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Research ArticleArticle

p38 Mitogen-Activated Protein Kinase Mediates Synergistic Induction of Inducible Nitric-Oxide Synthase by Lipopolysaccharide and Interferon-γ through Signal Transducer and Activator of Transcription 1 Ser727 Phosphorylation in Murine Aortic Endothelial Cells

Hong Huang, Jane L. Rose and Dale G. Hoyt
Molecular Pharmacology August 2004, 66 (2) 302-311; DOI: https://doi.org/10.1124/mol.66.2.302
Hong Huang
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Jane L. Rose
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Dale G. Hoyt
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Abstract

Nitric oxide (NO) can be produced in large amounts by up-regulation of inducible NO synthase (iNOS). iNOS is induced in many cell types by pro-inflammatory agents, such as bacterial lipopolysaccharide (LPS) and cytokines. Overproduction by endothelial cells (EC) may contribute to vascular diseases. In contrast to macrophages, murine aortic endothelial cells (MAEC) produced no NO in response to either LPS or interferon γ (IFNγ), whereas combined treatment was highly synergistic. In this study, we investigated the mechanisms of synergy in MAEC. LPS activated p38 mitogen-activated protein kinase (MAPK), whereas IFNγ activated Janus kinase and signal transducer and activator of transcription-1 (STAT1). Both pathways were required for iNOS induction because herbimycin A, a tyrosine kinase inhibitor, and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole · HCl (SB202190), a p38 MAPKα/β inhibitor, each blocked induction. LPS increased the phosphorylation of STAT1α at serine 727 in IFNγ-treated MAEC. SB202190, but not 2′-amino-3′-methoxyflavone (PD98059), an inhibitor of p44/p42 MAPK activation, abolished the phosphorylation and induction of iNOS. SB202190 did not affect tyrosine 701 phosphorylation or nuclear translocation of STAT1. However, STAT1-DNA binding activity was reduced by SB202190. Although LPS stimulated the DNA binding activity of nuclear factor κB and activating protein-1, combined treatment with IFNγ did not enhance activation, and SB202190 did not inhibit it. The results indicate that p38 MAPKα and/or β are required for the synergistic induction of iNOS by LPS and IFNγ in MAEC. Furthermore, the synergistic induction is associated with phosphorylation of STAT1α serine 727 in MAEC. This observation may explain potentially beneficial effects of p38 MAPK inhibitors in vascular inflammatory diseases.

  • Received January 7, 2004.
  • Accepted May 6, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (2)
Molecular Pharmacology
Vol. 66, Issue 2
1 Aug 2004
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p38 Mitogen-Activated Protein Kinase Mediates Synergistic Induction of Inducible Nitric-Oxide Synthase by Lipopolysaccharide and Interferon-γ through Signal Transducer and Activator of Transcription 1 Ser727 Phosphorylation in Murine Aortic Endothelial C…
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Research ArticleArticle

p38 Mitogen-Activated Protein Kinase Mediates Synergistic Induction of Inducible Nitric-Oxide Synthase by Lipopolysaccharide and Interferon-γ through Signal Transducer and Activator of Transcription 1 Ser727 Phosphorylation in Murine Aortic Endothelial Cells

Hong Huang, Jane L. Rose and Dale G. Hoyt
Molecular Pharmacology August 1, 2004, 66 (2) 302-311; DOI: https://doi.org/10.1124/mol.66.2.302

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Research ArticleArticle

p38 Mitogen-Activated Protein Kinase Mediates Synergistic Induction of Inducible Nitric-Oxide Synthase by Lipopolysaccharide and Interferon-γ through Signal Transducer and Activator of Transcription 1 Ser727 Phosphorylation in Murine Aortic Endothelial Cells

Hong Huang, Jane L. Rose and Dale G. Hoyt
Molecular Pharmacology August 1, 2004, 66 (2) 302-311; DOI: https://doi.org/10.1124/mol.66.2.302
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