Abbreviations used : FCS, fetal calf serum ; JNK, c-jun N-terminal kinase ; LDH, lactate dehydrogenase ; mab, monoclonal antibody ; MEM, minimal essential medium ; MOI, multiplicity of infection ; MS, multiple sclerosis ; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ; NF-κB, nuclear factor-κB ; OL, oligodendrocyte ; PBS, phosphate-buffered saline ; RT, room temperature ; SDS, sodium dodecyl sulfate ; TNF-α, tumor necrosis factor-α ; TUNEL, terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end-labeling.
p53 Induction by Tumor Necrosis Factor-α and Involvement of p53 in Cell Death of Human Oligodendrocytes
Article first published online: 18 JAN 2002
Journal of Neurochemistry
Volume 73, Issue 2, pages 605–611, August 1999
How to Cite
Ladiwala, U., Li, H., Antel, J. P. and Nalbantoglu, J. (1999), p53 Induction by Tumor Necrosis Factor-α and Involvement of p53 in Cell Death of Human Oligodendrocytes. Journal of Neurochemistry, 73: 605–611. doi: 10.1046/j.1471-4159.1999.0730605.x
- Issue published online: 18 JAN 2002
- Article first published online: 18 JAN 2002
- Tumor necrosis factor-α;
Abstract : Oligodendrocytes (OLs) and their myelin membranes are the primary targets in the autoimmune disease multiple sclerosis (MS). The inflammatory cytokine tumor necrosis factor-α (TNF-α) has been implicated as a mediator of OL cell injury. TNF-α is detectable within MS lesions and induces apoptosis of mature human OLs in vitro. One possible mechanism by which TNF-α mediates cell death is through the activation of c-jun N-terminal kinase (JNK). We have previously shown that treatment of human OLs with TNF-α leads to activation of JNK. Here we provide evidence that p53, a regulator of the cell cycle and apoptosis, is a mediator of TNF-α-induced apoptosis of OLs. Although p53 was undetectable by western blot analysis in adult human OLs, its levels increased within 24 h after TNF-α treatment (100 ng/ml). The induced p53 was immunolocalized to the nucleus prior to the appearance of significant numbers of apoptotic cells. Overexpression of p53 by adenovirus-mediated gene transfer into human OLs in vitro resulted in marked apoptosis as revealed by in situ cleavage of DNA (TUNEL positive), decreased mitochondrial function, and release of lactate dehydrogenase into the culture medium. These in vitro studies demonstrate that increased p53 levels are associated with apoptosis of human OLs. The findings further implicate p53 as a target for the JNK pathway activated during TNF-α-mediated cell death of human adult OLs.