INTERFERON-INDUCED EXPRESSION OF IF-1(H) AND IF-1(L) ALLELES IN NEWCASTLE-DISEASE VIRUS-INFECTED MOUSE MACROPHAGES IS ASSOCIATED WITH SPECIFIC DIFFERENCES IN VIRAL GENE-TRANSCRIPTION

We have studied the expression of cytokines and viral genes induced by Newcastle disease virus (NDV) and Sendai virus in bone marrow-derived macrophages (BMM) and lymphocytes from C57BL/6 mice and the congenic line B6.C-H-28(c). These mice carry the loci If-lh (high) or If-1(l) ( low), respectively, that are responsible for up to tenfold differences in the interferon (IFN)-alpha, IFN-beta, interleukin-6 (IL-6), and tu mor necrosis factor-alpha (TNF-alpha) response to NDV but not to Senda i virus, Only BMM but not spleen lymphocytes showed allele-specific di fferences in NDV-induced cytokine levels, indicating cell-specific If- 1 expression, The If-I locus harbors IFN-inducible gene(s) whose expre ssion is prevented in the presence of cycloheximide. Our data provide evidence that the If-1(l) allele acts by specifically suppressing the cytokine response to NDV, Cytokine production was dependent on infecti ous virions, and kinetic analyses revealed a close correlation between the amount of viral transcripts and individual cytokine mRNA, BMM fro m If-1(l) mice strongly restricted transcription of the NDV nucleoprot ein (NP) gene, whereas BMM from If-1(l) mice supported NP transcriptio n, Following treatment with IL-4, which inhibited constitutive IFN-bet a gene expression, however, If-1(l) BMM became highly permissive for t ranscription of the viral NP gene and released high amounts of cytokin es, We conclude that If-1(l) gene products are responsible for the low producer phenotype by efficiently interfering with NDV transcription, leading to strongly reduced intracellular levels of cytokine inducing viral dsRNA intermediates.