CEP-11004, an inhibitor of the SAPK/JNK pathway, reduces TNF-alpha release from lipopolysaccharide-treated cells and mice.
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
---|---|
Journal | European Journal of Pharmacology |
Volume | 515 |
Issue number | 1-3 |
Pages (from-to) | 179-87 |
Number of pages | 8 |
ISSN | 0014-2999 |
DOIs | |
Publication status | Published - 2005 |
Externally published | Yes |
Bibliographical note
Keywords: Animals; Carbazoles; Cell Line; Cell Survival; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Humans; Indoles; Interleukin-6; Lipopolysaccharides; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 8; Monocytes; Nitric Oxide; Phagocytosis; Phosphorylation; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tumor Necrosis Factor-alpha; p38 Mitogen-Activated Protein Kinases
ID: 5241822