Regulation of IL-12 Expression and Activity by Oncogenes

描述（申请人提供）：免疫能力是控制侵袭性肿瘤生长的最有效工具。白细胞介素-12（IL-12）是维持这种能力所必需的分子。IL-12通过其激活NK、T细胞和巨噬细胞的能力对许多鼠肿瘤以及人类癌症具有强大的抗肿瘤活性，使得肿瘤很难逃脱免疫识别和攻击。编码IL-12的两条异源链p40和p35的基因位于不同的染色体上。p40和p35共同形成具有生物活性的IL-12。p40和p35基因的高度协调表达是有效免疫应答的关键。IL-12异源二聚体的生物合成受免疫调节活性的复杂网络控制。与肿瘤发生在病因学上相关的肿瘤细胞及其产物可以深刻地影响与其相互作用的免疫系统的应答，例如，IL-12的产生及其生物活性，可能作为逃避免疫监视和/或阻止其攻击发展中的恶性肿瘤的手段。最近的证据表明，两个原癌基因，c-Fos和c-Maf是相关的碱性亮氨酸拉链转录因子，作为这一类的潜在候选者。本提案的总体目标是了解c-Fos和c-Maf如何在细胞和分子水平上与免疫系统相互作用，以发挥其对IL-12产生的有效抑制作用及其免疫调节活性，作为癌细胞逃避和延迟对其生长和扩散的不良免疫反应的内在方式。我们将：（1）研究AP-1形式的c-Fos调节巨噬细胞和树突状细胞产生IL-12的分子机制。(2)确定c-Maf介导的IL-12基因表达抑制的分子基础，其在该活性中与AP- 1的相互作用，以及其对抗原呈递细胞的基因表达和功能的整体影响。(3)在小鼠乳腺癌模型中检验AP-1抑制IL-12产生有助于肿瘤易感性的假设。这些研究将有助于阐明癌症诱导剂保护癌细胞的策略。它们还可能导致发现新的途径和识别新的靶点，以利于癌症治疗中的免疫干预。

DESCRIPTION (provided by applicant): Immune competence is the most effective tool with which to control the growth of invasive tumors. Interleukin-12 (IL-12) is a molecule essential for the maintenance of this competency. IL-12 has powerful anti-tumor activities against many murine tumors as well as human cancers through its ability to activate NK, T cells, and macrophages, making it very difficult for tumors to escape from immune recognition and attack. The genes encoding the two heterologous chains of IL-12, p40 and p35 are located on different chromosomes. Together, p40 and p35 form the biologically active IL-12. The highly coordinated expression of p40 and p35 genes is pivotal for effective immune responses. The biosynthesis of IL-12 heterodimer is controlled by a complex network of immune-modulating activities. Tumor cells and their products that are etiologically associated with tumorigenesis can profoundly influence the response of the immune system that they interact with, e.g., IL-12 production and its bioactivities, potentially as means of evading immune surveillance and or thwarting its attack on the developing malignancy. Recent evidence has implicated two proto-oncogenes, c-Fos and c-Maf that are related basic leucine zipper transcription factors, as potential candidates in this category. The overall aim of this proposal is to understand how c-Fos and c-Maf interact with the immune system at cellular and molecular levels to exert their potent inhibitory effects on IL-12 production and its immunoregulatory activities as an intrinsic way of cancer cells to escape and retard adverse immune response to their growth and spread. We will: (1) Investigate the molecular mechanism by which c-Fos in the form of AP-1 regulates the production of IL-12 in macrophages and dendritic cells. (2) Determine the molecular basis of c-Maf-mediated inhibition of IL-12 gene expression, its interaction with AP- 1 in this activity, and its global impact on gene expression and function of antigen-presenting cells. (3) Test the hypothesis that inhibition of IL-12 production by AP-1 is contributory to tumor susceptibility in a murine mammary adenocarcinoma model. These studies will shed light on the strategies of cancer-inducing agents for the protection of cancer cells. They may also lead to discovery of novel pathways and identification of new targets for the benefit of immune interventions in cancer therapy.