A new Proceedings of the National Academy of Sciences of the USA (PNAS) study suggests that prolonged stress results in glucocorticoid receptor resistance (GCR), which results in a dysfunctional stress-immunity interaction, and, in turn, interferes with appropriate regulation of inflammation.
The hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary system are the two major peripheral components of the stress system. Glucocorticoids (GCs), the end-products of the HPA axis, express potent immunoregulatory and immunomodulatory properties.
Stress-induced dysregulation of the HPA axis has been implicated in the pathogenesis of cardiovascular and autoimmune diseases, asthma, depression, diabetes and upper respiratory infections (URIs). It is not entirely clear which stress-induced changes in the HPA axis may play a downstream decisive role in disease risk, but this has often been attributed to direct effects of elevated circulating cortisol.
An area that has received much less attention is the question of how different tissues respond to cortisol and particularly the phenomenon of glucocorticoid receptor resistance (GCR), which refers to a decrease in the sensitivity of target tissues to GC’s effects.
‘Primary Generalized Glucocorticoid Resistance’ is a syndrome described and elucidated in the early 1980s by Chrousos et al., as a rare, familial or sporadic genetic disorder. This condition, also referred to as ‘Chrousos syndrome’, is characterized by target-tissue insensitivity to GCs and compensatory increased secretion of cortisol and adrenal steroids with mineralocorticoid and/or androgenic activity, causing hypermineralocorticoidism and hyperandrogenism without Cushing stigmata.
There are now a host of human states associated with tissue-speciﬁc changes of GC action. Decreased GC responsiveness is found in patients with chronic obstructive pulmonary disease and acute respiratory distress syndrome, and is also an issue for some patients with asthma, rheumatoid arthritis, inflammatory bowel disease and lymphoproliferative disorders.
For example, about 30% of patients with rheumatoid arthritis fail to respond to steroid therapy, whereas 5-10% of asthmatics fall into the category of relative GC insensitivity. In asthmatics, this sub-population is itself divided into smaller subsets which have different underlying mechanisms, ranging from an inherited genetic basis to altered GCs signaling triggered by exposure to environmental stressors such as cigarette smoking or infection.
In the PNAS study Sheldon Cohen and colleagues from the Department of Psychology, Carnegie Mellon University, Pittsburgh, PA, used the viral-challenge paradigm to study the general model of stress leading to disease via effects on the HPA axis and inﬂammatory regulation.
The authors of this study propose 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 upper respiratory infections (URI), which are generated by the proinﬂammatory response.
In their study, exposure to a long-term threatening stressful experience predicted an increased risk of developing a cold following exposure to a rhinovirus, and this was associated with GCR – individuals with GCR were at higher risk of subsequently developing a cold. In addition, greater GCR predicted the production of more local proinﬂammatory cytokines among infected subjects, as local IL-6 and TNF-alpha, but not IL-1beta, were correlated with GCR.
According to the authors this indicates that chronic stress may induce GCR, which, in turn, interferes with appropriate regulation of inﬂammation. Since inﬂammation is known to play an important role in the onset and progression of a wide range of diseases, the authors suggest that this model may have broad implications for understanding the role of stress in common human immune-related diseases.
SOURCE: Proc Natl Acad Sci U S A 2012 Apr 2. [Epub ahead of print]