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

Jamie Campbell, Cathleen J Ciesielski, Abigail E Hunt, Nicole J Horwood, Jonathan T Beech, Louise A Hayes, Agnes Denys, Marc Feldmann, Fionula M Brennan, Brian M J Foxwell

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109 Citations (Scopus)

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 languageEnglish
Pages (from-to)6928-6937
Number of pages10
JournalJournal of Immunology
Volume173
Issue number11
Publication statusPublished - 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

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