Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase

Mediation through different signaling pathways

Ji H. Paik, Jeong H. Ju, Joo Y. Lee, Mary D. Boudreau, Daniel H. Hwang

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

The efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is considered to be a result of their inhibitory effect on cyclooxygenase (COX) activity. Here, we report that flufenamic acid shows two opposing effects on COX-2 expression; it induces COX-2 expression in the colon cancer cell line (HT-29) and macrophage cell line (RAW 264.7); conversely, it inhibits tumor necrosis factor α (TNFα)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFα- or LPS-induced NFκB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFκB does not affect the NSAID-induced COX-2 expression. These results suggest that the NSAID-induced COX-2 expression is not mediated through activation of NFκB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor γ, 15-deoxy-Δ12,14-prostaglandin J2, also induces COX-2 expression and inhibits TNFα-induced NFκB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Δ12,14-prostaglandin J2 also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1α in RAW 264.7 cells. Together, these results indicate that the NSAIDs inhibit mitogen-induced COX-2 expression while they induce COX-2 expression. Furthermore, the results suggest that the anti-inflammatory effects of flufenamic acid and some other NSAIDs are due to their inhibitory action on the mitogen-induced expression of COX-2 and downstream markers of inflammation in addition to their inhibitory effect on COX enzyme activity.

Original languageEnglish (US)
Pages (from-to)28173-28179
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number36
DOIs
StatePublished - Sep 8 2000
Externally publishedYes

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Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Anti-Inflammatory Agents
Flufenamic Acid
Pharmaceutical Preparations
Lipopolysaccharides
Tumor Necrosis Factor-alpha
Chemical activation
Mitogens
Cells
Cell Line
HT29 Cells
Peroxisome Proliferator-Activated Receptors
Macrophages
Extracellular Signal-Regulated MAP Kinases
Enzyme activity
p38 Mitogen-Activated Protein Kinases
Nitric Oxide Synthase Type II
Mitogen-Activated Protein Kinases
Interleukin-1

ASJC Scopus subject areas

  • Biochemistry

Cite this

Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase : Mediation through different signaling pathways. / Paik, Ji H.; Ju, Jeong H.; Lee, Joo Y.; Boudreau, Mary D.; Hwang, Daniel H.

In: Journal of Biological Chemistry, Vol. 275, No. 36, 08.09.2000, p. 28173-28179.

Research output: Contribution to journalArticle

Paik, Ji H. ; Ju, Jeong H. ; Lee, Joo Y. ; Boudreau, Mary D. ; Hwang, Daniel H. / Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase : Mediation through different signaling pathways. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 36. pp. 28173-28179.
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