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

Daniel Hwang, Byeong C. Jang, Gang Yu, Mary Boudreau

Research output: Contribution to journalArticle

228 Scopus citations

Abstract

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-κB 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-κB 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-κB 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 IκB-α. Together, these results indicate that the activation of NF-κB 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.

Original languageEnglish (US)
Pages (from-to)87-96
Number of pages10
JournalBiochemical Pharmacology
Volume54
Issue number1
DOIs
StatePublished - Jul 1 1997
Externally publishedYes

Keywords

  • Cyclooxygenase
  • Lipopolysaccharide
  • Macrophages
  • Mitogen-activated protein kinases
  • NF-κB
  • Protein tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Pharmacology

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