Lipoteichoic acid-induced nitric oxide synthase expression in RAW 264.7 macrophages is mediated by cyclooxygenase-2, prostaglandin E2, protein kinase A, p38 MAPK, and nuclear factor-κB pathways

Yau Chong Chang, Pei Chih Li, Bing Chang Chen, Ming Shyan Chang, Jui Ling Wang, Wen Ta Chiu, Chien Huang Lin

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

We recently reported that lipoteichoic acid (LTA), a cell wall component of the gram-positive bacterium Staphylococcus aureus, stimulated inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) release, and cyclooxygenase-2 (COX-2) expression in RAW 264.7 macrophages. This study was carried out to further investigate the roles of COX-2 and prostaglandin E2 (PGE2) in LTA-induced iNOS expression and NO release in RAW 264.7 macrophages. Treatment of RAW 264.7 macrophages with LTA caused a time-dependent increase in PGE2 release. LTA-induced iNOS expression and NO release were inhibited by a non-selective COX inhibitor (indomethacin), a selective COX-2 inhibitor (NS-398), an adenylyl cyclase (AC) inhibitor (dideoxyadenosine, DDA), and a protein kinase A (PKA) inhibitor (KT-5720). Furthermore, both PGE2 and the direct PKA activator, dibutyryl-cAMP, also induced iNOS expression in a concentration-dependent manner. Stimulation of RAW 264.7 macrophages with LTA, PGE2, and dibutyryl-cAMP all caused p38 MAPK activation in a time-dependent manner. LTA-mediated p38 MAPK activation was inhibited by indomethacin, NS-398, and SB 203580, but not by PD 98059. The PGE2-mediated p38 MAPK activation was inhibited by DDA, KT-5720, and SB 203580, but not by PD 98059. LTA caused time-dependent activation of the nuclear factor-κB (NF-κB)-specific DNA-protein complex formation. The LTA-induced increase in κB-luciferase activity was inhibited by indomethacin, NS-398, KT-5720, and a dominant negative mutant of p38 αMAPK (p38 αMAPK DN). These results suggest that LTA-induced iNOS expression and NO release involve COX-2-generated PGE2 production, and AC, PKA, p38 MAPK, and NF-κB activation in RAW 264.7 macrophages.

Original languageEnglish
Pages (from-to)1235-1243
Number of pages9
JournalCellular Signalling
Volume18
Issue number8
DOIs
Publication statusPublished - Aug 2006
Externally publishedYes

Keywords

  • Cyclooxygenase-2
  • Inducible nitric oxide synthase
  • Lipoteichoic acid
  • Nitric oxide
  • Nuclear factor-κB
  • Prostaglandin E
  • Protein kinase A
  • RAW 264.7 macrophages

ASJC Scopus subject areas

  • Cell Biology

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