The regulation of major histocompatibility complex (MHC) class I, interferon (IFN)-beta, and anti-viral state expression in neurons was analyzed. Treatment of neurons with either double-stranded RNA (poly I: poly C) or virus, but not IFNs, induced high levels of IFN-beta, but not MHC class I genes. However, neurons treated with IFN-beta established an anti-viral state. Transfection of neurons with IFN-beta constructs showed that a region containing PRDI (IRF-E site) and PRDII (kappa B site) mediated induction, but closely related sites in a MHC class I construct did not. Gel mobility shift assays indicated that transcription factors containing the RelA (p65) component of NF-kappa B, but not p50, bound to PRDII. PRDI, however, bound to transcriptional antagonist IRF-2. Unique selective induction of these transcription factors is likely to mediate non-coordinate expression of IFN-beta, MHC class I, and anti-viral state genes in neurons.