Role of Neuroendocrine Stress Response in Inflammatory and Behavioral Illness.

神经内分泌应激反应在炎症和行为疾病中的作用。

• 批准号: 7735120
• 负责人: ESTHER M. STERNBERG
• 金额: $ 197.98万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7735120
• 关键词: Accounting; Address; Adrenergic Agents; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Anxiety; Autoimmune Diseases; Autoimmune Process; Bacterial Toxins; Behavior; Behavioral; Biological Markers; Blood; CALCA gene; Calcitonin Gene-Related Peptide; Cancer Survivor; Cardiovascular Diseases; Cell physiology; Cell surface; Cells; Chronic Fatigue Syndrome; Clinical; Clinical Research; Clostridium difficile tcdA protein; Clostridium sordellii lethal toxin LT; Collection; Complex; Condition; Coupled; Dendritic Cells; Dexamethasone; Diabetes Mellitus; Diagnostic; Disease; Disease remission; Dose; Elevation; Exhibits; Feedback; Female; Future; Genetic Polymorphism; Glucocorticoid Receptor; Glucocorticoids; Goals; Gonadal Steroid Hormones; Hamilton Rating Scale for Depression; Hormonal; Hormones; Host Defense; Human; Hypersensitivity; Immune; Immune response; Immunity; Immunology; In Vitro; Infection; Inflammation; Inflammatory; Internal Medicine; Interruption; Invasive; Knowledge; Life Cycle Stages; Light; Lymphoid; MALDI-TOF Mass Spectrometry; Major Depressive Disorder; Measures; Mediating; Medical; Mental Depression; Methods; Molecular; Mood Disorders; Moods; Morbidity - disease rate; Neuropeptides; Neurosecretory Systems; Nuclear Hormone Receptors; Obsessive-Compulsive Disorder; Organ; Osteoporosis; Pain; Patients; Pattern; Physiological; Plasma; Play; Population; Predisposition; Pregnancy; Prevalence; Production; Progesterone; Progesterone Receptors; Psychiatry; Publishing; Range; Recording of previous events; Recycling; Regulation; Relaxation; Reporting; Repression; Resistance; Response Elements; Risk; Role; S100A12 gene; Score; Severities; Skin; Specificity; Splenocyte; Stress; Study models; Substance P; Sweat; Sweating; Symptoms; T-Cell Proliferation; Tai Ji; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic Shock Syndrome; Toxin; Translational Research; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Vasoactive Intestinal Peptide; Woman; Women' s Role; adrenergic; anthrax lethal factor; biological adaptation to stress; chemokine receptor; cytokine; depressive symptoms; disturbance in affect; hormone regulation; human S100A12 protein; human tissue; hypothalamic-pituitary-adrenal axis; immunoaffinity chromatography; improved; in vivo; male; men; neuropeptide Y; preclinical study; prevent; programs; promoter; receptor; receptor expression; receptor function; response; tool; transcription factor; translational study; uptake

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.

