Abstract
Exposure of macrophages to LPS elicits the production of proinflammatory cytokines, such as TNF-alpha, through complex signaling mechanisms. Mitogen-activated protein (MAP) kinases play a critical role in this process. In the present study, we have addressed the role of MAP kinase phosphatase-1 (MKP-1) in regulating proinflammatory cytokine production using RAW264.7 macrophages. Analysis of MAP kinase activity revealed a transient activation of c-Jun N-terminal kinase (JNK) and p38 after LPS stimulation. Interestingly, MKP-1 was induced concurrently with the inactivation of JNK and p38, whereas blocking MKP-1 induction by triptolide prevented this inactivation. Ectopic expression of MKP-1 accelerated JNK and p38 inactivation and substantially inhibited the production of TNF-alpha and IL-6. Induction of MKP-1 by LPS was found to be extracellular signal-regulated kinase dependent and involved enhanced gene expression and increased protein stability. Finally, MKP-1 expression was also induced by glucocorticoids as well as cholera toxin B subunit, an agent capable of preventing autoimmune diseases in animal models. These findings highlight MKP-1 as a critical negative regulator of the macrophage inflammatory response, underscoring its premise as a potential target for developing novel anti-inflammatory drugs.
MeSH terms
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Animals
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Cell Cycle Proteins*
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Cell Line
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Cholera Toxin / pharmacology
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Cytokines / biosynthesis*
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Dexamethasone / pharmacology
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Diterpenes / pharmacology
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Dual Specificity Phosphatase 1
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Enzyme Induction / drug effects
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Enzyme Inhibitors / pharmacology
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Enzyme Stability / drug effects
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Epoxy Compounds
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Gene Expression
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Immediate-Early Proteins / biosynthesis*
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Immediate-Early Proteins / genetics
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Inflammation Mediators / metabolism*
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JNK Mitogen-Activated Protein Kinases
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Lipopolysaccharides / toxicity
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Macrophages / drug effects
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Macrophages / enzymology*
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Macrophages / immunology*
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Phenanthrenes*
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Phosphoprotein Phosphatases*
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / biosynthesis*
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Protein Tyrosine Phosphatases / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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p38 Mitogen-Activated Protein Kinases
Substances
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Cell Cycle Proteins
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Cytokines
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Diterpenes
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Enzyme Inhibitors
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Epoxy Compounds
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Immediate-Early Proteins
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Inflammation Mediators
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Lipopolysaccharides
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Phenanthrenes
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RNA, Messenger
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triptolide
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Dexamethasone
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Cholera Toxin
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse
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Protein Tyrosine Phosphatases