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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.

Original publication

DOI

10.4049/jimmunol.173.11.6928

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

12/2004

Volume

173

Pages

6928 - 6937

Addresses

Kennedy Institute of Rheumatology Division, Imperial College School of Medicine Hammersmith, London, United Kingdom.

Keywords

Synovial Membrane, Cells, Cultured, Cell Line, Fibroblasts, Macrophages, Humans, Adenoviridae, Arthritis, Rheumatoid, p38 Mitogen-Activated Protein Kinases, Lipopolysaccharides, Alanine, Aspartic Acid, Tumor Necrosis Factor-alpha, NF-kappa B, RNA, Messenger, 3' Untranslated Regions, Protein Kinase Inhibitors, Mutagenesis, Site-Directed, Genes, Reporter, Genetic Vectors, Promoter Regions, Genetic