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

• Published in: Brain (London, England : 1878) England : 1878), 2003-06, Vol.126 (6), p.1358-1370
• Main Authors: Jurewicz, Anna, Matysiak, Mariola, Tybor, Krzysztof, Selmaj, Krzysztof
• Format: Article
• Language: English
• Subjects: Adult; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; cell death; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Dermatology; Dose-Response Relationship, Drug; ERK = extracellular signal‐related kinase; FADD = Fas‐associated death domain protein; FITC = fluorescein isothiocyanate; GFP = green fluorescent protein; hOL = human adult oligodendrocyte; Humans; Intracellular Membranes - physiology; Investigative techniques, diagnostic techniques (general aspects); JNK; JNK = c‐jun NH2‐terminal kinase; MAP Kinase Kinase Kinase 1; MAPK = mitogen‐activated protein kinase; MAP = mitogen‐activated protein; Medical sciences; Mitochondria - physiology; Mitogen-Activated Protein Kinase 10; Mitogen-Activated Protein Kinases - physiology; multiple sclerosis; NF‐κB = nuclear factor κB; oligodendrocytes; Oligodendroglia - cytology; Oligodendroglia - drug effects; Oligodendroglia - enzymology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Permeability; PI = propidium iodide; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - physiology; RIP = receptor interacting protein; Signal Transduction - physiology; TdT = terminal deoxynucleotidyl transferase; TNF; TNF = tumour necrosis factor; TRADD = TNF‐R1‐associated death domain protein; TRAF2 = TNF receptor associated factor‐2; Tumor Necrosis Factor-alpha - pharmacology; TUNEL = terminal deoxynucleotidyl transferase‐mediated dUTP nick end‐labelling
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awg146

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.