Differential responses of oligodendrocytes to tumor necrosis factor and other pro-apoptotic agents: Role of ceramide in apoptosis

Staurosporine induced apoptosis in a human oligodendroglioma cell line (HOG ), neonatal rat oligodendrocyte (O2A(+)) precursors, and mature rat oligode ndrocytes, In all three cell culture systems, the activation of caspase-3-l ike activity (CPP32) coincided with the increased formation of ceramide fro m sphingomyelin and the onset of DNA fragmentation, Further, the addition o f exogenous C-2-ceramide induced CPP32 activation and DNA fragmentation in all three culture systems. Raising endogenous ceramide levels by the additi on of the ceramidase inhibitor, oleoylethanolamine, enhanced apoptosis in b oth a time- and concentration-dependent manner. Inhibitors of phosphatidyli nositol 3-kinase (wortmannin and LY294002) also induced caspase-3 (CPP32) a ctivation, increased ceramide formation, induced DNA fragmentation, and red uced cell viability. In contrast, cytokines such as tumor necrosis factor-a lpha (TNF-alpha) had a differential effect on the three cell cultures, Thus , TNF-alpha (160 ng/ml) induced 70% apoptosis in 24 hr in freshly isolated rat brain O2A(+) precursor cells, 60% apoptosis in 24 hr in a human oligode ndroglioma (HOG) cell line, but no apoptosis in mature neonatal rat oligode ndrocytes. Interferon-gamma augmented the activation of CPP32 by TNF-alpha in HOG cells and O2A(+) oligodendrocyte precursor cells but had no effect o n mature oligodendrocytes. Thus, the death pathway appears to be similar in the three cell lines but the lack of coupling between TNF-alpha receptors and the apoptotic pathway leads to a lack of response to cytokines in matur e oligodendrocytes, J, Neurosci. Res. 55:514-522, 1999. (C) 1999 Wiley-Liss , Inc.