Cellular Selenium Status and PGJ2 Metabolism

细胞硒状态和 PGJ2 代谢

• 批准号: 7893387
• 负责人: KUMBLE SANDEEP PRABHU
• 金额: $ 4.98万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893387
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Acquired Immunodeficiency Syndrome; Aerobic; Affect; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Arachidonic Acids; Arthritis; Atherosclerosis; Attenuated; Biochemical; Bone Marrow; C57BL/6 Mouse; Cardiovascular Diseases; Cell membrane; Cell physiology; Cells; Characteristics; Cigarette Smoker; Complement Factor B; Covalent Interaction; Data; Development; Diet; Dietary Intervention; Dinoprostone; Disease; Down-Regulation; Effector Cell; Endotoxins; Enzymes; Event; Exhibits; Family; Figs - dietary; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Glutathione; Glutathione S-Transferase; Hematopoietic; Immune System and Related Disorders; Immune response; Immunity; Individual; Inflammation; Inflammation Process; Inflammatory; Intracellular Membranes; Irrigation; Isoenzymes; Knockout Mice; Light; Link; Lipopolysaccharides; Macrophage Activation; Malignant Neoplasms; Membrane; Metabolic; Metabolism; Micronutrients; Molecular; Mus; Nuclear; Nutritional; Oxidation-Reduction; Oxidative Stress; Oxygen; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Personal Satisfaction; Phagocytes; Phosphotransferases; Physiological; Play; Process; Production; Property; Prostaglandin H2; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins I; Proteins; Reaction; Reactive Oxygen Species; Regulation; Research; Resolution; Respiratory Burst; Role; Selenium; Selenium Trace Element Nutrition; Shunt Device; Signal Pathway; Source; Stimulus; Supplementation; TNF gene; TNFRSF5 gene; Testing; Thromboxanes; Tissues; Transferase; base; cell mediated immune response; chemokine; cyclooxygenase 1; cyclooxygenase 2; cyclopentenone; cytokine; design; immune function; inhibitor/antagonist; insight; lipid mediator; macrophage; malignant breast neoplasm; member; mouse model; oxidant stress; progesterone 11-hemisuccinate-(2-iodohistamine); programs; promoter; prostaglandin R2 D-isomerase; protective effect; research study; response; selenium deficiency; selenoenzyme; selenoprotein; transcription factor

DESCRIPTION (provided by applicant): Macrophages play a central role in immunity, where a switch from initiation to resolution of inflammation is crucial for a robust and beneficial immune response. However, an imbalance in this switch culminates in prolonged inflammation that is seen in many disease states. Imbalances in the redox status of these cells could be one of the underlying crucial determinants of delayed and/or unsuccessful resolution. Selenoproteins, which contain selenium (Se), are a member of the cellular antioxidant machinery that effectively regulate the redox changes, and thus, brings in a nutritional component to immune function. Selenium-deficiency is characteristic of cigarette smokers and individuals with AIDS and breast cancer, where macrophage activation is accompanied by increased pro-inflammatory cytokines and prostaglandin (PG) E2, an oxidized arachidonic acid product of the cyclooxygenase (COX)-2 pathway. The pro- inflammatory gene expression is effected by differential modulation of the redox- sensitive transcription factor, NF-:B, and peroxisome proliferator activated receptor (PPAR)-3. Interestingly, Se-supplementation of macrophages leads to the preferential production of 15d-PGJ2 that covalently modifies the two transcription factors. The specific hypothesis to be tested is that Se-supplementation selectively modulates several enzymes associated with the arachidonic acid metabolism via the COX pathway, thereby influencing the preferential formation of anti-inflammatory 15d- PGJ2, which attenuates the expression of pro-inflammatory genes through the modulation of the NF-:B and PPAR-3. Synthesis of 15d-PGJ2, which occurs at the intracellular membrane-cytoplasmic interface, is susceptible to inactivation that potentially blunts its biologic activity. An additional complementary hypothesis to be tested is that the expression of a microsomal glutathione S-transferase (MGSTA1) is up- regulated during Se-deficiency, which is partially responsible for the metabolic inactivation of 15d-PGJ2. The hypotheses will be tested in C57BL/6 mice maintained on Se-deficient (0.01 ppm), Se-adequate (0.08 ppm), and Se-supplemented (0.4 ppm) diets as well as in the macrophages isolated from these mice in the following Specific Aims: 1) to examine the effect of cellular Se status on the regulation of PG production via the COX-1 and COX-2- dependent pathways, 2) to examine the role and regulation of microsomal PGE2 synthase and hematopoietic PGD2 synthase involved in inflammatory pathways during Se-deficiency, and 3) to elucidate the role of MGSTA1 in 15d-PGJ2 metabolism during Se deficiency. Our studies provide insight into a previously unappreciated link between cellular Se status and anti-inflammatory axis, producing increased 15d-PGJ2, by suppressing pro-inflammatory PGE2. The proposed studies will open new avenues of research where dietary interventions to counteracting NF-:B-dependent pro- inflammatory gene expression may be applied for long-term benefits and well-being of individuals suffering from HIV-AIDS, cancer, and atherosclerosis. Project Narrative: Professional phagocytes, such as macrophages, are good sources of cytokines, chemokines, enzymes, and lipid mediators and, thus, play a pivotal role not only in the onset of inflammation, but also in the resolution process. However, it is unclear as to what reprograms the macrophage to switch from pro-inflammatory gene expression networks to anti-inflammatory programs. Based on the preliminary data, we believe that cellular antioxidant status may play an important role in such reprogramming events. The primary objective of this project is to investigate the underlying molecular mechanism of the anti-inflammatory effects of selenium, a micronutrient and antioxidant, in primary macrophages. The proposed studies will delineate a selenium-dependent switch in arachidonic acid metabolism from pro-inflammatory prostaglandin (PG) E2 to an anti-inflammatory 15-deoxy-12,14-PGJ2 (15d-PGJ2) that effects the resolution process of inflammation. Studies proposed here will also unravel the anti-inflammatory mechanism of action of selenium, particularly on the suppression of IKK2/NF-:B- dependent inactivation of pro-inflammatory gene expression via a unique mechanism involving 15d-PGJ2.

