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Targeting activation of specific NF-?B subunits prevents stress-dependent atherothrombotic gene expression.

ABSTRACT: Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-?B (NF-?B) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-?B-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stress led to NF-?B-dependent expression of proinflammatory (tissue factor, intracellular adhesive molecule 1 [ICAM-1]) and protective genes (manganese superoxide dismutase [MnSOD]) via p50, p65 or cRel. Selective inhibition of the different subunits and the respective kinases showed that inhibition of cRel leads to the reduction of atherosclerotic lesions in apolipoprotein(-/-) (ApoE(-/-)) mice via suppression of proinflammatory gene expression. This observation may therefore provide a possible explanation for ineffectiveness of antioxidant therapies and suggests that selective targeting of cRel activation may provide a novel approach for the treatment of stress-related inflammatory vascular disease.

SUBMITTER: Djuric Z

PROVIDER: S-EPMC3533647 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Targeting activation of specific NF-κB subunits prevents stress-dependent atherothrombotic gene expression.

Djuric Zdenka Z Kashif Muhammed M Fleming Thomas T Muhammad Sajjad S Piel David D von Bauer Rüdiger R Bea Florian F Herzig Stephan S Zeier Martin M Pizzi Marina M Isermann Berend B Hecker Markus M Schwaninger Markus M Bierhaus Angelika A Nawroth Peter P PP

Molecular medicine (Cambridge, Mass.) 20121220

Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-κB (NF-κB) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-κB-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stre ...[more]

PMID: 23114885

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Project description:The nuclear factor kappa B (NF-κB) pathway is known to integrate signaling associated with very diverse intra- and extracellular stressors, including virus infections, and triggers a powerful (proinflammatory) response through the expression of NF-κB-regulated genes. Typically, the NF-κB pathway collects and transduces threatening signals at the cell surface or in the cytoplasm leading to nuclear import of activated NF-κB transcription factors. In the current work, we demonstrate that the swine alphaherpesvirus pseudorabies virus (PRV) induces a peculiar mode of NF-κB activation known as "inside-out" NF-κB activation. We show that PRV triggers the DNA damage response (DDR) and that this DDR response drives NF-κB activation since inhibition of the nuclear ataxia telangiectasia-mutated (ATM) kinase, a chief controller of DDR, abolished PRV-induced NF-κB activation. Initiation of the DDR-NF-κB signaling axis requires viral protein synthesis but occurs before active viral genome replication. In addition, the initiation of the DDR-NF-κB signaling axis is followed by a virus-induced complete shutoff of NF-κB-dependent gene expression that depends on viral DNA replication. In summary, the results presented in this study reveal that PRV infection triggers a noncanonical DDR-NF-κB activation signaling axis and that the virus actively inhibits the (potentially antiviral) consequences of this pathway, by inhibiting NF-κB-dependent gene expression. IMPORTANCE The NF-κB signaling pathway plays a critical role in coordination of innate immune responses that are of vital importance in the control of infections. The current report generates new insights into the interaction of the alphaherpesvirus pseudorabies virus (PRV) with the NF-κB pathway, as they reveal that (i) PRV infection leads to NF-κB activation via a peculiar "inside-out" nucleus-to-cytoplasm signal that is triggered via the DNA damage response (DDR), (ii) the DDR-NF-κB signaling axis requires expression of viral proteins but is initiated before active PRV replication, and (iii) late viral factor(s) allow PRV to actively and efficiently inhibit NF-κB-dependent (proinflammatory) gene expression. These data suggest that activation of the DDR-NF-κB during PRV infection is host driven and that its potential antiviral consequences are actively inhibited by the virus.

Dataset Information

Targeting activation of specific NF-?B subunits prevents stress-dependent atherothrombotic gene expression.

Publications

Targeting activation of specific NF-κB subunits prevents stress-dependent atherothrombotic gene expression.

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