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

✍ Scribed by Bobbie Scurlock; Glyn Dawson

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 244 KB
• Volume: 55
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/(sici)1097-4547(19990215)55:4<514::aid-jnr11>3.0.co;2-v

✦ Synopsis

Staurosporine induced apoptosis in a human oligodendroglioma cell line (HOG), neonatal rat oligodendrocyte (O2A ؉ ) precursors, and mature rat oligodendrocytes. In all three cell culture systems, the activation of caspase-3-like activity (CPP32) coincided with the increased formation of ceramide from sphingomyelin and the onset of DNA fragmentation. Further, the addition of exogenous C 2 -ceramide induced CPP32 activation and DNA fragmentation in all three culture systems. Raising endogenous ceramide levels by the addition of the ceramidase inhibitor, oleoylethanolamine, enhanced apoptosis in both a time-and concentration-dependent manner. Inhibitors of phosphatidylinositol 3-kinase (wortmannin and LY294002) also induced caspase-3 (CPP32) activation, increased ceramide formation, induced DNA fragmentation, and reduced cell viability. In contrast, cytokines such as tumor necrosis factor-␣ (TNF-␣) had a differential effect on the three cell cultures. Thus, TNF-␣ (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 oligodendroglioma (HOG) cell line, but no apoptosis in mature neonatal rat oligodendrocytes. Interferon-␥ augmented the activation of CPP32 by TNF-␣ in HOG cells and O2A ؉ oligodendrocyte precursor cells but had no effect on mature oligodendrocytes. Thus, the death pathway appears to be similar in the three cell lines but the lack of coupling between TNF-␣ receptors and the apoptotic pathway leads to a lack of response to cytokines in mature oligodendrocytes.