PT  - JOURNAL ARTICLE
AU  - Nuria A. Callejas
AU  - Antonio Castrillo
AU  - Lisardo Boscá
AU  - Paloma Martı́n-Sanz
TI  - Inhibition of Prostaglandin Synthesis Up-Regulates Cyclooxygenase-2 Induced by Lipopolysaccharide and Peroxisomal Proliferators
DP  - 1999 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1235--1241
VI  - 288
IP  - 3
4099  - http://jpet.aspetjournals.org/content/288/3/1235.short
4100  - http://jpet.aspetjournals.org/content/288/3/1235.full
SO  - J Pharmacol Exp Ther1999 Mar 01; 288
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