Abstract
The stress-activated protein kinase p38 stabilizes a number of mRNAs encoding inflammatory mediators, such as cyclooxygenase 2 (Cox-2). In HeLa cells the anti-inflammatory glucocorticoid dexamethasone destabilizes Cox-2 mRNA by inhibiting p38 function. Here we demonstrate that this effect is phosphatase dependent. Furthermore, in HeLa cells dexamethasone induced the sustained expression of mitogen-activated protein kinase phosphatase 1 (MKP-1), a potent inhibitor of p38 function. The inhibition of p38 and the induction of MKP-1 by dexamethasone occurred with similar dose dependence and kinetics. No other known p38 phosphatases were induced by dexamethasone, and other cell types which failed to express MKP-1 also failed to inhibit p38 in response to dexamethasone. The proinflammatory cytokine interleukin 1 (IL-1) induced MKP-1 expression in a p38-dependent manner and acted synergistically with dexamethasone to induce MKP-1 expression. In HeLa cells treated with IL-1 or IL-1 and dexamethasone, the dynamics of p38 activation mirrored the expression of MKP-1. These observations suggest that MKP-1 participates in a negative-feedback loop which regulates p38 function and that dexamethasone may inhibit proinflammatory gene expression in part by inducing MKP-1 expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins*
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Cyclooxygenase 2
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Dexamethasone / pharmacology*
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Dose-Response Relationship, Drug
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Dual Specificity Phosphatase 1
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects*
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Glucocorticoids / pharmacology
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HeLa Cells
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Humans
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Imidazoles / pharmacology
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism*
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Interleukin-1 / metabolism
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Membrane Proteins
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism*
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Oligonucleotide Array Sequence Analysis
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Phosphoprotein Phosphatases*
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / metabolism*
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Pyridines / pharmacology
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RNA Stability
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Time Factors
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p38 Mitogen-Activated Protein Kinases
Substances
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Cell Cycle Proteins
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Enzyme Inhibitors
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Glucocorticoids
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Imidazoles
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Immediate-Early Proteins
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Interleukin-1
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Isoenzymes
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Membrane Proteins
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Pyridines
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Dexamethasone
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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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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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Protein Tyrosine Phosphatases
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SB 203580