Abstract
Mitogen-activated protein (MAP) kinases play a critical role in innate immune responses to microbial infection through eliciting the biosynthesis of proinflammatory cytokines. MAP phosphatases (MKP)-1 is an archetypical member of the dual-specificity phosphatase family that deactivates MAP kinases. Induction of MKP-1 has been implicated in attenuating the lipopolysaccharide (LPS) and Peptidoglycan (PGN) responses, but how the expression of the MKP-1 is regulated is still not fully understood. Here, we show that inhibition of p38 MAP kinase by specific inhibitor SB 203580 or RNA interference (RNAi) markedly reduced the expression of MKP-1 in LPS or PGN-treated macrophages, which is correlated with prolonged activation of p38 and JNK. Depletion of MAPKAP kinase 2 (MK2), a downstream substrate of p38, by RNAi also inhibited the expression of MKP-1. The mRNA level of MKP-1 is not affected by inhibition of p38, but the expression of MKP-1 is inhibited by treatment of cycloheximide. Thus, p38 MAPK plays a critical role in mediating expression of MKP-1 at a post-transcriptional level. Furthermore, inhibition of p38 by SB 203580 prevented the expression of MKP-1 in LPS-tolerized macrophages, restored the activation of MAP kinases after LPS restimulation. These results indicate a critical role of p38-MK2-dependent induction of MKP-1 in innate immune responses.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins / metabolism*
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Cells, Cultured
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Drug Interactions
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Drug Tolerance
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Dual Specificity Phosphatase 1
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Enzyme Activation
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Feedback, Physiological*
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Gene Expression Regulation, Enzymologic*
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Imidazoles / pharmacology
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Immediate-Early Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase 4 / metabolism
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Macrophages / physiology*
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Male
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Mice
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Mice, Inbred BALB C
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Models, Biological
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Peptidoglycan / pharmacology
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Phosphoprotein Phosphatases / metabolism*
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Protein Biosynthesis
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Phosphatase 1
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Protein Serine-Threonine Kinases
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Protein Tyrosine Phosphatases / metabolism*
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Pyridines / pharmacology
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RNA Interference
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Signal Transduction
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
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p38 Mitogen-Activated Protein Kinases / physiology
Substances
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Cell Cycle Proteins
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Imidazoles
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Immediate-Early Proteins
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Peptidoglycan
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Pyridines
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Protein Kinases
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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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
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SB 203580