0026-895X/04/6602-302-311$20.00
Mol Pharmacol 66:302-311, 2004
p38 Mitogen-Activated Protein Kinase Mediates Synergistic Induction of Inducible Nitric-Oxide Synthase by Lipopolysaccharide and Interferon-
through Signal Transducer and Activator of Transcription 1 Ser727 Phosphorylation in Murine Aortic Endothelial Cells
Hong Huang,
Jane L. Rose, and
Dale G. Hoyt
Division of Pharmacology, the Ohio State University College of Pharmacy, and the Dorothy M. Davis Heart and Lung Research Institute, Columbus, Ohio
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
(IFN
), 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 IFN
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 MAPK
/
inhibitor, each blocked induction. LPS increased the phosphorylation of STAT1
at serine 727 in IFN
-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
B and activating protein-1, combined treatment with IFN
did not enhance activation, and SB202190 did not inhibit it. The results indicate that p38 MAPK
and/or
are required for the synergistic induction of iNOS by LPS and IFN
in MAEC. Furthermore, the synergistic induction is associated with phosphorylation of STAT1
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
Address correspondence to: Dr. Dale G. Hoyt, Division of Pharmacology, The Ohio State University College of Pharmacy, 500 West Twelfth Avenue, Columbus, OH 43210. E-mail: hoyt.27{at}osu.edu
This article has been cited by other articles:

|
 |

|
 |
 
N. Rodriguez, R. Lang, N. Wantia, C. Cirl, T. Ertl, S. Durr, H. Wagner, and T. Miethke
Induction of iNOS by Chlamydophila pneumoniae requires MyD88-dependent activation of JNK
J. Leukoc. Biol.,
December 1, 2008;
84(6):
1585 - 1593.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Liu, Y. Huang, R. I. Likhotvorik, L. Keshvara, and D. G. Hoyt
Protein Never in Mitosis Gene A Interacting-1 (PIN1) regulates degradation of inducible nitric oxide synthase in endothelial cells
Am J Physiol Cell Physiol,
September 1, 2008;
295(3):
C819 - C827.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
N. Koide, Mya Mya Mu, F. Hassan, S. Islam, G. Tumurkhuu, J. Dagvadorj, Y. Naiki, I. Mori, T. Yoshida, and T. Yokochi
Lipopolysaccharide enhances interferon-{gamma}-induced nitric oxide (NO) production in murine vascular endothelial cells via augmentation of interferon regulatory factor-1 activation
Innate Immunity,
June 1, 2007;
13(3):
167 - 175.
[Abstract]
[PDF]
|
 |
|
Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics