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CEP-11004, an inhibitor of the SAPK/JNK pathway, reduces TNF-alpha release from lipopolysaccharide-treated cells and mice.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2005 May 16; Vol. 515 (1-3), pp. 179-87. - Publication Year :
- 2005
-
Abstract
- CEP-11004, a mixed lineage kinase (MLK) inhibitor, was examined for its effects on tumor necrosis factor-alpha (TNF-alpha) production in human THP-1 monocytes, mouse BV-2 microglia, and C57Bl/6 mice. CEP-11004 inhibited TNF-alpha secretion up to 90% in THP-1 cells incubated with 3 mug/ml lipopolysaccharide, with an IC50 of 137+/-14 nM. CEP-11004 also inhibited TNF-alpha production in lipopolysaccharide-stimulated microglial cells, but did not inhibit the initial increase in TNF-alpha mRNA expression as measured by real-time polymerase chain reaction (PCR). The mitogen-activated protein kinases (MAPKs) phospho-c-jun N-terminal kinase (JNK), phospho-p38, and phospho-MAPK kinase 4 (MKK4) levels were increased in THP-1 cells following lipopolysaccharide treatment, and were reduced by CEP-11004 treatment. For in vivo studies, CEP-11004 was injected 2 h prior to lipopolysaccharide (20 mg/kg) administration. CEP-11004 significantly inhibited TNF-alpha production at doses of 1-10 mg/kg as measured by enzyme-linked immunosorbent assay (ELISA). These results suggest that MLK blockade may be useful in inhibiting pro-inflammatory cytokine production in a wide range of diseases.
- Subjects :
- Animals
Cell Line
Cell Survival drug effects
Dinoprostone biosynthesis
Dose-Response Relationship, Drug
Enzyme Activation drug effects
Enzyme-Linked Immunosorbent Assay
Humans
Interleukin-6 metabolism
MAP Kinase Kinase 4 metabolism
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 8 antagonists & inhibitors
Mitogen-Activated Protein Kinase 8 genetics
Monocytes cytology
Monocytes metabolism
Nitric Oxide biosynthesis
Phagocytosis drug effects
Phosphorylation drug effects
RNA, Messenger genetics
RNA, Messenger metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction drug effects
Tumor Necrosis Factor-alpha genetics
p38 Mitogen-Activated Protein Kinases metabolism
Carbazoles pharmacology
Indoles pharmacology
Lipopolysaccharides pharmacology
Mitogen-Activated Protein Kinase 8 metabolism
Monocytes drug effects
Tumor Necrosis Factor-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2999
- Volume :
- 515
- Issue :
- 1-3
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 15904918
- Full Text :
- https://doi.org/10.1016/j.ejphar.2005.04.016