Tumor-mediated impairment of IL-12 gene expression

肿瘤介导的 IL-12 基因表达损伤

• 批准号: 7036875
• 负责人: MARTA TORROELLA-KOURI
• 金额: $ 12.56万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036875
• 关键词: cytokine; gene expression; macrophage; neoplasm /cancer

DESCRIPTION (provided by applicant): Tumors invoke immunosuppression in the host by inducing an altered profile of cytokine expression. The crucial regulatory cytokine IL-12 operates as a bridge between innate and adaptive immunities. It is produced by macrophages and dendritic cells, and acts upon NK and T cells to induce their production of IFN-gamma, driving T cells to develop Th1 responses. IL-12 has also been recognized to exhibit strong anti-tumor properties. Therefore, by blocking IL-12 expression, the tumor might guarantee its own survival. The possibility of a tumor-induced downregulation of IL-12 gene expression as a tumor survival strategy has been scarcely explored. The long-term goal of my research is to clarify the role of macrophages in mammary tumor development. We have shown that the mouse mammary tumor D1-DMBA-3 directly produces factors, and induces B cells and macrophages from the host to produce factors that inhibit the production of IL-12 by peritoneal elicited macrophages from tumor-bearing animals. I hypothesize that these tumor-associated factors, in particular the tumor-produced phospholipids phosphatidylserine (PS) and the tumor-induced pro-inflammatory cytokine IL-6, exert their immunosuppressive effects at least in part by downregulating IL-12 gene expression at the transcriptional level in macrophages, resulting in evasion of the host's immune defenses and enhanced tumor growth. The objective of the present application is to reveal the molecular mechanisms of the D1-DMBA-3 tumor-mediated inhibition of IL-12 gene expression in macrophages from tumor-bearing animals. I plan to test my hypothesis by pursuing the following specific aims: 1) To elucidate the mechanisms by which the presence of the D1-DMBA-3 tumor, and specifically the tumor-derived factor phosphatidylserine (PS) and the tumor-induced cytokine IL-6, downregulate the production of IL-12 in macrophages from tumor-bearing animals as well as in macrophages from normal mice pretreated with these tumor-associated factors, respectively; 2) To investigate the consequences of manipulating the expression of the critical IL-12-inducing transcription factors NFkB and C/EBP on IL-12 expression in macrophages from normal and tumor-bearing animals, as well as in macrophages from normal mice pretreated with PS and IL-6; 3) To determine the effects of modulating PS and IL-6 in vivo on IL-12 production and mammary tumor progression. These studies constitute a first step towards the goal of manipulating the levels of IL-12 in tumor hosts, leading to appropriate immune activation.

描述（由申请人提供）：肿瘤通过诱导细胞因子表达谱的改变而引起宿主的免疫抑制。关键的调节细胞因子IL-12作为先天免疫和适应性免疫之间的桥梁。它由巨噬细胞和树突状细胞产生，作用于NK细胞和T细胞，诱导它们产生IFN-γ，驱动T细胞产生Th 1应答。IL-12也被认为表现出强的抗肿瘤特性。因此，通过阻断IL-12的表达，肿瘤可以保证自身的存活。肿瘤诱导的IL-12基因表达下调作为肿瘤生存策略的可能性几乎没有探索。我研究的长期目标是阐明巨噬细胞在乳腺肿瘤发展中的作用。我们已经表明，小鼠乳腺肿瘤D1-DMBA-3直接产生因子，并诱导宿主的B细胞和巨噬细胞产生抑制荷瘤动物腹腔诱导的巨噬细胞产生IL-12的因子。我推测，这些肿瘤相关因子，特别是肿瘤产生的磷脂磷脂酰丝氨酸（PS）和肿瘤诱导的促炎细胞因子IL-6，发挥其免疫抑制作用，至少部分通过下调IL-12基因表达在转录水平在巨噬细胞，导致逃避宿主的免疫防御和增强肿瘤生长。本申请的目的是揭示D1-DMBA-3肿瘤介导的抑制荷瘤动物巨噬细胞中IL-12基因表达的分子机制。我计划通过追求以下具体目标来检验我的假设：1）为了阐明D1-DMBA-3肿瘤的存在，特别是肿瘤衍生因子磷脂酰丝氨酸（PS）和肿瘤诱导的细胞因子IL-6的存在，下调来自荷瘤动物的巨噬细胞以及来自用这些肿瘤相关因子预处理的正常小鼠的巨噬细胞中IL-12的产生的机制，2）研究调控IL-12诱导关键转录因子NF κ B和C/EBP的表达对正常和荷瘤动物巨噬细胞以及PS和IL-6预处理的正常小鼠巨噬细胞IL-12表达的影响; 3）确定体内调节PS和IL-6对IL-12产生和乳腺肿瘤进展的影响。这些研究构成了操纵肿瘤宿主中IL-12水平的目标的第一步，从而导致适当的免疫激活。