Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

点击翻译按钮获取中文摘要

PROJECT I. Sweat Patch Biomarkers: Clinical Studies. In FY 2009, we showed that neural and immune biomarkers are detectable in sweat and strongly correlate with plasma levels in a group of women with major depressive disorder (MDD) in clinical remission (5). Specifically, pro-inflammatory cytokines were elevated, as was the sympathetic neuropeptide neuropeptide Y (NPY) and the sensory/pain-related neuropeptides, substance P (SP) and CGRP (calcitonin gene-related peptide), while the parasympathetic neuropeptide vasoactive intestinal polypeptide (VIP) was significantly decreased. This pattern is consistent with a shift in MDD from parasympathetic to sympathetic tone, and an underlying pro-inflammatory state that could account for enhanced susceptibility to conditions known to be co-morbidly expressed with MDD, including cardiovascular disease, osteoporosis and diabetes. Moreover, biomarker levels strongly correlated with symptoms of depression and anxiety, indicating functional significance of these biomarker profiles. In order to determine the extent to which particular biomarker profiles reflect specific diseases or a state of health, in FY09 we are applying sweat patch biomarkers in five ongoing IRB approved clinical protocols in collaboration with other NIH institutes and extramural insitutions, including: (i) Emory University TRD-Infliximab Study. (Emory University IRB 00011734, NIMH OHSR Exemption #4025); (ii) Brazil - OCD Study (NIH protocol IRB 3737); (iii) Emory/CDC CFS Study (Emory University IRB 000551-2005, NIMH OHSR Exemption #4026); (iv) NCCAM - Tai Chi/Cancer Survivor Study (NCI protocol #06-AT-0016); (v) GSA - Work Environment Study (NIA IRB 2003-142). Project II Summary: Animal Models of Glucocorticoid Resistance, Inflammation and Behavior: In our studies evaluating the effects of progesterone on immune cell (dendritic cell, DC) function and maturation and the role of female sex hormones in host defense, 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 (2-4). These effects, which are comparable to those of glucocorticoids on DC function, indicate that progesterone plays an important role in regulation of innate and adaptive immunity in females. In FY09 we found that progesterone effects on DC function vary throughout the rodent estrus cycle and are dependent on PR expression, which varies throughout the cycle in vitro and in vivo, and also differentially affects DCs from different tissues. This indicates that females immune responses vary physiologically throughout the estrus cycle, and has important implications for clinical susceptibility to infection and inflammation during the cycle and during pregnancy. Such physiological fluctuations in hormone status could also impact cellular responses that 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 by cells could contribute to differential mood disorder susceptibilities in females throughout the life cycle. In our bacterial toxin studies we identified bacterial toxins that through inactivation of the MAPK (mitogen-activated protein kinase), pathways, induce partial repression of nuclear hormone receptors (NHRs), including GR and PR (8). These toxins include Bacillus anthracis lethal toxin (LeTx), Clostridium sordellii lethal toxin (TcsL) and the C. difficile toxins, toxin A (TcdA) and B (TcdB). Our studies in FY09 indicate that bacterial toxin NHR repression is both receptor and promoter-dependent and is associated with the repression of other transcription factors (6). Preliminary evidence suggests that the toxins' effects are mediated through post-translational modifications to GR. These toxins could provide a tool to study the effects of induced glucocorticoid resistance on a variety of physiological systems.