Consequences of Chemokine-Receptor Interactions: Immune

趋化因子-受体相互作用的后果：免疫

• 批准号: 6762184
• 负责人: JOOST J OPPENHEIM
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/6762184
• 关键词: SCID mouse; angiogenesis; biological products; cathepsin G; cell differentiation; cell growth regulation; chemoattractants; chemokine; chenodeoxycholate; cytokine receptors; defensins; deoxycholate; endogenous opioid; gene expression; immunogenetics; immunomodulators; immunopharmacology; immunoregulation; intermolecular interaction; leukocyte activation /transformation; neoplastic process; protein structure function; tissue /cell culture; vascular endothelium

We have further pursued our studies showing that antimicrobial peptides involved in innate host defense also interact with receptors on host inflammatory cells resulting in adaptive immune responses. Human granulocyte derived -defensins are chemotactic for resting naive T cells and immature dendritic cells. The physiological relevance of these findings were documented by showing that the -defensins when coadministered in a vaccine act as potent immunoadjuvant that enhance the humoral as well as cellular immune response even to relatively weak idiotypic tumor antigens from a B cell lymphoma. In collaboration with NCI biophysicists led by Dr. Jacek Lubkowski, the epithelial cell derived -defensins which are chemotactic for immature dendritic cells and resting memory cells that express the CCR6 receptor for "LARC", were shown to have a tertiary structure resembling that of chemokines. Drs. De Yang and Oleg Chertov in our laboratory extended these findings to show that cathelicidin (LL37) another antimicrobial product of both neutrophils and epithelial cells can also mobilize leukocytes engaged in host defense by interacting with the FPRL-1 receptor. Furthermore the expression of classical chemoattractant receptors such as C5a, FPR and FPRL-1 on immature and mature dendritic cells has been demonstrated to further understand their role in the processing and delivery of antigen to T cells to help initiate immune responses. Dr. Oleg Chertov has identified cathepsin G released by neutrophils in the course of degranulation as a chemoattractant of phagocytes and as a vaccine immunoadjuvant if administered together with antigens. We have studied of the role of chemokines in angiogenesis and their contribution to tumor progression. Dr. Rosalba Salcedo showed that human microvascular endothelial cells (HMVEC) express more functional chemokines receptors than the less mature human umbilical vein endothelial cells (HUVEC). This enabled her to show that HMVEC express functional CCR2 and CCR3 as well as CXCR1-3 and react to chemokine ligands such as MCP-1 and Eotaxin. These ligands also have in vivo angiogenic activities in a matrigel plug assay. We previously reported that prior exposure to opiates such as endorphins and morphine by interacting with m,d and k opioid (GPCR) receptors can heterologously desensitize and phosphorylate a number of chemokine receptors, making them temporarily unresponsive to these chemokines. In collaboration with Dr. Tom Rogers we can show that this is a bidirectional process. Prior exposure to a number of chemokines results in the desensitization and phosphoylation of the opioid mu receptor. This may provide another mechanisms by which the pair signals from inflammatory sites are accentuated by suppression of the opioid signals. Analyses of components in Chinese herbal medicines and extracts of plants with purported anti-inflammatory properties available in the National Product Repository of the NCI have led us to identify a number of molecular entities that inhibit the chemotactic activities of a number of proinflammatory chemokines. Chenodeoxycholic acid (CDCA) to a lesser degree deoxyoxycholic acid (CDA) at nontoxic concentrations selectively inhibit ligands interacting with FPR and FPRL-1. However, these agents are also known to interact with nuclear receptors and therefore suppress cytokine production and immune responses. These agents consequently also have anti-angiogenic effects and we are investigating their effects on in vivo tumor growth in SCID mice. In collaboration with Dr. M. Cushman at Indiana University we have shown that cosalane compounds interfere with RANTES capacity to interact with CCR1 receptors. These compounds also have anti-angiogenic effects and are being tested on human tumor models in SCID mice. Another component in Chinese anti-inflammatory medicinals known as shikonin was found to selectively interfere with CCR1-ligand interactions. However, it also blocks the chemotactic effect of all chemokines by interfering with GPCR initiated signal transduction. We are at present studying the mechanism of action of this potentially potent anti-inflammatory and anti angiogenic agent.

