Abstract
The p43 protein is associated with human macromolecular aminoacyl tRNA synthetase complex and secreted to up-regulate diverse proinflammatory genes including TNF. Here we focused on the p43-induced TNF production and determined its responsible signal pathway. The p43-induced TNF production was mediated by the activation of MAPK family members, ERK and p38 MAPK, and by IkappaB degradation leading to the activation of NFkappaB. We also studied the upstream molecules for ERK and p38 MAPK by using a variety of inhibitors. The inhibitors for protein kinase C (PKC) and phospholipase C (PLC) prevented the p43-induced TNF production. Interestingly, all of the effective drugs inhibited the ERK activity, while the drugs had no effects on p38 MAPK activity and IkappaB degradation. Together, the p43-induced TNF production was controlled by NFkB, p38 MAPK, and ERK that is dependent on the activities of PLC and PKC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cytokines / biosynthesis
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Cytokines / physiology*
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Enzyme Inhibitors / pharmacology
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Estrenes / pharmacology
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Gene Expression Regulation / drug effects
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Humans
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I-kappa B Proteins / metabolism
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Leupeptins / pharmacology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Monocytes / drug effects
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Monocytes / metabolism*
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NF-kappa B / metabolism
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Neoplasm Proteins / physiology*
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Phosphatidylinositol 3-Kinases / physiology
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Phospholipase C gamma
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Protein Kinase C / physiology
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Pyrrolidinones / pharmacology
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RNA-Binding Proteins / physiology*
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Signal Transduction / physiology*
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Staurosporine / pharmacology
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Tumor Necrosis Factor-alpha / biosynthesis*
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Type C Phospholipases / physiology
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p38 Mitogen-Activated Protein Kinases
Substances
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Cytokines
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Enzyme Inhibitors
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Estrenes
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I-kappa B Proteins
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Leupeptins
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NF-kappa B
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Neoplasm Proteins
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Pyrrolidinones
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RNA-Binding Proteins
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Tumor Necrosis Factor-alpha
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small inducible cytokine subfamily E, member 1
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acetylleucyl-leucyl-norleucinal
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1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
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Phosphatidylinositol 3-Kinases
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Protein Kinase C
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Type C Phospholipases
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Phospholipase C gamma
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Staurosporine