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TNFα potentiates IFNγ‐induced cell death in oligodendrocyte progenitors
Author(s) -
Andrews T.,
Zhang P.,
Bhat N.R.
Publication year - 1998
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19981201)54:5<574::aid-jnr2>3.0.co;2-0
Subject(s) - oligodendrocyte , biology , cytotoxic t cell , microbiology and biotechnology , progenitor cell , tumor necrosis factor alpha , proinflammatory cytokine , cytokine , programmed cell death , apoptosis , interferon gamma , immunology , stem cell , in vitro , myelin , biochemistry , inflammation , endocrinology , central nervous system
Oligodendrocytes in multiple sclerosis brain may be under a direct attack by proinflammatory cytokines, particularly tumor necrosis factor‐α (TNFα) and interferon‐γ (IFNγ). 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‐(4,5‐dimethylthiazol‐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. IFNγ exerted a dose‐dependent cytotoxic effect on cultured CG4 cells, an oligodendrocyte progenitor cell line, and in primary cultures of purified oligodendrocyte progenitors. TNFα, while by itself being only mildly toxic, greatly potentiated the cytotoxicity of IFNγ. 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 cytokine‐treated cultures revealed an increased expression of the death receptor, Fas. The results suggest particular vulnerability of oligodendrocyte progenitors to a combination of TNFα and IFNγ involving an activation of the cell death program. J. Neurosci. Res. 54:574–583, 1998. © 1998 Wiley‐Liss, Inc.