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Brain Advance Access originally published online on May 6, 2003
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Brain, Vol. 126, No. 6, 1358-1370, June 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg146

TNF-induced death of adult human oligodendrocytes is mediated by c-jun NH2-terminal kinase-3

Anna Jurewicz1, Mariola Matysiak1, Krzysztof Tybor2 and Krzysztof Selmaj1

Departments of 1 Neurology and 2 Neurosurgery, Medical University of Lodz, Lodz, Poland

Correspondence to: Krzysztof Selmaj, MD, PhD, Department of Neurology, Medical University of Lodz, 22 Kopcinskiego Street, 90-153 Lodz, Poland E-mail: kselmaj{at}afazja.am.lodz.pl

Tumour necrosis factor (TNF) induces death of oligodendrocytes, the putative cell target in multiple sclerosis. We defined that the intracellular transduction pathway involved in TNF-induced death of human adult oligodendrocytes (hOLs) is dependent on c-jun NH2-terminal kinase (JNK) activation, but not the other mitogen-activated protein kinase (MAPK), p38. JNK activation, measured by c-jun phosphorylation and induction of the phosphorylated form of JNK, was enhanced, prolonged and correlated with cell death in hOLs exposed to TNF. Comparative autoradiographic analysis revealed that JNK-3, but not JNK-1 or JNK-2, is responsible for prolonged JNK activation in TNF exposed hOLs. Expression of a dominant-negative mutant of JNK upstream kinase, MKK4/SEK1, inhibited apoptosis induced by TNF, whereas expression of a constitutive active mutant of MEKK1, an upstream kinase to JNK, accelerates TNF-induced apoptosis. JNK activation occurred prior to changes of mitochondrial membrane potential in hOLs exposed to TNF. These results demonstrate that TNF-induced death in adult hOLs depends on prolonged JNK-3 activation, and that this apoptosis requires the mitochondrial dysfunction that occurs after JNK activation. This is the first evidence that a JNK-3 isoform is involved in oligodendrocyte death and might have significant importance in designing new molecules to protect hOLs demise in multiple sclerosis.


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