Modulation of astrocyte inducible nitric oxide synthase and cytokine expression by interferon β is associated with induction and inhibition of interferon γ-activated sequence binding activity

Although interferon (IFN)-β 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-β on astrocyte cytokine [tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6] and inducible nitric oxide synthase (iNOS) expression by ribonuclease protection assay and ELISA. We found that IFN-β inhibited astrocyte cytokine/iNOS induced by IL-1 plus IFN-γ, but in the absence of IFN-γ, IFN-β enhanced IL-1-induced cytokine/iNOS expression. Electrophoretic mobility shift analysis (EMSA) demonstrated that IFN-γ induced sustained IFN-γ-activated sequence (GAS) binding, while IFN-β induced transient GAS binding. When used together, IFN-β inhibited IFN-γ-induced GAS binding activity. Nuclear factor-kappa B (NF-κB) activation was not altered by either IFNs, whereas IFN stimulated response element (ISRE) was only activated by IFN-β and not IFN-γ. These results suggest that IFN-β can both mimic and antagonize the effect of IFN-γ by modulating induction of nuclear GAS binding activity. Our results demonstrating differential regulation of astrocyte cytokine/iNOS induction by IFN-β are novel and have implications for inflammatory diseases of the human CNS.