Transcriptional Control of Monocyte Gene Expression in Post-Traumatic Stress Disorder

Aoife O’Donovan,Hans Rempel,Maryann Lenoci,Steve Cole,Bing Sun,Lynn Pulliam,Thomas Neylan

doi:10.1155/2011/560572

Abstract

Post-traumatic stress disorder (PTSD) confers an increased risk for disorders with an inflammatory etiology. PTSD-related dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary adrenal (HPA) axis and associated alterations in inflammatory activity may contribute to this increased risk. However, little is known about convergent SNS, HPA and inflammatory signaling at the level of the immune cell transcriptome in PTSD. To explore such signaling, we examined the prevalence of specific transcription factor binding motifs in the promoter regions of differentially expressed genes in monocytes from individuals with PTSD and matched controls. Participants included 49 men (24 PTSD+ and 25 trauma-exposed controls) and 18 women (10 PTSD+ and 8 controls). Men with PTSD showed up-regulation of target genes for the NF-κB/Rel family of transcription factors, which convey inflammatory signals, up-regulation of target genes for CREB/ATF transcription factors, which convey adrenergic signals from the SNS, and down-regulation of target genes for the glucocorticoid receptor, which conveys glucocorticoid signals from the HPA axis. Women with PTSD also showed significant up-regulation of target genes for NF-κB and non-significant down-regulation of target genes for GR, but significant down-regulation of target genes for CREB/ATF. Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in PTSD.

Highlights

Post-traumatic stress disorder (PTSD) is associated with substantially increased risk for chronic diseases such as neurodegenerative disorders, cardiovascular disease, diabetes, asthma, and arthritis [8,10,49, 52,59]
We examined if differentially expressed genes in monocytes from patients with PTSD were significantly enriched with response elements for nuclear factor-κB (NF-κB), cyclic adenosine monophosphate response element binding protein (CREB)/activating transcription factor (ATF) and glucocorticoid receptors (GR) in separate male and female samples
Compared with trauma-exposed controls, men with PTSD had significant up-regulation of target genes for NF-κB and CREB/ATF and significant down-regulation of target genes for GR. These results indicate increased inflammatory and adrenergic signaling in conjunction with decreased glucocorticoid signaling in men with PTSD

Summary

Introduction

Post-traumatic stress disorder (PTSD) is associated with substantially increased risk for chronic diseases such as neurodegenerative disorders, cardiovascular disease, diabetes, asthma, and arthritis [8,10,49, 52,59]. This PTSD-related increased risk for disease does not appear to be accounted for by potential confounds and mediators such as family history, smoking, obesity, alcohol dependence, or depression [5]. Elevated inflammatory activity is increasingly recognized as a potential pathway to PTSD-related increased risk for physical disease. The precise nature of this dysregulation remains incompletely un-

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Conclusion