Abstract
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.
Original language | English |
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Pages (from-to) | 6928-6937 |
Number of pages | 10 |
Journal | Journal of Immunology |
Volume | 173 |
Issue number | 11 |
DOIs | |
Publication status | Published - 1 Dec 2004 |
Keywords
- 3' Untranslated Regions/physiology
- Adenoviridae/genetics
- Alanine/genetics
- Arthritis, Rheumatoid/drug therapy
- Aspartic Acid/genetics
- Cell Line
- Cells, Cultured
- Fibroblasts/enzymology
- Genes, Reporter/physiology
- Genetic Vectors
- Humans
- Lipopolysaccharides/antagonists & inhibitors
- Macrophages/enzymology
- Mutagenesis, Site-Directed
- NF-kappa B/antagonists & inhibitors
- Promoter Regions, Genetic/physiology
- Protein Kinase Inhibitors/therapeutic use
- RNA, Messenger/antagonists & inhibitors
- Synovial Membrane/enzymology
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors