A novel mechanism for TNF-alpha regulation by p38 MAPK: involvement of NF-kappa B with implications for therapy in rheumatoid arthritis.
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.
Campbell
Jamie
J
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine Hammersmith, London, United Kingdom.
Ciesielski
Cathleen J
CJ
Hunt
Abigail E
AE
Horwood
Nicole J
NJ
Beech
Jonathan T
JT
Hayes
Louise A
LA
Denys
Agnes
A
Feldmann
Marc
M
Brennan
Fionula M
FM
Foxwell
Brian M J
BM
D020413:3' Untranslated Regions / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics; D000409:Alanine / Q000235:genetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D017930:Genes, Reporter / Q000502:physiology; D005822:Genetic Vectors; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013583:Synovial Membrane / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D020413:3' Untranslated Regions; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D001224:Aspartic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D000409:Alanine