Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

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In our clinical study (Project 1) we validated a non-invasive method to measure stress and immune biomarkers in sweat in normal controls and have applied this method to measure stress and immune biomarkers in women with MDD mostly in clinical remission. In Project 2 we are studying the effects of progesterone on innate inflammatory cell (dendritic cells) responses, to determine whether progesterone and its receptor (PR) contribute to female susceptibility to such disorders. In Project 3 we are employing bacterial toxin repression of the GR and other nuclear hormone receptors (NHRs) as a model for studying environmentally induced glucocorticoid resistance. In Project 1 we used highly sensitive recycling immunoaffinity chromatography combined with mass spectrometry and MALDI-TOF to measure immune and stress biomarkers in skin sweat patches. Our findings published in Biol. Psychiatry (8) and Arch. Internal Medicine (9) indicate that women with MDD show significant elevations of pro-inflammatory cytokines and concurrent changes in stress neuropeptide biomarkers in sweat and plasma (8). The parasympathetic neuropeptide vasoactive intestinal polypeptide was decreased, while the sympathetic neuropeptide neuropeptide Y and pain neuropeptides CGRP and substance P were increased. This pattern of biomarkers indicates a shift from a parasympathetic relaxation response to an adrenergic stress response in women with MDD mostly in remission. The levels of biomarkers correlated with depression and anxiety scores (measured by Hamilton depression and anxiety scales, HAM-D and HAM-A), indicating that symptom severity is associated with dysregulation of these biomarkers, even during clinical remission. The pro-inflammatory cytokine elevation could account for increased morbidity of inflammation-related illnesses in MDD, including osteoporosis, diabetes and cardiovascular disease (8, 9). The highly correlated levels of biomarkers in sweat and plasma (8) indicate that this non-invasive, unobtrusive method for measuring a battery of biomarkers may be useful for a wide range of clinical studies and diagnostic assessments in future, where blood collection is contraindicated. Current directions focus on developing private public partnerships through the NIH Office of Private Public Parterships (NIH OD) to improve and further develop this method for wider use. Current studies are applying this method to other clinical populations, including patients with obsessive compulsive disorder, healthy office workers, cancer survivors practicing Tai Chi, and chronic fatigue syndrome patients. Project 2 addresses hormonal mechanisms contributing to enhanced female sensitivity to autoimmune/inflammatory conditions, which could also impact enhanced female sensitivity to mood disorders. This project evaluates the effects of progesterone on dendritic cell (DC) function and maturation in order to understand the role of these female sex hormones in host defense (2-7,13). We found that progesterone in non-pregnancy-associated concentrations and through a progesterone receptor (PR)-mediated mechanism suppresses mature DC production of pro-inflammatory cytokines, cell surface marker expression (co-stimulatory molecules and chemokine receptors) and stimulation of T cell proliferation, but has little effect on immature DC antigen uptake (3). These effects, which are comparable to those of glucocorticoids on DC function (4), indicate that progesterone plays an important role in regulation of innate and adaptive immunity in females (2). We also found that progesterone effects on DC function vary between males and females and are dependent on PR expression, which also differs in males and females (2). This finding has important implications for differential clinical susceptibility to infection and inflammation in males and females. Such physiological fluctuations in hormone status could impact cellular responses that could play a role in mood. Since cytokines are known to affect mood, and may play a role in some forms of depression as well as in mood alterations in sickness behavior, factors such as progesterone, which alter cytokine production, could hypothetically contribute to differential mood disorder susceptibilities in females throughout the life cycle. Current studies focus on determining whether these in vitro findings occur in vivo, and whether progesterone differentially affects DCs from lymphoid organs compared to DCs from organs with known progesterone sensitivity. These studies will shed light on tissue specific hormone effects that vary with the life cycle in women and could eventually inform the association of such autoimmune/inflammatory disorders with other conditions with a female preponderance, such as depression. In Project 3, we have found that Bacillus Anthracis lethal toxin (B. Anthracis LeTx) is a potent and selective repressor of NHRs, including GR and PR. These findings coupled with the findings in Project 2, could have implications for female susceptibility to the deleterious effect of these toxins at different times in the cycle, since PR is differentially expressed throughout the cycle. Further studies aim to identify the specificity and physiological significance of bacterial toxin repression of these receptors. Our previous molecular studies indicate that bacterial toxin repression of NHRs is both receptor and promoter dependent, with LeTx showing a greater repression of complex promoters compared to a simple glucocorticoid response element or GRE promoter. Our most recent studies suggest that the promoter-dependent repression of LeTx is associated with repression of other transcription factors by this toxin. We have also shown that the NHR repressive effect extends to other bacterial toxins, including Clostridium sordellii lethal toxin (TcsL) and Clostridium difficile Toxins A and B (TcdA and TcdB) (14). As with LeTx, this effect is highly sensitive (ng/ml) and non-competitive. In vitro studies show that TcsL prevents dexamethasone suppression of tumor necrosis factor (TNF)-alpha production by splenocytes in a dose-related manner, indicating that the GR repressive effect of TcsL may have functional relevance for preventing glucocorticoids' anti-inflammatory effects. Current studies aim to determine whether these toxins' in vitro effects of GR repression are relevant to their in vivo effects, and test potential therapeutic agents in vitro and in vivo. In parallel human tissue studies we are evaluating the prevalence in various clinical populations of glucocorticoid receptor polymorphisms associated with glucocorticoid resistance or sensitivity. Taken together these three lines of study shed light on mechanisms of inflammation and cytokine production that could contribute to mood and affective disorders such as MDD. These translational studies in humans and animals, at cellular and molecular levels are providing sensitive and powerful tools to measure stress and immune biomarkers to predict susceptibility of MDD patients to medical inflammatory-related illnesses such as osteoporosis, diabetes and cardiovascular disease. Understanding the role of female sex hormones in inflammation will also shed light on reasons for enhanced susceptibility of women to such illnesses.