PMID- 11076936
OWN - NLM
STAT- MEDLINE
DCOM- 20010405
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 9
DP  - 2001 Mar 2
TI  - Combinations of ERK and p38 MAPK inhibitors ablate tumor necrosis factor-alpha 
      (TNF-alpha ) mRNA induction. Evidence for selective destabilization of TNF-alpha 
      transcripts.
PG  - 6666-74
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a potent proinflammatory cytokine 
      whose synthesis and secretion are implicated in diverse pathologies. Hence, 
      inhibition of TNF-alpha transcription or translation and neutralization of its 
      protein product represent major pharmaceutical strategies to control 
      inflammation. We have studied the role of ERK and p38 mitogen-activated protein 
      (MAP) kinase in controlling TNF-alpha mRNA levels in differentiated THP-1 cells 
      and in freshly purified human monocytes. We show here that it is possible to 
      produce virtually complete inhibition of lipopolysaccharide-stimulated TNF-alpha 
      mRNA accumulation by using a combination of ERK and p38 MAP kinase inhibitors. 
      Furthermore, substantial inhibition is achievable using combinations of 1 microm 
      of each inhibitor, whereas inhibitors used individually are incapable of 
      producing complete inhibition even at high concentrations. Finally, addressing 
      mechanisms involved, we show that inhibition of p38 MAP kinase selectively 
      destabilizes TNF-alpha transcripts but does not affect degradation of c-jun 
      transcripts. These results impinge on the controversy in the literature 
      surrounding the mode of action of MAP kinase inhibitors on TNF-alpha mRNA and 
      suggest the use of combinations of MAP kinase inhibitors as an effective 
      anti-inflammatory strategy.
FAU - Rutault, K
AU  - Rutault K
AD  - Nuclear Signalling Laboratory, Department of Biochemistry, University of Oxford, 
      South Parks Road, Oxford OX1 3QU, United Kingdom.
FAU - Hazzalin, C A
AU  - Hazzalin CA
FAU - Mahadevan, L C
AU  - Mahadevan LC
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20001113
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Flavonoids)
RN  - 0 (Imidazoles)
RN  - 0 (Lipopolysaccharide Receptors)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (Pyridines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
RN  - OU13V1EYWQ (SB 203580)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
SB  - IM
MH  - Cell Differentiation/drug effects
MH  - Cells, Cultured
MH  - Flavonoids/pharmacology
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Intercellular Adhesion Molecule-1/analysis
MH  - Lipopolysaccharide Receptors/analysis
MH  - Lipopolysaccharides/pharmacology
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors/physiology
MH  - Monocytes/metabolism
MH  - Proto-Oncogene Proteins c-jun/genetics
MH  - Pyridines/pharmacology
MH  - RNA, Messenger/*analysis
MH  - Tetradecanoylphorbol Acetate/pharmacology
MH  - Tumor Necrosis Factor-alpha/analysis/*genetics
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2000/11/15 00:00
MHDA- 2001/04/06 10:01
CRDT- 2000/11/15 00:00
PHST- 2000/11/15 00:00 [pubmed]
PHST- 2001/04/06 10:01 [medline]
PHST- 2000/11/15 00:00 [entrez]
AID - S0021-9258(19)34680-0 [pii]
AID - 10.1074/jbc.M005486200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Mar 2;276(9):6666-74. doi: 10.1074/jbc.M005486200. Epub 2000 
      Nov 13.