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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2004-12-22
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pubmed:abstractText |
Endotoxin tolerance has been characterized as diminished TNF-alpha expression after a second LPS stimulus and is dependent on new protein synthesis. LPS-induced expression of TNF-alpha is partly regulated by the p38 mitogen-activated protein (MAP) kinase, which post-transcriptionally stabilizes TNF-alpha mRNA. The dual-specific phosphatase, MKP-1, has been shown to negatively regulate p38 via dephosphorylation. We hypothesized that MKP-1 expression induced during tolerance regulates TNF-alpha expression by inhibiting p38 activity. To test this hypothesis, tolerance was induced in THP-1 cells, and naive or tolerized cells were rechallenged 18 h later with LPS (1 microg/mL) and TNF-alpha production was measured. Under similar conditions, nuclear proteins were isolated after LPS stimulation and were analyzed for phospho-p38 and MKP-1 by Western blot. Transient overexpression of MKP-1 was achieved using an adenoviral expression strategy and infected cells subsequently treated with LPS for TNF-alpha production and p38 activation. Results showed that LPS tolerance was induced as reflected by decreased TNF-alpha. Induction of LPS hyporesponsiveness could be mimicked by overexpression of MKP-1 but not beta-gal. MKP-1 expression was noted only in LPS-tolerized or Ad-MKP-1 infected cells. In the canonical and Ad-MKP-1-mediated tolerance models, decreased phospho-p38 activity was observed. MKP-1s role in mediating endotoxin tolerance was further confirmed by demonstrating the inability to fully tolerize peritoneal macrophages isolated from MKP-1 null mutant (vs. wild type) mice (24% vs. 72% reductions, respectively). These data demonstrate that the dual specific phosphatase MKP-1 is an important mediator of endotoxin tolerance via p38 regulation.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DUSP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Dual Specificity Phosphatase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Dusp1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Endotoxins,
http://linkedlifedata.com/resource/pubmed/chemical/Immediate-Early Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoprotein Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Phosphatase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1073-2322
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
23
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
80-7
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15614136-Adenoviridae,
pubmed-meshheading:15614136-Animals,
pubmed-meshheading:15614136-Blotting, Western,
pubmed-meshheading:15614136-Cell Cycle Proteins,
pubmed-meshheading:15614136-Cell Line, Tumor,
pubmed-meshheading:15614136-Cell Nucleus,
pubmed-meshheading:15614136-Dose-Response Relationship, Drug,
pubmed-meshheading:15614136-Dual Specificity Phosphatase 1,
pubmed-meshheading:15614136-Endotoxins,
pubmed-meshheading:15614136-Enzyme Activation,
pubmed-meshheading:15614136-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:15614136-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:15614136-Humans,
pubmed-meshheading:15614136-Immediate-Early Proteins,
pubmed-meshheading:15614136-Immunoprecipitation,
pubmed-meshheading:15614136-Lipopolysaccharides,
pubmed-meshheading:15614136-Macrophages,
pubmed-meshheading:15614136-Mice,
pubmed-meshheading:15614136-Mice, Mutant Strains,
pubmed-meshheading:15614136-Mice, Transgenic,
pubmed-meshheading:15614136-Phosphoprotein Phosphatases,
pubmed-meshheading:15614136-Protein Phosphatase 1,
pubmed-meshheading:15614136-Protein Tyrosine Phosphatases,
pubmed-meshheading:15614136-RNA, Messenger,
pubmed-meshheading:15614136-RNA Processing, Post-Transcriptional,
pubmed-meshheading:15614136-Time Factors,
pubmed-meshheading:15614136-Tumor Necrosis Factor-alpha,
pubmed-meshheading:15614136-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2005
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pubmed:articleTitle |
Contribution of MKP-1 regulation of p38 to endotoxin tolerance.
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pubmed:affiliation |
Division of Critical Care Medicine, Cincinnati Children's Hospital Research Foundation, University of Cincinnati Medical School, Cincinnati, Ohio 45229-3039, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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