Organ-specific roles for transcription factor NF-κB in reovirus-induced apoptosis and disease
Reovirus induces apoptosis in cultured cells and in vivo. In cell culture models, apoptosis is contingent upon a mechanism involving reovirus-induced activation of transcription factor NF-κB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-κB in this process, we test...
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Published in | The Journal of clinical investigation Vol. 115; no. 9; pp. 2341 - 2350 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Clinical Investigation
01.09.2005
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Online Access | Get full text |
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Summary: | Reovirus induces apoptosis in cultured cells and in vivo. In cell culture models, apoptosis is contingent upon a mechanism involving reovirus-induced activation of transcription factor NF-κB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-κB in this process, we tested the capacity of reovirus to induce apoptosis in mice lacking a functional
nfkb1/p50
gene. The genetic defect had no apparent effect on reovirus replication in the intestine or dissemination to secondary sites of infection. In comparison to what was observed in wild-type controls, apoptosis was significantly diminished in the CNS of p50-null mice following reovirus infection. In sharp contrast, the loss of p50 was associated with massive reovirus-induced apoptosis and uncontrolled reovirus replication in the heart. Levels of IFN-β mRNA were markedly increased in the hearts of wild-type animals but not p50-null animals infected with reovirus. Treatment of p50-null mice with IFN-β substantially diminished reovirus replication and apoptosis, which suggests that IFN-β induction by NF-κB protects against reovirus-induced myocarditis. These findings reveal an organ-specific role for NF-κB in the regulation of reovirus-induced apoptosis, which modulates encephalitis and myocarditis associated with reovirus infection. |
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Bibliography: | Address correspondence to: Terence S. Dermody, Elizabeth B. Lamb Center for Pediatric Research, D7235 Medical Center North, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, Tennessee 37232, USA. Phone: (615) 343-9943; Fax: (615) 343-9723; E-mail: terry.dermody@vanderbilt.edu. |
ISSN: | 0021-9738 |
DOI: | 10.1172/JCI22428 |