title: Renal ischemia/reperfusion injury activates the enhancer domain of the human cytomegalovirus major immediate early promoter.
abstract: 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-kappaB 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-kappaB 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-kappaB may be of therapeutic value in patients with CMV infection.
authors.affiliation: Department of Surgery, Transplant Lab, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Varghese
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lee C
authors.initials: LC
authors.lastname: Zhao
authors.forename: Gail
authors.initials: G
authors.lastname: Thomas
authors.forename: Mary
authors.initials: M
authors.lastname: Hummel
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics*; D050882:CREB-Binding Protein; D003587:Cytomegalovirus / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000235:genetics*; D007668:Kidney / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency; D015427:Reperfusion Injury / Q000378:metabolism / Q000821:virology*; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C044582:immediate-early proteins, cytomegalovirus; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse