Inflammation Versus Glucocorticoids as Purveyors of Pathology During Stress: Have We Reached the Tipping Point?

There has been longstanding recognition that life stress in its myriad forms can influence health and the development of disease. However, the mechanisms of these effects of stress, especially in humans, have remained somewhat elusive and, although rarely articulated, lie at the core of our understanding of how neuroendocrine and immune pathways interact during stress to ultimately contribute to disease. One clue that has received increasing attention is the notion that chronic stress is associated with activation of innate immune, inflammatory responses. Indeed, stress-induced activation of innate immune responses and inflammatory signaling pathways is posited to be an important link between stress and illness, especially given that inflammation is increasingly recognized as a common mechanism of disease in a number of disorders, including cardiovascular disease, diabetes, and cancer (1,2). Glucocorticoids, the end product of activation of stress-induced neuroendocrine pathways and the hypothalamic-pituitary-adrenal (HPA) axis, are some of the most potent anti-inflammatory hormones in the body and thus serve to restrain innate immune responses during infection and other forms of immune activation (3). Nevertheless, much has been written regarding the potentially damaging effects of excessive glucocorticoids in the context of chronic stress (4), thus presenting a conundrum regarding the potential role of inflammation versus glucocorticoids as purveyors of pathology in the contributions of life stress to disease development and progression. Although some investigators have suggested that glucocorticoids might be pro-inflammatory under some circumstances and in some tissues (e.g. the brain) (5), it seems unlikely that an inflammatory response can prevail in an environment in which glucocorticoid signaling is intact (or even excessive). Some critical insights into the relative balance between glucocorticoids and the inflammatory response during chronic stress are provided in the study by Miller et al., which appears in the current issue of Biological Psychiatry (pages 266–272). With genome-wide microarrays and promoter-based bioinformatics techniques, the expression of transcripts bearing response elements for glucocorticoids and nuclear-factor kappa-B (NF-B), a lynchpin in the inflammatory response, were examined in peripheral blood monocytes isolated from a small sample of individuals experiencing the stress of caring for a family member suffering from brain cancer (n 11). Results were compared with an age-, gender-, and race-matched control group with no major life stressors over the preceding year (n 10). Monocytes were chosen for analysis, because they are a critical immune cell type responsible for initiation of innate immune responses to pathogens in large part through activation of pattern recognition receptors, called toll-like receptors (TLRs), which are linked to inflammatory signaling molecules including NF-B. In addition, assessments were made of peripheral blood biomarkers of inflammation including C-reactive protein (CRP), interleukin (IL)-6, and IL-1 receptor antagonist (IL-1ra) as well as measures of salivary cortisol production as determined immediately upon awakening and across the diurnal cycle over a 3-day period. Interestingly, chronic caregiving stress was associated with a significant downregulation of genes expressing one or more glucocorticoid response elements and an upregulation in genes expressing response elements for NF-B. Results for selected genes were confirmed with real time reverse transcription polymerase chain reaction. Moreover, evaluation of gene expression for surface markers differentiating resident versus activated monocytes revealed no differences in the relative populations of these cells between caregivers and control subjects. Caregivers also exhibited—consistent with the increased expression of genes bearing NF-B response elements—increased serum concentrations of IL-1ra as well as CRP, whose mean concentration in caregivers fell into the high-risk (high inflammation) category for the development of cardiovascular disease according to the guidelines of the