TNFα potentiates IFNγ-induced cell death in oligodendrocyte progenitors

✍ Scribed by T. Andrews; P. Zhang; N.R. Bhat

• Book ID: 101246006
• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 259 KB
• Volume: 54
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/(sici)1097-4547(19981201)54:5<574::aid-jnr2>3.0.co;2-0

✦ Synopsis

Oligodendrocytes in multiple sclerosis brain may be under a direct attack by proinflammatory cytokines, particularly tumor necrosis factor-␣ (TNF␣) and interferon-␥ (IFN␥). In this study, we have examined the in vitro cytotoxic effects of the two cytokines, individually and in combination, on oligodendrocyte lineage cells using morphological criteria, 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction assay (MTT), terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL), and agarose-gel electrophoretic analysis of fragmented DNA. IFN␥ exerted a dose-dependent cytotoxic effect on cultured CG4 cells, an oligodendrocyte progenitor cell line, and in primary cultures of purified oligodendrocyte progenitors. TNF␣, while by itself being only mildly toxic, greatly potentiated the cytotoxicity of IFN␥. The cytokine effects were developmentally modified in that their cytotoxic and cooperative effects became less evident in more differentiated cells. A cell-permeable peptide inhibitor (i.e., z-VAD.fmk) of caspases partially suppressed apoptotic changes elicited by the cytokine combination in CG4 cells but not in primary oligodendrocytes. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of mRNA prepared from cytokinetreated cultures revealed an increased expression of the death receptor, Fas. The results suggest particular vulnerability of oligodendrocyte progenitors to a combination of TNF␣ and IFN␥ involving an activation of the cell death program.