Frontline: Induction of apoptosis and modulation of c-FLIPL and p53 in immature dendritic cells infected with herpes simplex virus.
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.
Müller
Dagmar B
DB
Institute of Virology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Raftery
Martin J
MJ
Kather
Angela
A
Giese
Thomas
T
Schönrich
Günther
G
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
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