The involvement of a stress-activated pathway in equine influenza virus-mediated apoptosis.

Abstract

We have shown elsewhere that equine-2 influenza virus (EIV; subtype H3N8) induced pronounced cell death in infected cells through apoptosis as demonstrated by DNA fragmentation assay and a combined TUNEL and immunostaining scheme. In this study, we investigated the mechanism of EIV-mediated cytotoxicity on a permissive mammalian epithelial cell line, Madin-Darby canine kidney (MDCK) cells. EIV infection increased the cellular levels of oxidative stress and c-Jun/AP-1 protein (which is known to be affected by oxidative stress), as well as its DNA binding activity. Increased production of TGF-beta1, an inducer of c-Jun N-terminal kinase or stress-activated protein kinase (JNK/SAPK) activation, was also detected in EIV-infected MDCK cells. It has been reported that TGF-beta may initiate a signaling cascade leading to JNK/SAPK activation. Addition of c-Jun antisense oligodeoxynucleotide, antioxidant N-acetyl-cysteine (NAC), JNK/SAPK inhibitor carvedilol, or TGF-beta-neutralizing antibody effectively blocked c-Jun/AP-1 upregulation and TGF-beta1 production mediated by EIV infection. These treatments also attenuated EIV-induced cytopathogenic effects (CPE) and apoptosis. Our results suggest that a stress-activated pathway is involved in apoptosis mediated by EIV infection. It is likely that EIV infection turns on the JNK/SAPK cascade, which modulates the activity of apoptosis-promoting regulatory factor c-Jun/AP-1 and epithelial growth inhibitory cytokine TGF-beta.

• Authors: C Lin, S G Zimmer, Z Lu, R E Holland Jr, Q Dong, T M Chambers
• Journal: Virology (Virology) Vol. 287 Issue 1 Pg. 202-13 (Aug 15 2001) ISSN: 0042-6822 [Print] United States
• PMID: 11504555 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• Carbazoles
• Oligodeoxyribonucleotides, Antisense
• Propanolamines
• Transforming Growth Factor beta
• Carvedilol
• Mitogen-Activated Protein Kinase 8
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis
• Carbazoles (pharmacology)
• Carvedilol
• Cell Line
• Cytopathogenic Effect, Viral
• DNA Fragmentation
• Dogs
• Enzyme Activation
• In Situ Nick-End Labeling
• Influenza A virus
• Mitogen-Activated Protein Kinase 8
• Mitogen-Activated Protein Kinases (metabolism)
• Oligodeoxyribonucleotides, Antisense (pharmacology)
• Orthomyxoviridae Infections (enzymology)
• Oxidative Stress
• Propanolamines (pharmacology)
• Signal Transduction
• Transforming Growth Factor beta (biosynthesis)
• Virus Replication (drug effects)