期刊
JOURNAL OF GENERAL VIROLOGY
卷 92, 期 -, 页码 807-818出版社
SOC GENERAL MICROBIOLOGY
DOI: 10.1099/vir.0.028159-0
关键词
-
Tumor necrosis factor alpha (TNF-alpha) 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-alpha stimulation cannot activate nuclear factor kappa B (NF-kappa B) to the fullest extent in DENV-2-infected cells. Here, we investigate further responses of DENV-2-infected cells to TNF-alpha, focussing particularly on cell death and pro-survival signals. TNF-alpha stimulation of productively DENV-2-infected monocyte-derived macrophages or HEK-293 cells induced caspase-3-mediated cell death. While TNF-alpha induced comparable degradation of the inhibit or of NF-kappa B alpha (I kappa B-alpha) and NF-kappa B activation in mock-infected and DENV-2-infected cells early in infection, later in infection and coinciding with TNF-alpha-induced cell death, TNF-alpha-stimulated I kappa B-alpha degradation and NF-kappa B 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-alpha-stimulated survival signals. Transfection experiments demonstrated inhibition of TNF-alpha-stimulated NF-kappa B activation by expression of DENV-2 capsid (CA) but enhancement by DENV-2 NS5 protein. DENV-2 CA alone, however, did not induce TNF-alpha-stimulated cell death or inhibit SphK1 activity. Thus, productively DENV-2-infected cells have compromised TNF-alpha-stimulated survival pathways and show enhanced susceptibility to TNF-alpha-stimulated cell death, suggesting a role for TNF-alpha in the killing of healthy productively DENV-2-infected cells. Additionally, the altered ability of TNF-alpha to activate NF-kappa B as infection progresses is reflected by the opposing actions of DENV-2 CA and NS5 proteins on TNF-alpha-stimulated NF-kappa B activation and could have important consequences for NF-kappa B-driven release of inflammatory cytokines.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据