IFN-gamma mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression.
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.
Department of Molecular Immunology, Immunex Corporation, Seattle, WA 98101, USA. sedger1@immunex.com
L M
LM
Sedger
D M
DM
Shows
R A
RA
Blanton
J J
JJ
Peschon
R G
RG
Goodwin
D
D
Cosman
S R
SR
Wiley
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology; D004357:Drug Synergism; D005347:Fibroblasts; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000276:immunology
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma