Roles of Glycoconjugates and Redox Signaling in Tumor Biology

糖缀合物和氧化还原信号在肿瘤生物学中的作用

基本信息

批准号：
8554030
负责人：
david d roberts
金额：
$ 42.33万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/8554030
关键词：
Adverse effects Affinity Angiogenesis Inhibitors Animal Model Bacteria Binding Biological Process CD3 Antigens CD4 Positive T Lymphocytes CD44 Antigens CD44 gene Cancer Patient Cancer cell line Carbon Monoxide Cardiovascular Physiology Cardiovascular system Cell Adhesion Molecules Cell Line Cell surface Cells Cystathionine beta-Synthase Cysteine Desulfhydrase Development Diagnostic Diet Dose Enzymes Etiology Exhibits Extracellular Matrix FDA approved Family Glycoconjugates Glycolipids Glycoproteins Hemostatic function Heparan Sulfate Proteoglycan Human Hyaluronan Hydrogen Sulfide IL2RA gene Immunologic Surveillance Inflammatory Bowel Diseases Inorganic Sulfates Interleukin-2 Intestines Knockout Mice Ligands Maintenance Mediating Mediator of activation protein Metabolic Pathway Metabolism Mitogen-Activated Protein Kinases Molecular Mus Mutant Strains Mice Neoplasm Metastasis Oxidation-Reduction Pathologic Neovascularization Pathway interactions Pharmaceutical Preparations Physiological Play Polysaccharides Production Proteins Proteoglycan Relative (related person)Role Signal Transduction Signaling Molecule Splenocyte T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Therapeutic Uses Thrombospondin 1 Thrombospondins Thymus Gland Tumor Angiogenesis Tumor Biology Tumor Tissue Ulcerative Colitis Unspecified or Sulfate Ion Sulfates Wild Type Mouse angiogenesis autocrine blood pressure regulation glycosylation inhibitor/antagonist neoplastic cell neovascularization novel prevent response small molecule sulfate reducing bacteria therapeutic angiogenesis therapeutic target thymocyte tissue culture

项目摘要

Hydrogen sulfide (H2S) is an endogenous signaling molecule that may act via protein sulfhydrylation to regulate various physiological functions. H2S is also a byproduct of dietary sulfate metabolism by gut bacteria. Inflammatory bowel diseases such as ulcerative colitis are associated with an increase in the colonization of the intestine by sulfate reducing bacteria along with an increase in H2S production. Consistent with its increased production, H2S is implicated as a mediator of ulcerative colitis both in its genesis or maintenance. As T cells are well established mediators of inflammatory bowel disease, we investigated the effect of H2S exposure on T cell activation. Using primary mouse T lymphocytes (CD3+), OT-II CD4+ T cells, and the human Jurkat T cell line, we show that physiological levels of H2S potentiate TCR-induced activation. Nanomolar levels of H2S (50-500 nM) enhance T cell activation assessed by CD69 expression, interleukin-2 expression, and CD25 levels. Exposure of T cells to H2S dose-dependently enhances TCR-stimulated proliferation with a maximum at 300 nM (30% increase, p < 0.01). Furthermore, activation increases the capacity of T cells to make H2S via increased expression of cystathionine gamma-lyase and cystathionine beta-synthase. Disrupting this response by silencing these H2S producing enzymes impairs T cell activation, and proliferation and can be rescued by the addition of 300 nM H2S. Thus, H2S represents a novel autocrine immunomodulatory molecule in T cells.

硫化氢 (H2S) 是一种内源性信号分子，可通过蛋白质硫氢化作用来调节各种生理功能。 H2S 也是肠道细菌代谢膳食硫酸盐的副产品。溃疡性结肠炎等炎症性肠病与硫酸盐还原菌在肠道定植的增加以及硫化氢产生的增加有关。与其产量增加相一致，H2S 在溃疡性结肠炎的发生或维持过程中都被认为是溃疡性结肠炎的介质。由于 T 细胞是炎症性肠病的公认介质，因此我们研究了 H2S 暴露对 T 细胞激活的影响。使用原代小鼠 T 淋巴细胞 (CD3+)、OT-II CD4+ T 细胞和人 Jurkat T 细胞系，我们发现 H2S 的生理水平可增强 TCR 诱导的激活。纳摩尔水平的 H2S (50-500 nM) 增强了通过 CD69 表达、白细胞介素 2 表达和 CD25 水平评估的 T 细胞活化。 T 细胞暴露于 H2S 中会剂量依赖性地增强 TCR 刺激的增殖，最大浓度为 300 nM（增加 30%，p < 0.01）。此外，激活通过增加胱硫醚γ-裂解酶和胱硫醚β-合酶的表达增加了T细胞产生H2S的能力。通过沉默这些产生 H2S 的酶来破坏这种反应会损害 T 细胞的活化和增殖，并且可以通过添加 300 nM H2S 来挽救。因此，H2S 代表了 T 细胞中一种新型的自分泌免疫调节分子。