J Neurochem 2002 Dec;83(5):1120-8
Hua LL, Kim MO, Brosnan CF, Lee SC.
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Although interferon (IFN)-beta is firmly established as a therapeutic agent for multiple sclerosis, information regarding its role in astrocyte cytokine production is limited.
In primary cultures of human astrocytes, we determined the effects of IFN-beta on astrocyte cytokine [tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6] and inducible nitric oxide synthase (iNOS) expression by ribonuclease protection assay and ELISA.
We found that IFN-beta inhibited astrocyte cytokine/iNOS induced by IL-1 plus IFN-gamma, but in the absence of IFN-gamma, IFN-beta enhanced IL-1-induced cytokine/iNOS expression.
Electrophoretic mobility shift analysis (EMSA) demonstrated that IFN-gamma induced sustained IFN-gamma-activated sequence (GAS) binding, while IFN-beta induced transient GAS binding.
When used together, IFN-beta inhibited IFN-gamma-induced GAS binding activity.
Nuclear factor-kappa B (NF-kappaB) activation was not altered by either IFNs, whereas IFN stimulated response element (ISRE) was only activated by IFN-beta and not IFN-gamma.
These results suggest that IFN-beta can both mimic and antagonize the effect of IFN-gamma by modulating induction of nuclear GAS binding activity.
Our results demonstrating differential regulation of astrocyte cytokine/iNOS induction by IFN-beta are novel and have implications for inflammatory diseases of the human CNS.