Regulation of IL-12 Expression and Activity by Oncogenes

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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.