Interferon-Induced Expression of If-1 h and If-l 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-1^h (high) or If-1^l (low), respectively, that are responsible for up to tenfold differences in the interferon (IFN)-α, IFN-β, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) response to NDV but not to Sendai virus. Only BMM but not spleen lymphocytes showed allele-specific differences in NDV-induced cytokine levels, indicating cell-specific If-1 expression. The If-1 locus harbors IFN-inducible gene(s) whose expression 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 infectious virions, and kinetic analyses revealed a close correlation between the amount of viral transcripts and individual cytokine mRNA. BMM from If-1^l mice strongly restricted transcription of the NDV nucleoprotein (NP) gene, whereas BMM from If-1^h mice supported NP transcription. Following treatment with IL-4, which inhibited constitutive IFN-β gene expression, however, If-1^l BMM became highly permissive for transcription of the viral NP gene and released high amounts of cytokines. 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.