在我们的临床研究（项目 1）中，我们验证了一种非侵入性方法来测量正常对照者汗液中的压力和免疫生物标志物，并应用该方法来测量大多数处于临床缓解期的重度抑郁症女性的压力和免疫生物标志物。在项目 2 中，我们正在研究孕酮对先天炎症细胞（树突状细胞）反应的影响，以确定孕酮及其受体 (PR) 是否会导致女性对此类疾病的易感性。在项目 3 中，我们采用 GR 和其他核激素受体 (NHR) 的细菌毒素抑制作为研究环境诱导的糖皮质激素耐药性的模型。 在项目 1 中，我们使用高灵敏度的回收免疫亲和层析结合质谱和 MALDI-TOF 来测量皮肤汗斑中的免疫和压力生物标志物。我们的研究结果发表在《Biol》上。精神病学 (8) 和拱门。内科 (9) 表明，患有重度抑郁症 (MDD) 的女性的促炎细胞因子显着升高，并且汗液和血浆中应激神经肽生物标志物同时发生变化 (8)。副交感神经肽血管活性肠肽减少，而交感神经肽神经肽Y和疼痛神经肽CGRP和P物质增加。这种生物标志物模式表明，重度抑郁症女性大多处于缓解期，从副交感神经松弛反应转变为肾上腺素能应激反应。生物标志物的水平与抑郁和焦虑评分（通过汉密尔顿抑郁和焦虑量表、HAM-D和HAM-A测量）相关，表明症状严重程度与这些生物标志物的失调相关，即使在临床缓解期间也是如此。促炎细胞因子升高可能是 MDD 炎症相关疾病发病率增加的原因，包括骨质疏松症、糖尿病和心血管疾病 (8, 9)。汗液和血浆中生物标记物水平的高度相关性 (8) 表明，这种用于测量一组生物标记物的非侵入性、不显眼的方法可能对未来禁止采血的广泛临床研究和诊断评估有用。目前的方向侧重于通过 NIH 私人公共伙伴关系办公室 (NIH OD) 发展私人公共伙伴关系，以改进和进一步开发这种方法以供更广泛的使用。目前的研究正在将这种方法应用于其他临床人群，包括强迫症患者、健康的上班族、练习太极拳的癌症幸存者以及慢性疲劳综合症患者。 项目 2 涉及有助于增强女性对自身免疫/炎症性疾病敏感性的激素机制，这也可能影响增强女性对情绪障碍的敏感性。该项目评估孕酮对树突状细胞 (DC) 功能和成熟的影响，以便了解这些女性性激素在宿主防御中的作用 (2-7,13)。我们发现，非妊娠相关浓度的黄体酮通过黄体酮受体 (PR) 介导的机制抑制成熟 DC 促炎细胞因子的产生、细胞表面标志物表达（共刺激分子和趋化因子受体）和刺激 T 细胞增殖，但对未成熟 DC 抗原的摄取几乎没有影响 (3)。这些作用与糖皮质激素对 DC 功能的作用相当 (4)，表明孕酮在调节女性先天性和适应性免疫方面发挥着重要作用 (2)。 我们还发现，黄体酮对 DC 功能的影响在男性和女性之间存在差异，并且取决于 PR 表达，而 PR 表达在男性和女性中也存在差异 (2)。 这一发现对于男性和女性感染和炎症的临床易感性差异具有重要意义。激素状态的这种生理波动可能会影响细胞反应，从而影响情绪。由于已知细胞因子会影响情绪，并且可能在某些形式的抑郁症以及疾病行为的情绪改变中发挥作用，因此黄体酮等改变细胞因子产生的因素可能会导致女性在整个生命周期中不同的情绪障碍易感性。目前的研究重点是确定这些体外研究结果是否发生在体内，以及与已知黄体酮敏感性器官的 DC 相比，黄体酮是否对来自淋巴器官的 DC 产生不同的影响。这些研究将揭示随女性生命周期而变化的组织特异性激素效应，并最终可能揭示此类自身免疫/炎症性疾病与女性占优势的其他疾病（例如抑郁症）之间的关联。 在项目3中，我们发现炭疽杆菌致死毒素（B. Anthracis LeTx）是NHR（包括GR和PR）的有效选择性抑制因子。这些发现与项目 2 中的发现相结合，可能会对女性在周期的不同时间对这些毒素的有害影响的易感性产生影响，因为 PR 在整个周期中的表达存在差异。进一步的研究旨在确定细菌毒素抑制这些受体的特异性和生理意义。我们之前的分子研究表明，NHR 的细菌毒素抑制既依赖于受体又依赖于启动子，与简单的糖皮质激素反应元件或 GRE 启动子相比，LeTx 显示出对复杂启动子的更大抑制。我们最近的研究表明，LeTx 的启动子依赖性抑制与该毒素对其他转录因子的抑制有关。我们还表明，NHR 抑制作用延伸至其他细菌毒素，包括索氏梭菌致死毒素 (TcsL) 和艰难梭菌毒素 A 和 B（TcdA 和 TcdB）(14)。与 LeTx 一样，这种效应是高度敏感的（ng/ml）且非竞争性。体外研究表明，TcsL 以剂量相关的方式阻止地塞米松抑制脾细胞产生肿瘤坏死因子 (TNF)-α，这表明 TcsL 的 GR 抑制作用可能与阻止糖皮质激素的抗炎作用具有功能相关性。目前的研究旨在确定这些毒素的 GR 抑制的体外效应是否与其体内效应相关，并在体外和体内测试潜在的治疗剂。在平行的人体组织研究中，我们正在评估与糖皮质激素耐药性或敏感性相关的糖皮质激素受体多态性在各种临床人群中的患病率。 综上所述，这三方面的研究揭示了炎症和细胞因子产生的机制，这些机制可能导致情绪和抑郁症等情感障碍。这些针对人类和动物的细胞和分子水平转化研究为测量压力和免疫生物标志物提供了灵敏且强大的工具，以预测MDD患者对骨质疏松症、糖尿病和心血管疾病等炎症相关疾病的易感性。了解女性性激素在炎症中的作用也将有助于解释女性对此类疾病的易感性增加的原因。

项目成果

Lipopolysaccharide-induced oestrogen receptor regulation in the paraventricular hypothalamic nucleus of lewis and Fischer rats.

刘易斯和费舍尔大鼠室旁下丘脑核中脂多糖诱导的雌激素受体调节。

• DOI: 10.1046/j.1365-2826.2002.00841.x
• 发表时间: 2002
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: Tonelli,L;Kramer,P;Webster,JI;Wray,S;Listwak,S;Sternberg,E
• 通讯作者: Sternberg,E

Neuroendocrine responses regulating susceptibility and resistance to autoimmune/inflammatory disease in inbred rat strains.

神经内分泌反应调节近交大鼠品系对自身免疫/炎症疾病的易感性和抵抗力。

• DOI: 10.1034/j.1600-065x.2001.1840118.x
• 发表时间: 2001
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Tonelli,L;Webster,JI;Rapp,KL;Sternberg,E
• 通讯作者: Sternberg,E

Differential induction of interleukin-I beta mRNA in the brain parenchyma of Lewis and Fischer rats after peripheral injection of lipopolysaccharides.

外周注射脂多糖后，Lewis 和 Fischer 大鼠脑实质中白细胞介素 I β mRNA 的差异诱导。

• DOI: 10.1016/s0165-5728(03)00171-1
• 发表时间: 2003
• 期刊: Journal of neuroimmunology
• 影响因子: 3.3
• 作者: Tonelli,LeonardoH;Maeda,Shigeru;Rapp,KimberlyL;Sternberg,EstherM
• 通讯作者: Sternberg,EstherM

Neural immune pathways and their connection to inflammatory diseases.

神经免疫途径及其与炎症性疾病的联系。

• DOI: 10.1186/ar1002
• 发表时间: 2003
• 期刊: ARTHRITIS RESEARCH & THERAPY
• 影响因子: 4.9
• 作者: Eskandari, F;Webster, JI;Sternberg, EM
• 通讯作者: Sternberg, EM

The large clostridial toxins from Clostridium sordellii and C. difficile repress glucocorticoid receptor activity.

来自索氏梭菌和艰难梭菌的大梭菌毒素可抑制糖皮质激素受体活性。

• DOI: 10.1128/iai.00291-07
• 发表时间: 2007
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Tait,ASasha;Dalton,Monique;Geny,Blandine;D'Agnillo,Felice;Popoff,MichelR;Sternberg,EstherM
• 通讯作者: Sternberg,EstherM