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IFN-gamma mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression
L M Sedger1, D M Shows, R A Blanton
1Department of Molecular Immunology, Immunex Corporation, Seattle, WA 98101, USA. sedger1@immunex.com
Abstract:
TNF-related apoptosis-inducing ligand (TRAIL) is able to kill many transformed cells of diverse tissue types. We show that TRAIL is inducible by IFN-gamma, by TNF-alpha, and by infection with human CMV, and has potent antiviral activity in vitro. CMV infection and IFN-gamma also reciprocally modulate TRAIL receptor (TRAIL-R) expression. CMV infection increased the expression of TRAIL-R1 and -R2, whereas IFN-gamma down-regulated the expression of TRAIL-Rs on uninfected fibroblasts. Moreover, IFN-gamma significantly decreased the basal level of NF-kappaB activation, a known survival factor that inhibits apoptosis. Thus, TRAIL selectively kills virus-infected cells while leaving uninfected cells intact, and IFN-gamma potentiates these effects by dynamic modulation of TRAIL and TRAIL-R expression and by sensitizing cells to apoptosis. The regulation of TRAIL and TRAIL-R expression may represent a general mechanism that contributes to the control of TRAIL-mediated apoptosis.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively eliminates virus-infected cells. Interferon-gamma (IFN-gamma) enhances this antiviral effect by modulating TRAIL and its receptors, promoting apoptosis in infected cells.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in transformed cells.
- TRAIL exhibits potent antiviral activity in vitro.
- Cytomegalovirus (CMV) infection and IFN-gamma influence TRAIL and TRAIL receptor (TRAIL-R) expression.
Purpose of the Study:
- To investigate the role of TRAIL in antiviral defense against CMV.
- To elucidate the mechanisms by which IFN-gamma modulates TRAIL-mediated apoptosis during viral infection.
- To understand the interplay between viral infection, immune signaling, and apoptosis.
Main Methods:
- Induction of TRAIL by IFN-gamma, TNF-alpha, and CMV infection.
- Analysis of TRAIL and TRAIL-R expression in infected and uninfected cells.
- Assessment of NF-kappaB activation levels.
- In vitro antiviral activity assays.
Main Results:
- TRAIL is inducible by IFN-gamma, TNF-alpha, and CMV infection, demonstrating antiviral properties.
- CMV infection upregulates TRAIL-R1 and TRAIL-R2 expression.
- IFN-gamma downregulates TRAIL-R expression on uninfected fibroblasts and decreases NF-kappaB activation.
- TRAIL selectively eliminates virus-infected cells, with IFN-gamma potentiating this effect.
Conclusions:
- TRAIL plays a crucial role in the selective elimination of virus-infected cells.
- IFN-gamma enhances TRAIL-mediated antiviral activity through dynamic modulation of TRAIL and TRAIL-R expression.
- Modulation of TRAIL and TRAIL-R expression represents a key mechanism in controlling TRAIL-mediated apoptosis during viral infections.