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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121 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
DOIs
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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