p53 induction by tumor necrosis factor-alpha and involvement of p53 in cell death of human oligodendrocytes

Oligodendrocytes (OLs) and their myelin membranes are the primary targets i n the autoimmune disease multiple sclerosis (MS). The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been implicated as a mediator of OL cell injury. TNF-alpha is detectable within MS lesions and induces ap optosis of mature human OLs in vitro. One possible mechanism by which TNF-a lpha mediates cell death is through the activation of c-jun N-terminal kina se (JNK). We have previously shown that treatment of human OLs with TNF-alp ha reads to activation of JNK. Here we provide evidence that p53, a regulat or of the cell cycle and apoptosis, is a mediator of TNF-alpha-induced apop tosis of OLs. Although p53 was undetectable by western blot analysis in adu lt human OLs, its levels increased within 24 h after TNF-alpha treatment (1 00 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 m arked apoptosis as revealed by in situ cleavage of DNA (TUNEL positive), de creased mitochondrial function, and release of lactate dehydrogenase into t he culture medium, These in vitro studies demonstrate that increased p53 le vels are associated with apoptosis of human OLs. The findings further impli cate p53 as a target for the JNK pathway activated during TNF-alpha-mediate d cell death of human adult OLs.