A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling

Abstract

Background: Chronic stressors are known to increase vulnerability to medical illness, but the mechanisms underlying this phenomenon are poorly understood.

Methods: To identify transcriptional control pathways that are modified by chronic stress, we conducted genomewide expression microarrays on familial caregivers of brain-cancer patients (n = 11) and matched control subjects (n = 10). Analyses were conducted on peripheral blood monocytes, which are cells that have the ability to initiate and maintain many inflammatory responses. Salivary cortisol was collected over the course of 3 days as volunteers went about normal activities.

Results: Caregivers' patterns of cortisol secretion were similar to those of matched control subjects. However, their monocytes showed diminished expression of transcripts bearing response elements for glucocorticoids, and heightened expression of transcripts with response elements for NF-kappaB, a key pro-inflammatory transcription factor. Caregivers also showed relative elevations in the inflammatory markers C-reactive protein and interleukin-1 receptor antagonist.

Conclusions: These findings suggest that even in the absence of excess adrenocortical output, stress brings about functional resistance to glucocorticoids in monocytes, which enables activation of pro-inflammatory transcription control pathways. This persistent activation of inflammatory mechanisms may contribute to stress-related morbidity and mortality.

Figure 1. Psychological consequences of caregiving

Self-reports of well-being were collected from 11 adults facing a severe chronic stressor (primary caregiver for family member with brain cancer) and 10 demographically-matched nonstressed controls. Caregivers showed (a) higher levels of stress (p = .003), (b) decreased life satisfaction (p = .04), and (c) decreased positive emotions (p’s < .004).

Figure 2. Differential gene expression in chronically stressed individuals

Microarray analysis of gene expression in peripheral blood monocytes identified 614 transcripts showing > 50% difference in mean expression levels across groups (green = under-expression in chronic stress, red = over-expression).

Figure 3. Transcriptional activity of GR and NF-κB signaling pathways and expression of inflammatory biomarkers in circulation

In TELiS bioinformatics analysis of response element prevalence in promoters of differentially expressed genes, (a) GR response elements are under-represented in genes up-regulated in stressed caregivers, whereas (b) transcripts bearing response elements for NF-κB are over-represented. In serum caregivers display significantly higher concentrations of the inflammatory biomarkers (c) C-reactive protein and (d) interleukin-1 receptor antagonist.

Figure 4. Diurnal cortisol cycles in caregivers and controls

Caregivers showed higher cortisol than controls 4 hours after waking (t = 4.19, p = .029), but did not differ significantly at other times of day, or on global indices such as diurnal rhythm of secretion and total output over the day (p’s >.59).