TY - JOUR
T1 - Inhibition of microglial inflammation by the MLK inhibitor CEP-1347.
AU - Lund, Søren
AU - Porzgen, Peter
AU - Mortensen, Anne Louise
AU - Hasseldam, Henrik
AU - Bozyczko-Coyne, Donna
AU - Morath, Siegfried
AU - Hartung, Thomas
AU - Bianchi, Marina
AU - Ghezzi, Pietro
AU - Bsibsi, Malika
AU - Dijkstra, Sipke
AU - Leist, Marcel
N1 - Keywords: Animals; Anti-Inflammatory Agents; Carbazoles; Cell Line; Cells, Cultured; Cytokines; Down-Regulation; Encephalitis; Enzyme Inhibitors; Gliosis; Humans; Indoles; Inflammation Mediators; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Microglia; Trans-Activation (Genetics); Tumor Necrosis Factor-alpha; p38 Mitogen-Activated Protein Kinases
PY - 2005
Y1 - 2005
N2 - CEP-1347 is a potent inhibitor of the mixed lineage kinases (MLKs), a distinct family of mitogen-activated protein kinase kinase kinases (MAPKKK). It blocks the activation of the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of Parkinson's disease (PD). Microglial activation may involve kinase pathways controlled by MLKs and might contribute to the pathology of neurodegenerative diseases. Therefore, the possibility that CEP-1347 modulates the microglial inflammatory response [tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1)] was explored. Indeed, the MLK inhibitor CEP-1347 reduced cytokine production in primary cultures of human and murine microglia, and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins or the plaque forming peptide Abeta1-40. Moreover, CEP-1347 inhibited brain TNF production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a MLK inhibitor, CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways. These data imply MLKs as important, yet unrecognized, modulators of microglial inflammation, and demonstrate a novel anti-inflammatory potential of CEP-1347.
AB - CEP-1347 is a potent inhibitor of the mixed lineage kinases (MLKs), a distinct family of mitogen-activated protein kinase kinase kinases (MAPKKK). It blocks the activation of the c-Jun/JNK apoptotic pathway in neurons exposed to various stressors and attenuates neurodegeneration in animal models of Parkinson's disease (PD). Microglial activation may involve kinase pathways controlled by MLKs and might contribute to the pathology of neurodegenerative diseases. Therefore, the possibility that CEP-1347 modulates the microglial inflammatory response [tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1)] was explored. Indeed, the MLK inhibitor CEP-1347 reduced cytokine production in primary cultures of human and murine microglia, and in monocyte/macrophage-derived cell lines, stimulated with various endotoxins or the plaque forming peptide Abeta1-40. Moreover, CEP-1347 inhibited brain TNF production induced by intracerebroventricular injection of lipopolysaccharide in mice. As expected from a MLK inhibitor, CEP-1347 acted upstream of p38 and c-Jun activation in microglia by dampening the activity of both pathways. These data imply MLKs as important, yet unrecognized, modulators of microglial inflammation, and demonstrate a novel anti-inflammatory potential of CEP-1347.
U2 - 10.1111/j.1471-4159.2005.03014.x
DO - 10.1111/j.1471-4159.2005.03014.x
M3 - Journal article
C2 - 15748162
SN - 0022-3042
VL - 92
SP - 1439
EP - 1451
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 6
ER -
