CEP-11004, an inhibitor of the SAPK/JNK pathway, reduces TNF-alpha release from lipopolysaccharide-treated cells and mice.

TY - JOUR

T1 - CEP-11004, an inhibitor of the SAPK/JNK pathway, reduces TNF-alpha release from lipopolysaccharide-treated cells and mice.

AU - Ciallella, John R

AU - Saporito, Michael

AU - Lund, Soren

AU - Leist, Marcel

AU - Hasseldam, Henrik

AU - McGann, Natalie

AU - Smith, Charles S

AU - Bozyczko-Coyne, Donna

AU - Flood, Dorothy G

N1 - 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

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1016/j.ejphar.2005.04.016

DO - 10.1016/j.ejphar.2005.04.016

M3 - Journal article

C2 - 15904918

SN - 0014-2999

VL - 515

SP - 179

EP - 187

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1-3

ER -