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

Abstract

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 reovirusinduced 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 organspecific role for NF-κB in the regulation of reovirus-induced apoptosis, which modulates encephalitis and myocarditis associated with reovirus infection.

Warm Hepatic Ischemia-Reperfusion Promotes Growth of Colorectal Carcinoma Micrometastases in Mouse Liver via Matrix Metalloproteinase-9 Induction

“…A standard curve was generated from cDNA from regenerating mouse liver 6 h after hepatectomy. Real-time PCR reactions were carried out using the Bio-Rad iCycler and iQ Supermix buffer containing DNA polymerase and SYBR Green (Bio-Rad Laboratories) as described elsewhere (34). Cycling conditions were as follows: 95jC for 10 min and then 45 cycles at 95jC for 15 s, 60jC for 30 s, and 72jC for 15 s. Data were analyzed using Bio-Rad iCycler PCR detection and analysis software version 3.0 (Bio-Rad Laboratories).…”

Rodent models of heart failure: an updated review

“…A retrovirus model of encephalitis and myocarditis in mice showed that nuclear factor-kB activation confers protection against virally mediated apoptosis and its expression is preserved in the presence of interferon-b. The absence of any of these molecules in the myocardium leads to striking viral infection and cell death [214]. Transgenic knockout models of components of the immune system have provided interesting insights in the pathogenesis of viral myocarditis [163].…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…For example, nfkb1 À/À mice are highly susceptible to Leishmania major (Artis et al, 2003), Listeria monocytogenes and Streptococcus pneumoniae (Sha et al, 1995), they respond normally to Haemophilus influenza and Escherichia coli (Sha et al, 1995), but are more resistant to encephalomyocarditis virus (Sha et al, 1995). nfkb1-dependent susceptibility to particular pathogens can even be extended to differences between particular organs (O'Donnell et al, 2005). Whereas reovirus-induced apoptosis is reduced in the central nervous system of nfkb1 À/À mice, viral replication and cell death are increased in the heart.…”