Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide: mediation through both mitogen-activated protein kinase and NF-kappaB signaling pathways in macrophages

Biochem Pharmacol. 1997 Jul 1;54(1):87-96. doi: 10.1016/s0006-2952(97)00154-8.


The mitogen-inducible cyclooxygenase (COX-2) is selectively expressed in lipopolysaccharide (LPS)-stimulated macrophages. However, the signaling pathways that lead to the expression of COX-2 in LPS-stimulated macrophages are not well understood. LPS activates members of mitogen-activated protein kinases (MAPKs) and NF-kappaB transcription factor in macrophages. We have shown that protein tyrosine kinase (PTK) inhibitors suppress the LPS-induced expression of COX-2 in macrophages (Chanmugam et al., J Biol Chem 270: 5418-5426, 1995). These PTK inhibitors also inhibit LPS-induced activation of MAPKs. Thus, in the present study, we determined whether the activation of MAPKs and NF-kappaB is necessary for the signaling pathway for the LPS-induced expression of COX-2 in the murine macrophage cell line RAW 264.7. The findings demonstrated that inhibition of extracellular signal-regulated protein kinases 1 and 2 (ERK-1 and -2) by the selective inhibitor PD98059 or inhibition of P38 by the specific inhibitor SB203580 results in partial suppression of COX-2 expression. However, activation of MAPKs by phorbol 12-myristate 13-acetate, H2O2, sorbitol, sodium vanadate, or a combination of these agents failed to induce the expression of COX-2. Inhibitors of NF-kappaB suppressed COX-2 expression without affecting tyrosine phosphorylation of MAPKs. The PTK inhibitors that suppressed the activation of MAPKs and COX-2 expression also inhibited the degradation of IkappaB-alpha. Together, these results indicate that the activation of NF-kappaB is required to induce the expression of COX-2 in LPS-stimulated RAW 264.7 cells. Inhibition of ERK-1 and 2 or P38 results in partial suppression of COX-2 expression. However, the activation of MAPKs alone is not sufficient to induce the expression of COX-2 in these cells.

Publication types

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

MeSH terms

  • Animals
  • Benzoquinones
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • DNA-Binding Proteins / analysis
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • I-kappa B Proteins*
  • Imidazoles / pharmacology
  • Lactams, Macrocyclic
  • Lactones / pharmacology
  • Lipopolysaccharides*
  • Macrolides
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Mice
  • Mitogens / pharmacology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Pyridines / pharmacology
  • Quinones / pharmacology
  • RNA, Messenger / analysis
  • Rifabutin / analogs & derivatives
  • Signal Transduction


  • Benzoquinones
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • I-kappa B Proteins
  • Imidazoles
  • Lactams, Macrocyclic
  • Lactones
  • Lipopolysaccharides
  • Macrolides
  • Mitogens
  • NF-kappa B
  • Nfkbia protein, mouse
  • Pyridines
  • Quinones
  • RNA, Messenger
  • NF-KappaB Inhibitor alpha
  • Rifabutin
  • herbimycin
  • Prostaglandin-Endoperoxide Synthases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • monorden
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one