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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

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.

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

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