Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase.
Herpes simplex virus type 1 (HSV-1) triggered apoptosis in hippocampal cultures, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry with antibody specific for the large fragment of activated caspase 3. The levels of phosphorylated (activated) c-Jun N-terminal kinase (JNK) were also increased in HSV-1-infected hippocampal cultures as were the levels of activated c-Jun, its target. JNK activation was involved in HSV-1-induced apoptosis as evidenced by apoptosis inhibition with the JNK inhibitor SP600125. HSV-2 activated the mitogen-activated protein kinase/extracellular regulated protein kinase (MEK/ERK) survival pathway and did not trigger apoptosis in hippocampal cultures. The MEK specific inhibitor U0126 inhibited ERK activation and caused a significant increase in the percent TUNEL(+) cells in HSV-2-infected cultures, indicating that the failure of HSV-2 to trigger apoptosis is due to its ability to activate the MEK/ERK survival pathway. JNK was also activated in brain tissues from patients with HSV-associated acute focal encephalitis (HSE) that were positive for HSV-1 antigen. JNK activation correlated with apoptosis, as determined by immunohistochemistry with antibody to activated caspase 3 or cleaved poly (ADP-ribose) polymerase (PARP). The data suggest that HSE has an apoptotic component that may contribute to disease pathogenesis.
Perkins
Dana
D
Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore 21201, USA.
Gyure
Kymberly A
KA
Pereira
Edna F R
EF
Aurelian
Laure
L
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D018792:Encephalitis, Viral / Q000378:metabolism / Q000473:pathology*; D006561:Herpes Simplex / Q000378:metabolism / Q000473:pathology*; D018259:Herpesvirus 1, Human; D018258:Herpesvirus 2, Human; D006624:Hippocampus / Q000166:cytology; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases