Tumor-mediated impairment of IL-12 gene expression

肿瘤介导的 IL-12 基因表达损伤

• 批准号: 7882528
• 负责人: MARTA TORROELLA-KOURI
• 金额: $ 15.39万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882528
• 关键词: Accounting; Address; Animals; Antigen Presentation; Automobile Driving; B-Lymphocytes; Bacterial Infections; Breast Adenocarcinoma; CCAAT-Enhancer-Binding Proteins; Data; Dendritic Cells; Depressed mood; Development; Dominant-Negative Mutation; Down-Regulation; Exhibits; Experimental Neoplasms; Figs - dietary; Gene Expression; Genes; Genetic Transcription; Goals; Immune; Immune response; Immunosuppression; Impairment; Inflammatory; Interferon Type II; Interleukin-12; Interleukin-12 Gene; Interleukin-6; Investigation; Malignant Neoplasms; Mammary Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Mus; Peritoneal; Phosphatidylserines; Phospholipids; Physiological; Prevention; Production; Property; Proteins; Research; Role; T-Lymphocyte; Testing; Therapeutic; Tumor Immunity; Tumor-Derived; adaptive immunity; base; cytokine; immune activation; in vivo; interleukin-12 subunit p40; mRNA Stability; macrophage; overexpression; reconstitution; research study; response; transcription factor; tumor; tumor growth; tumor progression

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的变化而在宿主中调用免疫抑制。至关重要的调节细胞因子IL-12是先天和适应性免疫之间的桥梁。它是由巨噬细胞和树突状细胞产生的，并作用于NK和T细胞以诱导其产生IFN-GAMMA，驱动T细胞发展Th1反应。 IL-12也已被认为具有强大的抗肿瘤特性。因此，通过阻止IL-12表达，肿瘤可以保证其自身的生存。几乎无法探索肿瘤诱导的IL-12基因表达下调作为肿瘤存活策略的可能性。我的研究的长期目标是阐明巨噬细胞在乳腺肿瘤发育中的作用。我们已经表明，小鼠乳腺肿瘤D1-DMBA-3直接产生因素，并诱导宿主的B细胞和巨噬细胞产生因腹膜抑制IL-12产生的因素，从腹膜抑制肿瘤动物的巨噬细胞。我假设这些与肿瘤相关的因素，尤其是肿瘤产生的磷脂磷脂酶（PS）（PS）和肿瘤诱导的促炎性细胞因子IL-6，至少在下调IL-12的传染性范围内，至少在降低了IL-12的传统水平，从而在MAIR型膜片中降低了示例性的示例性，从而在MAIR-12中施加了免疫抑制作用。 生长。本应用的目的是揭示D1-DMBA-3肿瘤介导的分子机制在巨噬细胞中抑制IL-12基因表达的抑制。我计划通过追求以下特定目的来检验我的假设：1）阐明D1-DMBA-3肿瘤的存在的机制，特别是肿瘤衍生的因子磷脂酰胺丝氨酸（PS）的机制，肿瘤诱导的细胞因子IL-6伴随着含量的动物在含量中的生产，从而使IL-12的生产中的含量良好，从而使IL-12的产生，从而在较低的动物中产生，从而在tamor-12中降低了毛囊的产生这些与肿瘤相关的因素分别； 2）调查操纵临界IL-12诱导转录因子的表达的后果NFKB和C/EBP对正常和肿瘤动物的巨噬细胞中IL-12表达的表达，以及在用PS和IL-6预处理的正常小鼠的巨噬细胞中。 3）确定调节体内PS和IL-6对IL-12产生和乳腺肿瘤进展的影响。这些研究构成了朝着操纵肿瘤宿主中IL-12水平的目标的第一步，从而导致适当的免疫激活。

项目成果

Blood monocytes from mammary tumor-bearing mice: Early targets of tumor-induced immune suppression?

• DOI: 10.3892/ijo_00000740
• 发表时间: 2010-10-01
• 期刊: INTERNATIONAL JOURNAL OF ONCOLOGY
• 影响因子: 5.2
• 作者: Caso, Raul;Silvera, Risset;Torroella-Kouri, Marta
• 通讯作者: Torroella-Kouri, Marta

Tumor microenvironment profoundly modifies functional status of macrophages: peritoneal and tumor-associated macrophages are two very different subpopulations.

• DOI: 10.1016/j.cellimm.2013.06.008
• 发表时间: 2013-05
• 期刊: Cellular immunology
• 影响因子: 4.3
• 作者: Rodríguez D;Silvera R;Carrio R;Nadji M;Caso R;Rodríguez G;Iragavarapu-Charyulu V;Torroella-Kouri M
• 通讯作者: Torroella-Kouri M

Role of the proteasome in the downregulation of transcription factors NFkappaB and C/EBP in macrophages from tumor hosts.

蛋白酶体在肿瘤宿主巨噬细胞转录因子 NFkappaB 和 C/EBP 下调中的作用。

• 发表时间: 2010
• 期刊: Oncology reports
• 影响因子: 4.2
• 作者: Perry,Giselle;Iragavarapu-Charyulu,Viyaya;Harhaj,EdwardW;Torroella-Kouri,Marta
• 通讯作者: Torroella-Kouri,Marta