Two Distinct Phases of Virus-induced Nuclear Factor κB Regulation Enhance Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Virus-infected Cells

Clarke, Penny; Meintzer, Suzanne M.; Moffitt, Lisa A.; Tyler, Kenneth L.

doi:10.1074/jbc.m300265200

Cited by 50 publications

(67 citation statements)

References 61 publications

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“…18 Although required for apoptosis, T3 reovirus-induced activation of NF-κB is transient and at later times post infection (PI) the activation of NF-κB by a wide variety of stimuli is inhibited in infected cells. 18,19 In this report we show that NF-κB is also activated following infection with the Type 1 reovirus strain, Lang (T1L), which induces apoptosis inefficiently in infected cells (APO−), and that this activation parallels that of the strongly apoptotic (APO+) T3 reovirus strain, Abney (T3A). [20][21][22] In contrast, T1L does not inhibit NF-κB activation at later times PI, whereas T3A does.…”

Section: Introductionmentioning

confidence: 92%

“…The activation of NF-κB following reovirus infection is required for T3A-induced apoptosis in HEK293 cells. 19 In addition, the ability of reovirus to inhibit NF-κB activation at later times PI may sensitize cells to TRAIL-induced apoptosis and may be required for apoptosis in TRAIL-resistant cells. 19 To determine the importance of NF-κB regulation in reovirus-induced apoptosis we investigated NF-κB activation following infection with T1L (APO−).…”

Section: Activation Of Nf-κb Is Not Sufficient For Apoptosis Induced mentioning

confidence: 99%

“…19 In addition, the ability of reovirus to inhibit NF-κB activation at later times PI may sensitize cells to TRAIL-induced apoptosis and may be required for apoptosis in TRAIL-resistant cells. 19 To determine the importance of NF-κB regulation in reovirus-induced apoptosis we investigated NF-κB activation following infection with T1L (APO−). EMSA analysis, using nuclear extracts from T1L-infected HEK293 cells, was used to demonstrate the presence of activated NF-κB in the nucleus of T1L (APO−)-infected cells as early as 2 h PI.…”

Section: Activation Of Nf-κb Is Not Sufficient For Apoptosis Induced mentioning

confidence: 99%

“…19 Since reovirus-induced apoptosis is mediated by death ligands and since death ligand-induced apoptosis is enhanced in cells where NF-κB activity is blocked, the ability of reovirus to inhibit stimulus-induced activation likely promotes reovirus-induced apoptosis. 19 Having shown that T1L (APO−)-induced activation of NF-κB is not followed by a later inhibition phase, we next investigated whether T1L (APO−) infection inhibited stimulusinduced activation of NF-κB. Both TNF and the topoisomerase-II inhibitor, etoposide, which are strong inducers of NF-κB, were used as stimuli for our experiments.…”

Section: T3a (Apo+) But Not Tll (Apo−) Inhibits Stimulus-induced Acmentioning

confidence: 99%

“…14-17 Infection with T3 reoviruses induces the activation of NF-κB in a variety of cell types, including human embryonic kidney 293 (HEK293) and HeLa cells. 18,19 This activation is required for T3 reovirus-induced apoptosis in these cells, which is inhibited by stable over-expression of an IκB super-repressor or treatment of cells with a proteosome inhibitor (Z-L 3 VS) that blocks IκB degradation. 18,19 T3 reovirus-induced apoptosis is also inhibited in immortalized mouse embryo fibroblasts (MEFs) with targeted disruptions in the genes encoding the p50 or p65 subunits of NF-κB.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of NF-κ B activity and cFLIP expression contribute to viral-induced apoptosis

et al. 2005

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Virus-induced activation of nuclear factor-kappa B (NF-κB) is required for Type 3 (T3) reovirusinduced apoptosis. We now show that NF-κB is also activated by the prototypic Type 1 reovirus strain Lang (T1L), which induces significantly less apoptosis than T3 viruses, indicating that NF-κB activation alone is not sufficient for apoptosis in reovirus-infected cells. A second phase of virusinduced NF-κB regulation, where NF-κB activation is inhibited at later times following infection with T3 Abney (T3A), is absent in T1L-infected cells. This suggests that inhibition of NF-κB activation at later times post infection also contributes to reovirus-induced apoptosis. Reovirusinduced inhibition of stimulus-induced activation of NF-κB is significantly associated with apoptosis following infection of HEK293 cells with reassortant reoviruses and is determined by the T3 S1 gene segment, which is also the primary determinant of reovirus-induced apoptosis. Inhibition of stimulusinduced activation of NF-κB also occurs following infection of primary cardiac myocytes with apoptotic (8B) but not non-apoptotic (T1L) reoviruses. Expression levels of the NF-κB-regulated cellular FLICE inhibitory protein (cFLIP) reflect NF-κB activation in reovirus-infected cells. Further, inhibition of NF-κB activity and cFLIP expression promote T1L-induced apoptosis. These results demonstrate that inhibition of stimulus-induced activation of NF-κB and the resulting decrease in cFLIP expression promote reovirus-induced apoptosis.

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Section: Introductionmentioning

confidence: 92%

Section: Activation Of Nf-κb Is Not Sufficient For Apoptosis Induced mentioning

confidence: 99%

Section: Activation Of Nf-κb Is Not Sufficient For Apoptosis Induced mentioning

confidence: 99%

Section: T3a (Apo+) But Not Tll (Apo−) Inhibits Stimulus-induced Acmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of NF-κ B activity and cFLIP expression contribute to viral-induced apoptosis

et al. 2005

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A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection

et al. 2008

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Mechanisms of Apoptosis During Reovirus Infection

Clarke

Richardson-Burns

DeBiasi

et al.

Role of Apoptosis in Infection

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Reovirus infection has proven to be an excellent experimental system for studying mechanisms of virus-induced pathogenesis. Reoviruses induce apoptosis in a wide variety of cultured cells in vitro and in target tissues in vivo, including the heart and central nervous system. In vivo, viral infection, tissue injury, and apoptosis colocalize, suggesting that apoptosis is a critical mechanism by which disease is triggered in the host. This review examines the mechanisms of reovirus-induced apoptosis and investigates the possibility that inhibition of apoptosis may provide a novel strategy for limiting virus-induced tissue damage following infection.

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Two Distinct Phases of Virus-induced Nuclear Factor κB Regulation Enhance Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Virus-infected Cells

Abstract: Experimental infection with mammalian reoviruses has provided a classic model of viral pathogenesis (for review, see Ref.

Cited by 50 publications

References 61 publications

Inhibition of NF-κ B activity and cFLIP expression contribute to viral-induced apoptosis

Inhibition of NF-κ B activity and cFLIP expression contribute to viral-induced apoptosis

A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection

Mechanisms of Apoptosis During Reovirus Infection

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