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Original Article

Novel Cell Type–Specific Antiviral Mechanism of Interferon Action in Macrophages

^a Department of Pathology and Immunology and the Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110
Dept. of Pathology and Immunology and Dept. of Molecular Microbiology, Washington University School of Medicine, Box 8118, 660 South Euclid Ave., St. Louis, MO 63110.314-362-4096314-362-9223

virgin{at}immunology.wustl.edu

Interferon (IFN)- and macrophages (M) play key roles in acute, persistent, and latent murine cytomegalovirus (MCMV) infection. IFN- mechanisms were compared in embryonic fibroblasts (MEFs) and bone marrow M (BMM). IFN- inhibited MCMV replication in a signal transducer and activator of transcription (STAT)-1–dependent manner much more effectively in BMM (100-fold) than MEF (5–10-fold). Although initial STAT-1 activation by IFN- was equivalent in MEF and BMM, microarray analysis demonstrated that IFN- regulates different sets of genes in BMM compared with MEFs. IFN- inhibition of MCMV growth was independent of known mechanisms involving IFN-/β, tumor necrosis factor , inducible nitric oxide synthase, protein kinase RNA activated (PKR), RNaseL, and Mx1, and did not involve IFN-–induced soluble mediators. To characterize this novel mechanism, we identified the viral targets of IFN- action, which differed in MEF and BMM. In BMM, IFN- reduced immediate early 1 (IE1) mRNA during the first 3 h of infection, and significantly reduced IE1 protein expression for 96 h. Effects of IFN- on IE1 protein expression were independent of RNaseL and PKR. In contrast, IFN- had no significant effects on IE1 protein or mRNA expression in MEFs, but did decrease late gene mRNA expression. These studies in primary cells define a novel mechanism of IFN- action restricted to M, a cell type key for MCMV pathogenesis and latency.

Key Words: interferon • cytomegalovirus • signal transducer and activator of transcription 1 • microarray analysis • macrophage

Abbreviations used in this paper: BM, bone marrow; EMSA, electrophoretic mobility shift assay; HBV, hepatitis B virus; HCMV, human CMV; IE, immediate early; iNOS, inducible nitric oxide synthase; MCMV, murine CMV; MEF, murine embryonic fibroblast; M, macrophage; MOI, multiplicity of infection; PKR, protein kinase RNA activated; STAT, signal transducer and activator of transcription.

© 2001 The Rockefeller University Press

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