of treatment with reversible COX-2 inhibitors may cause a transient overproduction of prostaglandins. The American Society for Pharmacology and Experimental Therapeutics