Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk | Forum

Sheldon Cohen, Denise Janicki-Deverts, William J. Doyle, Gregory E. Miller, Ellen Frank, Bruce S. Rabin, and Ronald B. Turner

PNAS April 17, 2012 109 (16) 5995-5999; https://doi.org/10.1073/pnas.1118355109

1. Edited* by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved February 27, 2012 (received for review November 72011)

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We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

We proposed that exposure to a major stressful life event can result in GCR, which, in turn, would interfere with HPA down-regulation of local proinflammatory cytokine response to an infectious agent. Without appropriate cortisol regulation of the local cytokine response, there would be an exaggerated expression of the signs of URI, which are generated by the proinflammatory response. In study 1, stress—defined as a recent stressful life experience associated with long-term threat—predicted an increased risk of developing a cold following exposure to a rhinovirus (also reported in ref. 15). New analyses indicate that this same stress measure was also associated with GCR, with stressed persons showing less sensitivity of lymphocyte and neutrophil counts to distributional changes associated with greater circulating levels of cortisol. In turn, GCR was prospectively associated with increased risk of developing a common cold following experimental inoculation with a cold virus. These data are consistent with a model wherein stress leads to GCR, which in turn results in greater risk for developing a cold. In study 2, GCR predicted how much local proinflammatory cytokine was produced in response to infection. Because the analyses in both studies were prospective, we can eliminate reverse causation (colds did not cause stress, colds did not cause GCR, and cytokine release did not cause GCR) as an alternative explanation. The use of multiple control variables also eliminates many potential spurious explanations.

The GCR measure used in study 1 is indirect. However, experimental studies have shown that glucocorticoid-induced leukocyte redistribution is specifically attributable to glucocorticoid receptor signaling (25), and that the indirect assessment used here correlates with blunting of lymphocyte redistribution in response to dexamethasone injection (24). Even so, it is possible that the action of another hormone or mechanism both highly correlated with cortisol and having the same impact on leukocyte trafficking as cortisol could account for these effects. Likely alternative explanations include that the associations are attributable to subject health (e.g., infections) or to receptor sensitivity to E and/or NE. Health is not an issue here, because subjects are carefully screened for excellent health. Further, we found that neither E nor NE were correlated with leukocyte counts under any of the relevant conditions (similar results in ref. 5). We also found consistent evidence across studies 1 and 2, even though study 2 used a standard direct assessment of GCR.

We found no effects of cortisol levels on disease risk (e.g., refs. 19, 20), GCR, or inflammation. This apparent lack of a role for circulating cortisol levels is consistent with the possibility that impaired target tissue response to the regulatory effects of this hormone may overshadow any modulatory influences that might result from changes in circulating concentrations of cortisol itself.

In the case of the common cold, a disease for which expression of the signs/symptoms of illness is driven by the inflammatory response, the failure of the HPA to regulate the production of local proinflammatory cytokines contributes to the risk for clinical illness. Because inflammation plays a role in progression of multiple diseases, this model not only provides an explanation for the increased risk for URI under stress, but might provide a more general explanation for why prolonged stress would play a role in other inflammatory diseases as well. Moreover, although the focus here has been on GCR in circulating leukocytes and neutrophils, stress could also be associated with illness expression through its effect on the glucocorticoid sensitivity of other cells involved in immune defenses (26). For example, glucocorticoid receptors (GR) are expressed by cells involved with antigen presentation, such as dendrocytes and macrophages, not only in circulation but also at specific sites of infection and in draining lymph nodes.

Parodoxically, proinflammatory cytokines are thought to both up-regulate immunity to the virus and produce cold symptoms (13). However, here stress and GCR, conditions associated with increased levels of local proinflammatory cytokine, predicted a greater risk of clinical illness. These data are consistent with those of other viral-challenge studies that found a positive association between proinflammatory cytokine levels and symptom expression (16).

An unexplained inconsistency in the data from study 2 is that local IL-6 and TNF-α, but not IL-1β, were correlated with GCR measured by the whole blood ex vivo assay. It is possible that this discrepancy is due to the relative insensitivity of the IL-1β assay. Alternatively, it may reflect a differential sensitivity of these cytokines to glucocorticoid suppression (27).

Finally, future research on GCR would benefit from quantification of GR subtypes, whose relative abundance might underlie the findings observed here. Chronic stress does not appear to affect expression of GRα, the active isoform of the receptor (11). However, there is evidence linking stress and cytokines to higher levels of GRβ and a lower GRα/GRβ ratio (28). This could prove important because GRβ is a dominant negative receptor for cortisol, which can suppress GRα activity and thereby contribute to GCR (28).