EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA AND TUMOR-NECROSIS-FACTOR-BETA ON HUMAN OLIGODENDROCYTES AND NEURONS IN CULTURE

Cytokines produced by infiltrating hematogenous cells or by glial cell s activated during the course of central nervous system disease or tra uma are implicated as mediators of tissue injury. In this study, we ha ve assessed the extent and mechanism of injury of human-derived CNS ol igodendrocytes and neurons in vitro mediated by the cytokines tumor ne crosis factor alpha and beta and compared these with the tumor necrosi s factor independent effects mediated by activated CD4(+) T-cells. We found that activated CD4(+) T-cells, but not tumor necrosis factor alp ha or beta, could induce significant release of lactate dehydrogenase, a measure of cell membrane lysis, from oligodendrocytes within 24 hr. Neither induced DNA fragmentation as measured using a fluorescence ni ck-end labelling technique. After a more prolonged time period (96 hr) , tumor necrosis factor a did induce nuclear fragmentation changes in a significant proportion of oligodendrocytes without increased lactate dehydrogenase release. The extent of DNA fragmentation was comparable to that induced by serum deprivation. Tumor necrosis factor beta effe cts were even more pronounced. In contrast to oligodendrocytes, the ex tent of DNA fragmentation, assessed by propidium iodide staining, indu ced in neurons by tumor necrosis factor a was less than that induced b y serum deprivation. In-situ hybridization studies of human adult glia l cells in culture indicated that astrocytes, as well as microglia, ca n express tumor necrosis factor alpha mRNA.