Glucocorticoid/cytokine mechanisms in endotoxemia.

内毒素血症中的糖皮质激素/细胞因子机制。

基本信息

批准号：
7214680
负责人：
PAUL GUYRE
金额：
$ 37.45万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7214680
关键词：
5&apos Flanking Region Acute Acute-Phase Proteins Address Anti-Inflammatory Agents Anti-inflammatory Autoimmunity Biological Assay CD14 gene Clinical Condition Cultured Cells Cytokine Signaling Dexamethasone Disease Dominant-Negative Mutation Dose Endotoxemia Endotoxins Enzyme-Linked Immunosorbent Assay Foundations Genes Genetic Transcription Glucocorticoid Receptor Glucocorticoids Human Hydrocortisone Immune Immunoassay Immunophenotyping In Vitro Individual Inflammation Inflammatory Inflammatory Response Infusion procedures Interleukin-1 Interleukin-6 Ischemia Lead Ligand Binding Light Lipopolysaccharides Luciferases Macrophage Activation Measures Mediator of activation protein Messenger RNA Modeling Molecular Morbidity - disease rate Numbers Paper Patients Personal Satisfaction Phenotype Physiological Play Production Protein Isoforms Range Receptor Signaling Regulation Reporter Reporting Reverse Transcriptase Polymerase Chain Reaction Role Sepsis Shapes Signaling Molecule Stimulus System Testing Time Trauma Variant Western Blotting base cytokine dosage in vivo insight interest intravenous administration macrophage monocyte mortality mutant outcome forecast programs receptor response toll-like receptor 4 transcription factor vector

项目摘要

DESCRIPTION (provided by applicant): The hypothesis to be tested in this proposal is that glucocorticoids (GC) exert a biphasic effect on the control of key components of the lipopolysaccharride (LPS)-induced monocyte/ macrophage (MOMac) activation program. A model was proposed by the PI and Co-I to reconcile the stimulatory ("permissive") actions of moderate cortisol levels with the suppressive actions of high cortisol levels. This model predicts a bell-shaped curve for the effects of cortisol on inflammatory mediators that peaks at or near the upper levels of diurnal cortisol variation. As the permissive effects of GC are less well understood than the inhibitory actions, they provide the focus of our proposed studies on mediators and regulators of MOMac activation. The Specific Aims are: (1) To test the hypothesis that GC exert a biphasic influence on cytokine production and MOMac phenotype in response to LPS, and (2) To elucidate the molecular mechanisms of permissive and suppressive effects of GC on the MOMac activation program. We propose to address these questions employing both in vitro and human in vivo systems. Initially, we will use cultures of elutriated MO that will be exposed to LPS under conditions in which cortisol is maintained at levels predicted to be sub-permissive, permissive or suppressive. We will use ELISA and flow cytometric analyses to determine the interactive effects of cortisol and LPS on two key components of the MOMac activation program--IL-6 and CD163. Using LPS and cortisol at dosages and times that are first determined to result in maximal enhancement or inhibition of CD 163 and IL-6, we will examine additional cytokines, signaling molecules and receptors that have been shown to be induced or suppressed by LPS. We will also use a well-controlled paradigm of human experimental endotoxemia to elucidate the physiologic and molecular mechanisms that lead GC to either suppress or enhance the production and actions of putative pro- and anti-inflammatory molecules during the response to endotoxin in vivo. We believe that these studies will yield important insights into the mechanisms by which GC can both enhance and suppress immune and inflammatory functions, leading to more effective approaches to their use in clinical settings of inflammation.

描述（由申请人提供）：本提案中要测试的假设是糖皮质激素（GC）对脂多糖（LPS）诱导的单核细胞/巨噬细胞（MOMac）激活程序的关键成分的控制发挥双相作用。 PI 和 Co-I 提出了一个模型，以协调中等皮质醇水平的刺激（“许可”）作用与高皮质醇水平的抑制作用。该模型预测皮质醇对炎症介质的影响呈钟形曲线，该曲线在每日皮质醇变化的上限或附近达到峰值。由于 GC 的许可作用不如抑制作用更好地理解，因此它们为我们提出的 MOMac 激活调节剂和调节剂研究提供了重点。具体目标是：(1) 检验 GC 对 LPS 响应的细胞因子产生和 MOMac 表型产生双相影响的假设，以及 (2) 阐明 GC 对 MOMac 激活程序的许可和抑制作用的分子机制。我们建议采用体外和人体体内系统来解决这些问题。最初，我们将使用淘析的 MO 培养物，将其在皮质醇维持在预计亚允许、允许或抑制水平的条件下暴露于 LPS。我们将使用 ELISA 和流式细胞术分析来确定皮质醇和 LPS 对 MOMac 激活程序的两个关键组件（IL-6 和 CD163）的相互作用。使用 LPS 和皮质醇的剂量和时间首先确定可最大程度地增强或抑制 CD 163 和 IL-6，我们将检查已被证明可被 LPS 诱导或抑制的其他细胞因子、信号分子和受体。我们还将使用人类实验性内毒素血症的良好控制范例来阐明导致 GC 在体内内毒素反应期间抑制或增强假定的促炎和抗炎分子的产生和作用的生理和分子机制。我们相信，这些研究将对 GC 增强和抑制免疫和炎症功能的机制产生重要的见解，从而为其在炎症的临床环境中使用提供更有效的方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cortisol exerts bi-phasic regulation of inflammation in humans.

皮质醇对人类炎症发挥双相调节作用。

DOI：
发表时间：
2011
期刊：
影响因子：
0
作者：
Yeager, Mark P;Pioli, Patricia A;Guyre, Paul M
通讯作者：
Guyre, Paul M

In vivo exposure to high or low cortisol has biphasic effects on inflammatory response pathways of human monocytes.

体内暴露于高或低皮质醇对人类单核细胞的炎症反应途径具有双相效应。

DOI：
发表时间：
2008-11
期刊：
影响因子：
5.7
作者：
Yeager, Mark P;Pioli, Patricia A;Wardwell, Kathleen;Beach, Michael L;Martel, Peter;Lee, Hong K;Rassias, Athos J;Guyre, Paul M
通讯作者：
Guyre, Paul M

Cortisol antiinflammatory effects are maximal at postoperative plasma concentrations.

皮质醇的抗炎作用在术后血浆浓度时最大。

DOI：
发表时间：
2005-07
期刊：
影响因子：
8.8
作者：
Yeager, Mark P;Rassias, Athos J;Fillinger, Mary P;Discipio, Anthony W;Gloor, Kelly E;Gregory, Janice A;Guyre, Paul M
通讯作者：
Guyre, Paul M