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Renal Ischemia/Reperfusion Injury Activates the Enhancer Domain of the Human Cytomegalovirus Major Immediate Early Promoter
Author(s) -
Kim Soo Jung,
Varghese Thomas K.,
Zhang Zheng,
Zhao Lee C.,
Thomas Gail,
Hummel Mary,
Abecassis Michael
Publication year - 2005
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2005.00912.x
Subject(s) - enhancer , transgene , reporter gene , signal transduction , medicine , tumor necrosis factor alpha , genetically modified mouse , human cytomegalovirus , reperfusion injury , microbiology and biotechnology , gene , biology , cancer research , gene expression , immunology , ischemia , virus , genetics
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‐κB 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‐κB 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‐κB may be of therapeutic value in patients with CMV infection.