Interferon-gamma-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis.
BACKGROUND
The histopathology of multiple sclerosis (MS) is characterized by a loss of myelin and oligodendrocytes, relative preservation of axons, and a modest inflammatory response. The reasons for this selective oligodendrocyte death and demyelination are unknown.


METHODS
In light of the T lymphocyte and macrophage infiltrates in MS lesions and the numerous cytokines these cells secrete, the direct influence of cytokines on survival of cultured oligodendrocytes and sensory neurons was investigated. Expression of cytokines in vivo was determined by immunolabeling cryostat sections of snap-frozen tissue containing chronic active lesions from four different patients. The samples were also analyzed for the presence of apoptotic nuclei by in situ labeling of 3'-OH ends of degraded nuclear DNA.


RESULTS
The results showed: (i) interferon-gamma (IFN gamma) to be a potent inducer of apoptosis among oligodendrocytes in vitro and that this effect can be reversed by leukemia inhibitory factor (LIF); (ii) IFN gamma has a minimal effect on the survival of cultured neurons; (iii) IFN gamma at the margins of active MS plaques but not in unaffected white matter; (iv) evidence for apoptosis of oligodendrocytes at the advancing margins of chronic active MS plaques.


CONCLUSIONS
Injury to a substantial number of oligodendrocytes in MS is the results of programmed cell death rather than necrotic cell death mechanisms. We postulate that IFN gamma plays a role in the pathogenesis of MS by activating apoptosis in oligodendrocytes.
Vartanian
T
T
Department of Neurology, Beth Israel Hospital, Boston, Massachusetts, USA.
Li
Y
Y
Zhao
M
M
Stefansson
K
K
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D002478:Cells, Cultured; D004249:DNA Damage; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D017628:Microglia / Q000502:physiology; D009103:Multiple Sclerosis / Q000209:etiology*; D009475:Neurons, Afferent / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D013778:Tetrazolium Salts / Q000378:metabolism
D000906:Antibodies; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D013778:Tetrazolium Salts; D009569:Nitric Oxide; D007371:Interferon-gamma