Mounting evidence indicates that chronic psychological stressors – such as caring for a demented family member, having a severely troubled marriage, or working in a hostile environment – contribute to the development and progression of medical illnesses (1
). Stressed persons are prone to viral infections, more frequent and severe flare-ups of asthma, multiple sclerosis, and arthritis, and to developing premature coronary disease (2
The mechanisms responsible for this phenomenon are not well understood. There has been much speculation regarding the contribution of the hypothalamic-pituitary-adrenocortical (HPA) axis, which releases cortisol into circulation following exposure to many life stressors (8
). In leukocytes, cortisol ligates cytosolic glucorticoid receptors (GR), and these complexes translocate to the nucleus, where they inhibit activity of several immunoregulatory transcription control pathways, including nuclear-factor kappa-B (NF-κB), activator-protein 1 (AP-1), and JAK-STAT factors (10
). Because of cortisol’s ability to inhibit a broad array of cellular immune functions, a prevailing assumption has been that it contributes to stress-evoked disease through immuno-suppressive mechanisms.
However, with increasing recognition that inflammation is a key pathogenic mechanism in many infectious, autoimmune, cardiovascular, and psychiatric diseases (11
), the adequacy of this explanation has been called into question (14
). This is because when taken to its logical end, this hypothesis suggests a paradoxical and inaccurate conclusion: that in boosting cortisol output and slowing immune activity, chronic stressors should ameliorate the symptoms of inflammation-related diseases. Of course, this conclusion is at odds with the excess morbidity and mortality documented in chronically stressed individuals (1
To resolve this paradox, researchers have advanced an alternative hypothesis focusing on cellular resistance to cortisol-mediated signaling (14
). It specifies that chronic stressors elicit sustained elevations in cortisol which, over time, prompt immune cells to undergo a compensatory downregulation of GR activity. This adaptively limits cortisol’s ability to further dampen immune responses. However, in cells like monocytes that are tightly regulated by cortisol, this dynamic also diminishes the potency of an important hormonal constraint, which acts to tonically inhibit NF-κB, AP-1, and other pro-inflammatory transcriptional control pathways (10
). The long-term result of this process is mild, low-grade inflammation, fostered by monocytes that have acquired resistance to cortisol. The resulting persistent inflammation is hypothesized to contribute to the infectious, autoimmune, and cardiac diseases to which stress is linked.
Support for this account has accrued in studies of humans and animals (14
), where chronic stressors have been shown to diminish the capacity of glucocorticoids to suppress endotoxin-stimulated cytokine production. While these findings provide encouraging support for the glucocorticoid-resistance hypothesis, it is difficult to draw definitive conclusions from them, because they rely on ex vivo
methods, synthetic analogues of cortisol, and/or high doses of endotoxin to activate monocytes. A further problem is that existing research has relied upon culture systems that interrogate only a single activation pathway, which involves toll-like receptor 4 and the MyD88 adaptor molecule (21
). Glucocorticoids regulate monocyte behavior through modulation of multiple signaling pathways (22
), so a thorough evaluation of the resistance hypothesis requires a model system that fully captures these dynamics in vivo
Here we address these problems by conducting genome-wide transcriptional surveys on the monocytes of two groups of volunteers: those in the midst of a severe chronic stressor – acting as caregiver for a family member with malignant brain cancer – and a matched sample of healthy controls. When used in concert with promoter-based bioinformatics techniques (23
), these genome-wide transcriptional profiles reveal how strongly cortisol signals are being registered across the entire transcriptome. On the basis of the glucocorticoid-resistance hypothesis, we expected that the stress of caregiving would diminish glucocorticoid-mediated transcription in monocytes, and at the same time enhance transcription of pro-inflammatory mRNAs. The latter outcome was expected to be especially pronounced for genes controlled by NF-κB, which is subject to potent counter-regulation by GR-dependent mechanisms (10
). Because monocytes initiate and maintain inflammatory responses to many pathogenic stimuli, we also expected these stress-related dynamics to be accompanied by higher systemic concentrations of inflammatory molecules like C-reactive protein and interleukin-6.