Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways

J Biol Chem. 2000 Sep 8;275(36):28173-9. doi: 10.1074/jbc.M002329200.

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 alpha (TNFalpha)- or lipopolysaccharide (LPS)-induced COX-2 expression. This inhibition correlates with the suppression of TNFalpha- or LPS-induced NFkappaB activation by flufenamic acid. The inhibitor of extracellular signal-regulated protein kinase, p38, or NFkappaB 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 NFkappaB and mitogen-activated protein kinases. An activator of peroxisome proliferator-activated receptor gamma, 15-deoxy-Delta(12,14)-prostaglandin J(2), also induces COX-2 expression and inhibits TNFalpha-induced NFkappaB activation and COX-2 expression. Flufenamic acid and 15-deoxy-Delta(12,14)-prostaglandin J(2) also inhibit LPS-induced expression of inducible form of nitric-oxide synthase and interleukin-1alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Colonic Neoplasms
  • Cyclooxygenase 2
  • Enzyme Induction
  • Flufenamic Acid / pharmacology*
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Humans
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology*
  • Macrophages / enzymology
  • Membrane Proteins
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Sulindac / analogs & derivatives
  • Sulindac / pharmacology
  • Transcription Factors / drug effects
  • Transcription Factors / physiology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • 15-deoxy-delta(12,14)-prostaglandin J2
  • Anti-Inflammatory Agents, Non-Steroidal
  • Isoenzymes
  • Lipopolysaccharides
  • Membrane Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Sulindac
  • Flufenamic Acid
  • sulindac sulfide
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Prostaglandin D2