title: Frontline: Induction of apoptosis and modulation of c-FLIPL and p53 in immature dendritic cells infected with herpes simplex virus.
abstract: Herpes simplex virus (HSV) can perturb the function of dendritic cells (DC). The underlying mechanisms are not defined. In the present study we demonstrate that HSV induces a substantial number of immature DC to undergo apoptosis by a mechanism involving caspase-8. We found strongly enhanced expression of TNF-alpha and TRAIL but not CD95 ligand after HSV infection. Blocking experiments suggested that these classical death ligands contribute to HSV-induced cell death of immature DC. Because uninfected DC are resistant to the apoptosis-inducing effect of death ligands we searched for a viral "competence-to-die" signal. Further analysis revealed that HSV-infected immature DC down-regulate long cellular FLICE-inhibitory protein (c-FLIP(L)) and up-regulate p53 whereas other apoptosis-regulating proteins (e.g. Bcl-2, RIP, FADD) were not affected. Down-regulation of c-FLIP(L) was not due to diminished gene transcription or reduced mRNA stability because the level of c-FLIP(L) mRNA was rather increased. Moreover, down-regulation of c-FLIP(L) could not be blocked by the anti-herpetic drug acyclovir. Finally, the underlying mechanism was also operative in human umbilical vein endothelial cells, which show a similar susceptibility to HSV infection and strength of c-FLIP(L) expression. These results suggest that HSV targets c-FLIP(L) protein in immature DC and other infectable cells to disrupt their function.
authors.affiliation: Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Dagmar B
authors.initials: DB
authors.lastname: Müller
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Raftery
authors.forename: Angela
authors.initials: A
authors.lastname: Kather
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Günther
authors.initials: G
authors.lastname: Schönrich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000276:immunology*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology*; D005434:Flow Cytometry; D006561:Herpes Simplex / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases