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., 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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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.

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
Related URLs:	https://www.ncbi.nlm.nih.gov/pubmed/1555...
Depositing User:	LivePure Connector
Date Deposited:	06 Mar 2019 10:30
Last Modified:	06 Feb 2025 08:18
URI:	https://ueaeprints.uea.ac.uk/id/eprint/70128
DOI:	10.4049/jimmunol.173.11.6928

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