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Research ArticleArticle

Inhibition of Prostaglandin Synthesis Up-Regulates Cyclooxygenase-2 Induced by Lipopolysaccharide and Peroxisomal Proliferators

Nuria A. Callejas, Antonio Castrillo, Lisardo Boscá and Paloma Martı́n-Sanz
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 1235-1241;
Nuria A. Callejas
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Antonio Castrillo
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Lisardo Boscá
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Paloma Martı́n-Sanz
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Paloma Martı́n-Sanz, Instituto de Bioquı́mica, Facultad de Farmacia, 28040 Madrid, Spain.

  • ↵1 This work was supported by Grants 95/0966 and 98/0220 from Fondo de Investigaciones Sanitarias, Spain

  • Abbreviations:
    COX
    Cyclooxygenase
    LPS
    lipopolysaccharide
    ETYA
    5,8,11,14-eicosatetrayonic acid
    PP
    peroxisome proliferator
    PPAR
    peroxisome-proliferator activated receptor
    PG
    prostaglandin
    DMEM
    Dulbecco’s modified Eagle’s medium
    FCS
    fetal calf serum
    SSC
    standard saline citrate
    • Received July 16, 1998.
    • Accepted October 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

Inhibition of Prostaglandin Synthesis Up-Regulates Cyclooxygenase-2 Induced by Lipopolysaccharide and Peroxisomal Proliferators

Nuria A. Callejas, Antonio Castrillo, Lisardo Boscá and Paloma Martı́n-Sanz
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1235-1241;

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Research ArticleArticle

Inhibition of Prostaglandin Synthesis Up-Regulates Cyclooxygenase-2 Induced by Lipopolysaccharide and Peroxisomal Proliferators

Nuria A. Callejas, Antonio Castrillo, Lisardo Boscá and Paloma Martı́n-Sanz
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1235-1241;
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