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by Herpes Simplex Virus-Infected Macrophages Is Regulated by a Dual Mechanism: Transcriptional Regulation by NF-
B and Activating Transcription Factor 2/Jun and Translational Regulation Through the AU-Rich Region of the 3' Untranslated Region1
ren R. Paludan2,*
ren C. Mogensen*
*
Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark; and
Department of Molecular Biology, Universite Libre de Bruxelles, Brussels, Belgium
Here we have investigated the regulation of TNF-
expression in
macrophages during HSV-2 infection. Despite a low basal level of
TNF- mRNA present in resting macrophages, no TNF- protein is
detectable. HSV-2 infection marginally increases the level of TNF-
mRNA and protein in resting macrophages, whereas a strong increase is
observed in IFN-
-activated cells infected with the virus. By
reporter gene assay it was found that HSV infection augments TNF-
promoter activity. Moreover, treatment of the cells with actinomycin D,
which totally blocked mRNA synthesis, only partially prevented
accumulation of TNF- protein, indicating that the infection lifts a
block on translation of TNF- mRNA. EMSA analysis showed that
specific binding to the 
B#3 site of the murine TNF- promoter was
induced within 1 h after infection and persisted beyond 5 h
where TNF- expression is down-modulated. Binding to the cAMP
responsive element site was also induced but more transiently with
kinetics closely following activation of the TNF- promoter.
Inhibitors against either NF-B activation or the activating
transcription factor 2 kinase p38 abrogated TNF- expression, showing
a requirement for both signals for activation of the promoter. This
observation was corroborated by reporter gene assays. As to the
translational regulation of TNF-, the AU-rich sequence in the 3'
untranslated region of the mRNA was found to be responsible for this
control because deletion of this region renders mRNA constitutively
translationable. These results show that TNF- production is induced
by HSV-2 in macrophages through both transcriptional and translational
regulation.
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