描述(由申请人提供)：巨噬细胞在免疫中发挥核心作用，其中从启动炎症到消退炎症的转换对于强大和有益的免疫反应至关重要。然而，这种转换的不平衡会导致在许多疾病状态下出现的长期炎症。这些细胞氧化还原状态的不平衡可能是延迟和/或不成功解决的根本关键决定因素之一。硒蛋白含有硒，是细胞抗氧化机制中的一员，有效地调节氧化还原变化，从而为免疫功能带来一种营养成分。吸烟者以及艾滋病和乳腺癌患者的特征是缺硒，巨噬细胞的激活伴随着促炎细胞因子和前列腺素(PG)E2的增加，前列腺素(PG)E2是环氧合酶(COX)-2途径的氧化花生四烯酸产物。促炎症基因的表达受氧化还原敏感的转录因子、核因子-B和过氧化物酶体增殖物激活受体(PPAR)-3的差异调控。有趣的是，巨噬细胞的补硒导致15d-PGJ2的优先产生，15d-PGJ2共价修饰这两个转录因子。需要检验的特定假设是，补硒通过COX途径选择性地调节与花生四烯酸代谢相关的几种酶，从而影响抗炎15d-PGJ2的优先形成，而15d-PGJ2通过调节NF-：B和PPAR-3来减弱促炎基因的表达。15d-PGJ2的合成发生在细胞内膜-细胞质界面，很容易失活，这可能会削弱其生物活性。另一个有待检验的补充假说是，微粒体谷胱甘肽S转移酶(MGSTA1)在缺硒期间表达上调，这是15d-PGJ2代谢失活的部分原因。这些假说将在低硒(0.01ppm)、适硒(0.08ppm)和补硒(0.4ppm)饲料维持的C57BL/6小鼠以及从这些小鼠分离的巨噬细胞中进行验证，目的如下：1)研究细胞Se状态对通过依赖COX-1和COX-2的途径调节PG产生的影响；2)研究微粒体PGE2合成酶和造血细胞PGD2合成酶在缺硒期间炎症途径中的作用和调节；3)阐明MGSTA1在缺硒期间15d-PGJ2代谢中的作用。我们的研究提供了对细胞硒状态和抗炎轴之间以前不为人知的联系的洞察，通过抑制促炎PGE2产生增加的15d-PGJ2。拟议的研究将开辟新的研究途径，在这些研究中，通过饮食干预来对抗依赖于核因子：B的促炎基因表达可能会应用于HIV-AIDS、癌症和动脉粥样硬化患者的长期利益和福祉。 项目简介：专业吞噬细胞，如巨噬细胞，是细胞因子、趋化因子、酶和脂质介质的良好来源，因此，不仅在炎症的发生中发挥关键作用，而且在消退过程中也发挥关键作用。然而，目前还不清楚是什么重新编程了巨噬细胞，使其从促炎基因表达网络切换到抗炎程序。根据初步数据，我们认为细胞抗氧化状态可能在这种重新编程事件中发挥重要作用。本项目的主要目的是研究微量营养素和抗氧化剂硒在原代巨噬细胞中抗炎作用的潜在分子机制。拟议的研究将描绘花生四烯酸代谢中的一个硒依赖的开关，从促炎症的前列腺素(PG)E2转变为抗炎的15-脱氧-12，14-前列腺素J2(15d-PGJ2)，影响炎症的消退过程。本文提出的研究还将揭示硒的抗炎作用机制，特别是通过涉及15d-PGJ2的独特机制抑制IKK2/NF-B依赖的促炎基因表达的失活。