Novel Cell Type-Specific Antiviral Mechanism of Interferon {gamma} Action in Macrophages

doi:10.1084/jem.193.4.483

Published online 19 February 2001.

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© The Rockefeller University Press, 0022-1007/2001/2/483/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 4, February 19, 2001 483-496

Original Article

Novel Cell Type–Specific Antiviral Mechanism of Interferon ${gamma}$ Action in Macrophages

Rachel M. Presti^a, Daniel L. Popkin^a, Megan Connick^a, Susanne Paetzold^a, and Herbert W. Virgin, IV^a

^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)- ${gamma}$ and macrophages (M ${phi}$ ) play key roles in acute,persistent, and latent murine cytomegalovirus (MCMV) infection.IFN- ${gamma}$ mechanisms were compared in embryonic fibroblasts (MEFs)and bone marrow M ${phi}$ (BMM ${phi}$ ). IFN- ${gamma}$ inhibited MCMV replication ina signal transducer and activator of transcription (STAT)-1 ${alpha}$ –dependentmanner much more effectively in BMM ${phi}$ ( $~$ 100-fold) than MEF (5–10-fold).Although initial STAT-1 ${alpha}$ activation by IFN- ${gamma}$ was equivalent inMEF and BMM ${phi}$ , microarray analysis demonstrated that IFN- ${gamma}$ regulatesdifferent sets of genes in BMM ${phi}$ compared with MEFs. IFN- ${gamma}$ inhibitionof MCMV growth was independent of known mechanisms involvingIFN- ${alpha}$ /β, tumor necrosis factor ${alpha}$ , inducible nitric oxidesynthase, protein kinase RNA activated (PKR), RNaseL, and Mx1,and did not involve IFN- ${gamma}$ –induced soluble mediators. Tocharacterize this novel mechanism, we identified the viral targetsof IFN- ${gamma}$ action, which differed in MEF and BMM ${phi}$ . In BMM ${phi}$ , IFN- ${gamma}$ reduced immediate early 1 (IE1) mRNA during the first 3 h ofinfection, and significantly reduced IE1 protein expressionfor 96 h. Effects of IFN- ${gamma}$ on IE1 protein expression were independentof RNaseL and PKR. In contrast, IFN- ${gamma}$ had no significant effectson IE1 protein or mRNA expression in MEFs, but did decreaselate gene mRNA expression. These studies in primary cells definea novel mechanism of IFN- ${gamma}$ action restricted to M ${phi}$ , a cell typekey for MCMV pathogenesis and latency.

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

Abbreviations used in this paper: BM, bone marrow; EMSA, electrophoreticmobility 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 ${phi}$ , macrophage;MOI, multiplicity of infection; PKR, protein kinase RNA activated;STAT, signal transducer and activator of transcription.

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