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.

我们进一步的研究表明，参与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，导致适应性免疫反应。人粒细胞衍生的防御素对静息的幼稚 T 细胞和未成熟的树突状细胞具有趋化作用。这些发现的生理相关性通过以下方式记录：β-防御素在疫苗中共同施用时充当有效的免疫佐剂，增强体液和细胞免疫应答，甚至针对来自B细胞淋巴瘤的相对较弱的独特型肿瘤抗原。与 Jacek Lubkowski 博士领导的 NCI 生物物理学家合作，上皮细胞衍生的 β 防御素对未成熟的树突状细胞和表达“LARC”CCR6 受体的静息记忆细胞具有趋化作用，被证明具有类似于趋化因子的三级结构。博士。我们实验室的 De Yang 和 Oleg Chertov 扩展了这些发现，表明中性粒细胞和上皮细胞的另一种抗菌产品导管素 (LL37) 也可以通过与 FPRL-1 受体相互作用来动员白细胞参与宿主防御。此外，经典趋化受体（例如 C5a、FPR 和 FPRL-1）在未成熟和成熟树突细胞上的表达已被证明可以进一步了解它们在处理和向 T 细胞递送抗原以帮助启动免疫反应中的作用。 Oleg Chertov 博士已鉴定出中性粒细胞在脱粒过程中释放的组织蛋白酶 G 作为吞噬细胞的化学引诱剂，如果与抗原一起施用，则可作为疫苗免疫佐剂。 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) 比不太成熟的人类脐静脉内皮细胞 (HUVEC) 表达更多功能性趋化因子受体。这使她能够证明 HMVEC 表达功能性 CCR2 和 CCR3 以及 CXCR1-3，并与趋化因子配体（如 MCP-1 和 Eotaxin）发生反应。这些配体在基质胶塞测定中也具有体内血管生成活性。 我们之前报道过，通过与 m、d 和 k 阿片类药物 (GPCR) 受体相互作用，预先接触内啡肽和吗啡等阿片类药物可以使许多趋化因子受体异源脱敏和磷酸化，使它们暂时对这些趋化因子无反应。通过与汤姆·罗杰斯博士的合作，我们可以证明这是一个双向过程。先前暴露于多种趋化因子会导致阿片类 mu 受体脱敏和磷酸化。这可能提供另一种机制，通过抑制阿片类信号来增强来自炎症部位的成对信号。 通过对 NCI 国家产品存储库中具有抗炎特性的中草药和植物提取物中的成分进行分析，我们发现了许多抑制多种促炎趋化因子趋化活性的分子实体。无毒浓度的鹅去氧胆酸 (CDCA) 至较低程度的脱氧胆酸 (CDA) 选择性抑制与 FPR 和 FPRL-1 相互作用的配体。然而，这些药物也已知会与核受体相互作用，从而抑制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。 我们与印第安纳大学的 M. Cushman 博士合作，证明了 cosalane 化合物会干扰 RANTES 与 CCR1 受体相互作用的能力。这些化合物还具有抗血管生成作用，并且正在 SCID 小鼠的人类肿瘤模型上进行测试。中药抗炎药物中的另一种成分紫草素被发现可以选择性地干扰 CCR1 配体相互作用。然而，它还通过干扰 GPCR 启动的信号转导来阻断所有趋化因子的趋化作用。我们目前正在研究这种潜在有效的抗炎和抗血管生成剂的作用机制。