TRAIL-induced death of human adult oligodendrocytes is mediated by JNK pathway.
Tumor necrosis-related apoptosis-inducing ligand (TRAIL) induces apoptosis of oligodendrocytes, target cells of immune attack in multiple sclerosis (MS). TRAIL-induced human oligodendrocyte (hOL) death depends on TRAIL ligation with its receptor 1 (TRAIL-R1). However, the intracellular signaling initiated with ligation of TRAIL-R1 in hOLs is unknown. We defined that intracellular transduction signaling involved in TRAIL-induced death of hOLs is associated with strong activation of c-jun NH2-terminal kinase (JNK) and a dominant negative mutant of MKK4/SEK1, MAP kinase upstream of JNK, inhibited TRAIL-induced apoptosis of hOLs. The immunoprecipitation experiments showed that JNK3 isoform was predominantly activated upon hOLs exposure to TRAIL and JNK-3 activation occurred before mitochondrial membrane dysfunction. The other mitogen-activated protein kinase p38 and ERK, as well as calpains and serine proteases, were not activated during TRAIL-induced hOL death. Accordingly, the calpain inhibitor, ZLLY.FMK, p38 kinase inhibitor, SB 203580, and serine proteases inhibitor, TPCK, did not protect hOLs from TRAIL-induced apoptosis. These results demonstrate that JNK pathway is critically involved in hOL death induced by TRAIL and might have significant importance in designing new molecules to protect immune-mediated hOLs demise.
Jurewicz
Anna
A
Department of Neurology, Medical University of Lodz, Lodz, Poland.
Matysiak
Mariola
M
Andrzejak
Stanisław
S
Selmaj
Krzysztof
K
D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007527:Isoenzymes / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D017628:Microglia / Q000201:enzymology / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D009836:Oligodendroglia / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases