Inhibition of Tumor Progression Locus 2 Protein Kinase Decreases Lipopolysaccharide-Induced Tumor Necrosis Factor α Production Due to the Inhibition of the Tip-Associated Protein Induction in RAW264.7 Cells
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概要
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The activation of mitogen-activated protein kinases (MAPKs) is critically involved in inflammatory events through mediation of the production of various inflammatory cytokines. The Tpl2 (tumor progression locus 2)-MEK (MAPK/ERK kinase)-ERK (extracellular signal-regulated kinase) signaling pathway plays an essential role in the production of tumor necrosis factor α (TNFα) in macrophages stimulated with lipopolysaccharide (LPS). Here, we studied the molecular mechanisms of Tpl2-mediated TNFα production using a potent Tpl2 kinase inhibitor, 1,7-naphtyridine-3-carbonitrile, and LPS-stimulated RAW264.7 cells. This inhibitor was effective in suppressing the in vitro Tpl2 kinase activity, and caused a significant reduction in TNFα production via specific suppression of the phosphorylation of MEK and ERK but not that of p38 and c-Jun N-terminal kinase (JNK). A p38 inhibitor, SB203580, also inhibited the TNFα production dose-dependently. Although the TNFα mRNA level was not altered by either inhibitor, the Tpl2 inhibitor increased the nuclear TNFα mRNA level, while decreasing that in the cytoplasm. Tip-associated protein (TAP), a key molecule in the nucleocytoplasmic transport of TNFα mRNA, was up-regulated by LPS, but this increase was impaired by the Tpl2 inhibitor. In all cases, SB203580 was without effect in the presence of LPS. These results suggest that the LPS-induced TNFα production via the Tpl2-MEK-ERK signaling pathway is regulated by changing the TAP level at the nucleocytoplasmic transport level. These results improve understanding of TNFα regulatory mechanisms and might provide a new therapeutic strategy against inflammatory diseases.
著者
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Taki Hirofumi
Department Of Communications And Computer Engineering Graduate School Of Informatics Kyoto Universit
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Miyashiro Masahiko
Pharmacology Research Laboratories Tanabe Seiyaku Co. Ltd.
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Tobe Kazuyuki
Department Of Metabolic Diseases University Of Tokyo
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Sugita Takahisa
Pharmacology Research Laboratories I Research Division Mitsubishi Tanabe Pharma Corporation
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Hirata Kazuya
Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Co.
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Ogawa Hirofumi
Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama
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Tobe Kazuyuki
Department Of Metabolic Diseases
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Tobe Kazuyuki
Department Of Internal Medicine (1) University Of Toyama
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Tobe Kazuyuki
Department of Internal Medicine, Faculty of Medicine, University of Toyama
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Miyashiro Masahiko
Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Co.
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Taki Hirofumi
Department of Internal Medicine, Faculty of Medicine, University of Toyama
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Sugita Takahisa
Pharmacology Laboratory, Research Division, Mitsubishi Tanabe Pharma Co.
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