A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis

Campbell, Jamie, Ciesielski, Cathleen J., Hunt, Abigail E., Horwood, Nicole J. ORCID: https://orcid.org/0000-0002-6344-1677, Beech, Jonathan T., Hayes, Louise A., Denys, Agnes, Feldmann, Marc, Brennan, Fionula M. and Foxwell, Brian M. J. (2004) A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis. Journal of Immunology, 173 (11). pp. 6928-6937. ISSN 0022-1767

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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.

Item Type: Article
Uncontrolled Keywords: physiology,genetics,genetics,drug therapy,genetics,cell line,cells, cultured,enzymology,physiology,genetic vectors,humans,antagonists & inhibitors,enzymology,mutagenesis, site-directed,antagonists & inhibitors,physiology,therapeutic use,antagonists & inhibitors,enzymology,antagonists & inhibitors,antagonists & inhibitors,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
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Depositing User: LivePure Connector
Date Deposited: 06 Mar 2019 10:30
Last Modified: 23 Jul 2024 15:40
URI: https://ueaeprints.uea.ac.uk/id/eprint/70128
DOI: 10.4049/jimmunol.173.11.6928

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