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Tumour necrosis factor alpha (TNF-alpha) stimulation of cells with established dengue virus type 2 infection induces cell death that is accompanied by a reduced ability of TNF-alpha to activate nuclear factor kappaB and reduced sphingosine kinase-1 activity.
- Source :
-
The Journal of general virology [J Gen Virol] 2011 Apr; Vol. 92 (Pt 4), pp. 807-18. Date of Electronic Publication: 2010 Dec 09. - Publication Year :
- 2011
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Abstract
- Tumor necrosis factor alpha (TNF-α) has an antiviral role in some infections but in dengue virus (DENV) infection it is linked to severe pathology. We have previously shown that TNF-α stimulation cannot activate nuclear factor κB (NF-κB) to the fullest extent in DENV-2-infected cells. Here, we investigate further responses of DENV-2-infected cells to TNF-α, focussing particularly on cell death and pro-survival signals. TNF-α stimulation of productively DENV-2-infected monocyte-derived macrophages or HEK-293 cells induced caspase-3-mediated cell death. While TNF-α induced comparable degradation of the inhibitor of NF-κB alpha (IκB-α) and NF-κB activation in mock-infected and DENV-2-infected cells early in infection, later in infection and coinciding with TNF-α-induced cell death, TNF-α-stimulated IκB-α degradation and NF-κB activation was reduced. This was associated with reduced levels of sphingosine kinase-1 (SphK1) activity in DENV-2-infected cells; SphK1 being a known mediator of TNF-α-stimulated survival signals. Transfection experiments demonstrated inhibition of TNF-α-stimulated NF-κB activation by expression of DENV-2 capsid (CA) but enhancement by DENV-2 NS5 protein. DENV-2 CA alone, however, did not induce TNF-α-stimulated cell death or inhibit SphK1 activity. Thus, productively DENV-2-infected cells have compromised TNF-α-stimulated survival pathways and show enhanced susceptibility to TNF-α-stimulated cell death, suggesting a role for TNF-α in the killing of healthy productively DENV-2-infected cells. Additionally, the altered ability of TNF-α to activate NF-κB as infection progresses is reflected by the opposing actions of DENV-2 CA and NS5 proteins on TNF-α-stimulated NF-κB activation and could have important consequences for NF-κB-driven release of inflammatory cytokines.
- Subjects :
- Cells, Cultured
Dengue Virus immunology
Epithelial Cells immunology
Epithelial Cells virology
Humans
Macrophages immunology
Macrophages virology
Tumor Necrosis Factor-alpha metabolism
Cell Death
Dengue Virus pathogenicity
NF-kappa B metabolism
Phosphotransferases (Alcohol Group Acceptor) metabolism
Tumor Necrosis Factor-alpha immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1465-2099
- Volume :
- 92
- Issue :
- Pt 4
- Database :
- MEDLINE
- Journal :
- The Journal of general virology
- Publication Type :
- Academic Journal
- Accession number :
- 21148274
- Full Text :
- https://doi.org/10.1099/vir.0.028159-0