title: Interferon-induced expression of If-1h and If-1l alleles in Newcastle disease virus-infected mouse macrophages is associated with specific differences in viral gene transcription.
abstract: 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-28c. These mice carry the loci If-1h (high) or If-1l (low), respectively, that are responsible for up to tenfold differences in the interferon (IFN)-alpha, IFN-beta, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) 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-1l 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 lf-1l mice strongly restricted transcription of the NDV nucleoprotein (NP) gene, whereas BMM from If-1h mice supported NP transcription. Following treatment with IL-4, which inhibited constitutive IFN-beta gene expression, however, If-1l BMM became highly permissive for transcription of the viral NP gene and released high amounts of cytokines. We conclude that If-1l 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.
authors.affiliation: Institut für Zellbiologie, Abt. Immunologie, Eberhard-Karls-Universität, Tübingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Nickolaus
authors.forename: H G
authors.initials: HG
authors.lastname: Rammensee
authors.forename: R
authors.initials: R
authors.lastname: Zawatzky
mesh_terms: D000483:Alleles; D000818:Animals; D003513:Cycloheximide / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D005814:Genes, Viral; D007369:Interferon Inducers; D008214:Lymphocytes / Q000187:drug effects; D008264:Macrophages / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009521:Newcastle Disease / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D007369:Interferon Inducers; D003513:Cycloheximide