我们进一步追求研究表明，涉及先天宿主防御的抗菌肽也与宿主炎症细胞上的受体相互作用，从而产生适应性免疫反应。人类粒细胞衍生的-Defensin是静止的幼稚T细胞和未成熟的树突状细胞的趋化性。这些发现的生理相关性是通过证明-Defensin在疫苗中共同采用的 - 二防御素作为有效的免疫辅助作用，从而增强了体液和细胞免疫反应，即使是对来自B细胞淋巴瘤的相对较弱的对二色型肿瘤抗原的反应也是如此。与由Jacek Lubkowski博士领导的NCI生物物理学家合作，源自未成熟的树突状细胞和静息记忆细胞的上皮细胞衍生的 - 二防御素，表达了“ LARC”的CCR6受体的静止记忆细胞，被证明具有第三级结构。博士。我们实验室中的de Yang和Oleg Chertov扩展了这些发现，以表明cathelicidin（LL37）的中性粒细胞和上皮细胞的另一种抗菌产物也可以动员白细胞通过与FPRL-1受体相互作用而参与宿主防御的白细胞。此外，已经证明，经典的趋化受体在未成熟和成熟的树突状细胞上的表达，例如C5A，FPR和FPRL-1，进一步了解了它们在抗原向T细胞的加工和递送中的作用，以帮助引发免疫反应。 Oleg Chertov博士在脱脂过程中确定了由中性粒细胞释放为吞噬细胞的化学吸收剂，如果与抗原一起施用，则鉴定为吞噬细胞的化学吸引力。 我们研究了趋化因子在血管生成中的作用及其对肿瘤进展的贡献。 Rosalba Salcedo博士表明，人类微血管内皮细胞（HMVEC）比不太成熟的人脐静脉内皮细胞（HUVEC）表达更多功能性趋化因子受体。这使她能够表明HMVEC表达功能性CCR2和CCR3以及CXCR1-3，并对MCP-1和Eotaxin等趋化因子配体反应。这些配体在母质塞测定法中还具有体内血管生成活性。 我们先前曾报道过，通过与M，D和K Opioid（GPCR）受体相互作用，事先暴露于鸦片类药物，例如内啡肽和吗啡，可以异源脱敏并磷酸化许多趋化因子受体，从而使它们暂时对这些趋化因子无反应。与汤姆·罗杰斯（Tom Rogers）博士合作，我们可以证明这是一个双向过程。事先暴露于多种趋化因子会导致阿片类MU受体的脱敏和磷酸化。这可能提供了另一种机制，通过抑制阿片类药物信号，对炎症部位的一对信号可以通过这些机制来强调。 在NCI国家产品存储库中提供的具有抗炎特性的植物中的植物中的成分和提取物的分析使我们确定了许多抑制多种促炎性趋化因子的趋化活性的分子实体。在无毒浓度下，氯氧化胆酸（CDCA）选择性地抑制与FPR和FPRL-1相互作用的配体。但是，这些药物也已知与核受体相互作用，因此抑制了细胞因子的产生和免疫反应。因此，这些药物也具有抗血管生成作用，我们正在研究它们对SCID小鼠体内肿瘤生长的影响。 与印第安纳大学的M. Cushman博士合作，我们已经表明，Cosalane化合物会干扰与CCR1受体互动的能力。这些化合物还具有抗血管生成作用，并正在SCID小鼠的人类肿瘤模型上进行测试。发现中国抗炎药中的另一个成分被称为湿kon蛋白，可有选择地干扰CCR1-配合的相互作用。但是，它还通过干扰GPCR引发的信号转导，阻断了所有趋化因子的趋化作用。目前，我们正在研究这种潜在有效的抗炎和抗血管生成剂的作用机理。