Interferon (IFN)-gamma and macrophages (M phi) play key roles in acute, per
sistent, and latent murine cytomegalovirus (MCMV) infection. IFN-gamma mech
anisms were compared in embryonic fibroblasts (MEFs) and bone marrow M phi
(BMM phi). IFN-gamma inhibited MCMV replication in a signal transducer and
activator of transcription (STAT)-1 alpha -dependent manner much more effec
tively in BMM phi (similar to 100-fold) than MEF (5-10-fold). Although init
ial STAT-1 alpha activation by IFN-gamma was equivalent in MEF and BMM phi,
microarray analysis demonstrated that IFN-gamma regulates different sets o
f genes in BMM phi compared with MEFs. IFN-gamma inhibition of MCMV growth
was independent of known mechanisms involving IFN-alpha/beta, tumor necrosi
s factor alpha, inducible nitric oxide synthase, protein kinase RNA activat
ed (PKR), RNaseL, and Mx1, and did not involve IFN-gamma -induced soluble m
ediators. To characterize this novel mechanism, we identified the viral tar
gets of IFN-gamma action, which differed in MEF and BMM phi. In BMM phi, IF
N-gamma reduced immediate early 1 (IE1) mRNA during the first 3 h of infect
ion, and significantly reduced IE1 protein expression for 96 h. Effects of
IFN-gamma on IE1 protein expression were independent ofRNaseL and PKR. In c
ontrast, IFN-gamma had no significant effects on IE1 protein or mRNA expres
sion in MEFs, but did decrease late gene mRNA expression. These studies in
primary cells define a novel mechanism of IFN-gamma action restricted to M
phi, a cell type key for MCMV pathogenesis and latency.