Interferon-gamma protects against cuprizone-induced demyelination

Evidence suggests that interferon-gamma (IFN-gamma), a proinflammatory cyto kine secreted by activated T lymphocytes, contributes a deleterious effect to immune-mediated demyelinating disorders such as multiple sclerosis and e xperimental autoimmune encephalomyelitis (EAE). Nevertheless, mouse strains that are normally resistant to EAE induction become susceptible when the g ene encoding either IFN-gamma or its receptor is mutated, demonstrating tha t the role that this cytokine plays in demyelinating disorders is complex. We have examined the effect of IFN-gamma in a chemically induced model of C NS demyelination. Mice that receive through their diet the copper chelator cuprizone display extensive demyelination of the corpus callosum. Remarkabl y, transgenic mice that ectopically express low levels of IFN-gamma in the CNS did not display evidence of demyelination when treated with cuprizone, nor did they shows signs of oligodendroglial death, astrogliosis, or microg liosis, which are typically seen in treated animals. Myelin protein gene ex pression was, however, dramatically reduced in both the treated control and the transgenic animals, indicating that demyelination is not an obligatory consequence of a large diminution of myelin protein synthesis. Interesting ly, the CNS of the IFN-gamma -expressing mice contained elevated levels of insulin-like growth factor I, which has been demonstrated to have a protect ive effect against the demyelinating action of cuprizone.