Inhibition of microglial inflammation by the MLK inhibitor CEP-1347.
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.
Lund
Søren
S
Disease Biology, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. sorl@lundbeck.com
Porzgen
Peter
P
Mortensen
Anne Louise
AL
Hasseldam
Henrik
H
Bozyczko-Coyne
Donna
D
Morath
Siegfried
S
Hartung
Thomas
T
Bianchi
Marina
M
Ghezzi
Pietro
P
Bsibsi
Malika
M
Dijkstra
Sipke
S
Leist
Marcel
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005911:Gliosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D002227:Carbazoles; D016207:Cytokines; D004791:Enzyme Inhibitors; D007211:Indoles; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; C106592:3,9-bis((ethylthio)methyl)-K-252a; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C486650:Map3k9 protein, mouse