Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 5, Issue 7, Pages 1606-1613Publisher
WILEY
DOI: 10.1111/j.1600-6143.2005.00912.x
Keywords
cytomegalovirus; NF-kappa B; AP-1; ROS; virus latency; reactivation; ischemia/reperfusion injury
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Funding
- NIAID NIH HHS [R01 AI42898, R01 AI042898] Funding Source: Medline
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Reactivation of latent human cytomegalovirus is of significant concern in immunocompromised transplant patients and is likely to occur through transcriptional activation of immediate early (ie) gene expression through mechanisms that are not well understood. TNF-mediated activation of NF-kappa B has been proposed to be one pathway leading to transcriptional activation of CMV ie gene expression. Using transgenic mice carrying a lacZ reporter gene under the control of the HCMV major ie promoter/enhancer (MIEP-lacZ mice) and MIEP-lacZ mice deficient in TNF receptor 1 and TNF receptor 2 (MIEP-lac Z TNFR DKO mice), we demonstrate that renal ischemia/reperfusion (I/R) injury activates the HCMV enhancer independently of TNF. Induction of MIEP-lacZ expression was preceded by TNFR-independent formation of reactive oxygen species (ROS), weak and transient activation of NF-kappa B and strong and sustained activation of AP-1. Our studies show that, in addition to TNF-mediated signaling, TNF-independent signaling induced by I/R injury can contribute to the activation of the HCMV enhancer. This likely occurs through ROS-mediated activation of AP-1. Targeting MAP kinase signaling pathways as well as NF-kappa B may be of therapeutic value in patients with CMV infection.
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