11171562

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3

Nitric oxide (NO.) produced by inducible nitric oxide synthase (iNOS) mediates a number of important physiological and pathophysiological processes. The objective of this investigation was to examine the role of mitogen-activated protein kinases (MAPKs) in the regulation of iNOS and NO. by interferon-gamma (IFN-gamma) + lipopolysaccharide (LPS) in macrophages using specific inhibitors and dominant inhibitory mutant proteins of the MAPK pathways. The signaling pathway utilized by IFN-gamma in iNOS induction is well elucidated. To study signaling pathways that are restricted to the LPS-signaling arm, we used a subclone of the parental RAW 264.7 cell line that is unresponsive to IFN-gamma alone with respect to iNOS induction. In this RAW 264.7gammaNO(-) subclone, IFN-gamma and LPS are nevertheless required for synergistic activation of the iNOS promoter. We found that extracellular signal-regulated kinase (ERK) augmented and p38(mapk) inhibited IFN-gamma + LPS induction of iNOS. Dominant-negative MAPK kinase-4 inhibited iNOS promoter activation by IFN-gamma + LPS, also implicating the c-Jun NH(2)-terminal kinase (JNK) pathway in mediating iNOS induction. Inhibition of the ERK pathway markedly reduced IFN-gamma + LPS-induced tumor necrosis factor-alpha protein expression, providing a possible mechanism by which ERK augments iNOS expression. The inhibitory effect of p38(mapk) appears more complex and may be due to the ability of p38(mapk) to inhibit LPS-induced JNK activation. These results indicate that the MAPKs are important regulators of iNOS-NO. expression by IFN-gamma + LPS.

eng

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MEDLINE

0363-6143

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C441-50

pubmed-meshheading:11171562-Animals, pubmed-meshheading:11171562-Cell Line, pubmed-meshheading:11171562-Drug Synergism, pubmed-meshheading:11171562-Enzyme Induction, pubmed-meshheading:11171562-Enzyme Inhibitors, pubmed-meshheading:11171562-Genes, Dominant, pubmed-meshheading:11171562-Imidazoles, pubmed-meshheading:11171562-Interferon-gamma, pubmed-meshheading:11171562-Interleukin-1, pubmed-meshheading:11171562-JNK Mitogen-Activated Protein Kinases, pubmed-meshheading:11171562-Lipopolysaccharides, pubmed-meshheading:11171562-MAP Kinase Kinase 1, pubmed-meshheading:11171562-MAP Kinase Kinase 4, pubmed-meshheading:11171562-Macrophages, pubmed-meshheading:11171562-Mice, pubmed-meshheading:11171562-Mitogen-Activated Protein Kinase Kinases, pubmed-meshheading:11171562-Mitogen-Activated Protein Kinases, pubmed-meshheading:11171562-Nitric Oxide Synthase, pubmed-meshheading:11171562-Nitric Oxide Synthase Type II, pubmed-meshheading:11171562-Nitrites, pubmed-meshheading:11171562-Nuclear Proteins, pubmed-meshheading:11171562-Phosphorylation, pubmed-meshheading:11171562-Promoter Regions, Genetic, pubmed-meshheading:11171562-Protein-Serine-Threonine Kinases, pubmed-meshheading:11171562-Pyridines, pubmed-meshheading:11171562-Tumor Necrosis Factor-alpha

IFN-gamma + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't