Organ-specific roles for transcription factor NF-kappaB in reovirus-induced apoptosis and disease.

O'Donnell SM, Hansberger MW, Connolly JL, Chappell JD, Watson MJ, Pierce JM, Wetzel JD, Han W, Barton ES, Forrest JC, Valyi-Nagy T, Yull FE, Blackwell TS, Rottman JN, Sherry B, Dermody TS
J Clin Invest. 2005 115 (9): 2341-50

PMID: 16100570 · PMCID: PMC1184036 · DOI:10.1172/JCI22428

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-kappaB complexes containing p50 and p65/RelA subunits. To explore the in vivo role of NF-kappaB 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-beta 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-beta substantially diminished reovirus replication and apoptosis, which suggests that IFN-beta induction by NF-kappaB protects against reovirus-induced myocarditis. These findings reveal an organ-specific role for NF-kappaB in the regulation of reovirus-induced apoptosis, which modulates encephalitis and myocarditis associated with reovirus infection.

MeSH Terms (18)

Animals Animals, Newborn Apoptosis Brain Cell Line Heart In Situ Nick-End Labeling Interferon-beta Intestinal Mucosa Intestines Mice Mice, Knockout Myocarditis Myocardium NF-kappa B p50 Subunit Reoviridae Reoviridae Infections Virus Replication

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