Abstract
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 NH~2~‐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. © 2005 Wiley‐Liss, Inc.