Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-gamma and TNF-alpha in mouse macrophages
| Autor: | E D, Chan, B W, Winston, S T, Uh, M W, Wynes, D M, Rose, D W, Riches |
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| Rok vydání: | 1999 |
| Předmět: |
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase Kinases Mice Inbred C3H MAP Kinase Kinase 4 Tumor Necrosis Factor-alpha Macrophages JNK Mitogen-Activated Protein Kinases MAP Kinase Kinase Kinase 1 Nitric Oxide Synthase Type II 3T3 Cells Protein Serine-Threonine Kinases Protein-Tyrosine Kinases p38 Mitogen-Activated Protein Kinases Enzyme Activation Interferon-gamma Mice Gene Expression Regulation Enzyme Induction Calcium-Calmodulin-Dependent Protein Kinases Mutation Animals Mitogen-Activated Protein Kinases Nitric Oxide Synthase Promoter Regions Genetic |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 162(1) |
| ISSN: | 0022-1767 |
| Popis: | The expression of inducible nitric oxide synthase (iNOS) by macrophages is stimulated by coexposure to IFN-gamma and a number of stimuli, including TNF-alpha. Recent work has shown that TNF-alpha activates members of the mitogen-activated protein kinase family that subsequently trans-activate transcription factors implicated in the regulation of iNOS expression. The objective of this study was to systematically evaluate the role of: 1) p42mapk/erk2, 2) p46 c-Jun NH2-terminal kinase/stress-activated protein kinase (p46 JNK/SAPK), and 3) p38mapk in the induction of iNOS expression during costimulation of mouse macrophages with IFN-gamma and TNF-alpha. All three kinases were activated during costimulation with IFN-gamma and TNF-alpha. However, specific antagonism of the p42mapk/erk2 and p38mapk with PD98059 and SKF86002, respectively, had no effect on the induction of iNOS expression. In contrast, blockade of all three kinases with N-acetylcysteine completely blocked the induction of iNOS expression. In addition, specific antagonism of the JNK/SAPK upstream kinases MEKK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase) and MKK4 (mitogen-activated protein kinase kinase 4) with dominant inhibitory mutants blocked transcriptional activation of the iNOS promoter in response to costimulation with IFN-gamma and TNF-alpha. Collectively, these findings support the involvement of p46 JNK/SAPK and its upstream kinases in regulating the induction of iNOS following ligation of the TNF-alpha receptor CD120a (p55) in the presence of IFN-gamma. |
| Databáze: | OpenAIRE |
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