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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
2004-11-23
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pubmed:abstractText |
TNF-alpha is a key factor in a variety of inflammatory diseases. This study examines the role of p38 MAPK in the regulation of TNF-alpha in primary human cells relevant to inflammation, e.g., macrophages and rheumatoid synovial cells. Using a dominant negative variant (D168A) of p38 MAPK and a kinase inhibitor, SB203580, we confirm in primary human macrophages that p38 MAPK regulates TNF-alpha production using a posttranscriptional mechanism requiring the 3' untranslated region of the gene. However, in LPS-activated primary human macrophages we also detect a second previously unidentified mechanism, the p38 MAPK modulation of TNF-alpha transcription. This is mediated through p38 MAPK regulation of NF-kappaB. Interestingly this mechanism was not observed in rheumatoid synovial cells. Importantly however, the dominant negative mutant of p38 MAPK, but not SB203580 was effective at inhibiting spontaneous TNF-alpha production in these ex vivo rheumatoid synovial cell cultures. These data indicate there are potential major differences in the role of p38 MAPK in inflammatory signaling that have a bearing on the use of this kinase as a target for therapy. These results indicate despite disappointing results with p38 MAPK inhibitors in the clinic, this kinase is a valid target in rheumatoid disease.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0022-1767
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
173
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6928-37
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15557189-3' Untranslated Regions,
pubmed-meshheading:15557189-Adenoviridae,
pubmed-meshheading:15557189-Alanine,
pubmed-meshheading:15557189-Arthritis, Rheumatoid,
pubmed-meshheading:15557189-Aspartic Acid,
pubmed-meshheading:15557189-Cell Line,
pubmed-meshheading:15557189-Cells, Cultured,
pubmed-meshheading:15557189-Fibroblasts,
pubmed-meshheading:15557189-Genes, Reporter,
pubmed-meshheading:15557189-Genetic Vectors,
pubmed-meshheading:15557189-Humans,
pubmed-meshheading:15557189-Lipopolysaccharides,
pubmed-meshheading:15557189-Macrophages,
pubmed-meshheading:15557189-Mutagenesis, Site-Directed,
pubmed-meshheading:15557189-NF-kappa B,
pubmed-meshheading:15557189-Promoter Regions, Genetic,
pubmed-meshheading:15557189-Protein Kinase Inhibitors,
pubmed-meshheading:15557189-RNA, Messenger,
pubmed-meshheading:15557189-Synovial Membrane,
pubmed-meshheading:15557189-Tumor Necrosis Factor-alpha,
pubmed-meshheading:15557189-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2004
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pubmed:articleTitle |
A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis.
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pubmed:affiliation |
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine Hammersmith, London, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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