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Expression of TNF-alpha by herpes simplex virus-infected macrophages is regulated by a dual mechanism: transcriptional regulation by NF-kappa B and activating transcription factor 2/Jun and translational regulation through the AU-rich region of the 3' untranslated region.
J Immunol. 2001 Aug 15; 167(4):2202-8.JI

Abstract

Here we have investigated the regulation of TNF-alpha expression in macrophages during HSV-2 infection. Despite a low basal level of TNF-alpha mRNA present in resting macrophages, no TNF-alpha protein is detectable. HSV-2 infection marginally increases the level of TNF-alpha mRNA and protein in resting macrophages, whereas a strong increase is observed in IFN-gamma-activated cells infected with the virus. By reporter gene assay it was found that HSV infection augments TNF-alpha promoter activity. Moreover, treatment of the cells with actinomycin D, which totally blocked mRNA synthesis, only partially prevented accumulation of TNF-alpha protein, indicating that the infection lifts a block on translation of TNF-alpha mRNA. EMSA analysis showed that specific binding to the kappaB#3 site of the murine TNF-alpha promoter was induced within 1 h after infection and persisted beyond 5 h where TNF-alpha 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-alpha promoter. Inhibitors against either NF-kappaB activation or the activating transcription factor 2 kinase p38 abrogated TNF-alpha 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-alpha, 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-alpha production is induced by HSV-2 in macrophages through both transcriptional and translational regulation.

Authors+Show Affiliations

Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark. srp@microbiology.au.dkNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11490006

Citation

Paludan, S R., et al. "Expression of TNF-alpha By Herpes Simplex Virus-infected Macrophages Is Regulated By a Dual Mechanism: Transcriptional Regulation By NF-kappa B and Activating Transcription Factor 2/Jun and Translational Regulation Through the AU-rich Region of the 3' Untranslated Region." Journal of Immunology (Baltimore, Md. : 1950), vol. 167, no. 4, 2001, pp. 2202-8.
Paludan SR, Ellermann-Eriksen S, Kruys V, et al. Expression of TNF-alpha by herpes simplex virus-infected macrophages is regulated by a dual mechanism: transcriptional regulation by NF-kappa B and activating transcription factor 2/Jun and translational regulation through the AU-rich region of the 3' untranslated region. J Immunol. 2001;167(4):2202-8.
Paludan, S. R., Ellermann-Eriksen, S., Kruys, V., & Mogensen, S. C. (2001). Expression of TNF-alpha by herpes simplex virus-infected macrophages is regulated by a dual mechanism: transcriptional regulation by NF-kappa B and activating transcription factor 2/Jun and translational regulation through the AU-rich region of the 3' untranslated region. Journal of Immunology (Baltimore, Md. : 1950), 167(4), 2202-8.
Paludan SR, et al. Expression of TNF-alpha By Herpes Simplex Virus-infected Macrophages Is Regulated By a Dual Mechanism: Transcriptional Regulation By NF-kappa B and Activating Transcription Factor 2/Jun and Translational Regulation Through the AU-rich Region of the 3' Untranslated Region. J Immunol. 2001 Aug 15;167(4):2202-8. PubMed PMID: 11490006.
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TY - JOUR T1 - Expression of TNF-alpha by herpes simplex virus-infected macrophages is regulated by a dual mechanism: transcriptional regulation by NF-kappa B and activating transcription factor 2/Jun and translational regulation through the AU-rich region of the 3' untranslated region. AU - Paludan,S R, AU - Ellermann-Eriksen,S, AU - Kruys,V, AU - Mogensen,S C, PY - 2001/8/8/pubmed PY - 2002/1/5/medline PY - 2001/8/8/entrez SP - 2202 EP - 8 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 167 IS - 4 N2 - Here we have investigated the regulation of TNF-alpha expression in macrophages during HSV-2 infection. Despite a low basal level of TNF-alpha mRNA present in resting macrophages, no TNF-alpha protein is detectable. HSV-2 infection marginally increases the level of TNF-alpha mRNA and protein in resting macrophages, whereas a strong increase is observed in IFN-gamma-activated cells infected with the virus. By reporter gene assay it was found that HSV infection augments TNF-alpha promoter activity. Moreover, treatment of the cells with actinomycin D, which totally blocked mRNA synthesis, only partially prevented accumulation of TNF-alpha protein, indicating that the infection lifts a block on translation of TNF-alpha mRNA. EMSA analysis showed that specific binding to the kappaB#3 site of the murine TNF-alpha promoter was induced within 1 h after infection and persisted beyond 5 h where TNF-alpha 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-alpha promoter. Inhibitors against either NF-kappaB activation or the activating transcription factor 2 kinase p38 abrogated TNF-alpha 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-alpha, 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-alpha production is induced by HSV-2 in macrophages through both transcriptional and translational regulation. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/11490006/Expression_of_TNF_alpha_by_herpes_simplex_virus_infected_macrophages_is_regulated_by_a_dual_mechanism:_transcriptional_regulation_by_NF_kappa_B_and_activating_transcription_factor_2/Jun_and_translational_regulation_through_the_AU_rich_region_of_the_3'_untranslated_region_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=11490006 DB - PRIME DP - Unbound Medicine ER -