MOLECULAR REGULATION OF INTERLEUKIN 12 GENE EXPRESSION

白细胞介素-12是一种关键的细胞因子，代表了细胞因子之间的联系。 有效宿主免疫防御的细胞和体液分支 设备.它是诱导T细胞依赖性和 巨噬细胞的独立激活，T辅助1型的产生， 细胞毒性T细胞，对细菌和寄生虫感染的抗性，以及 消除肿瘤。IL-12是由两个亚基组成的异源二聚体， p40和p35在不同的人类染色体上编码。的 这两个基因的表达高度协调，形成 在有效的免疫应答过程中具有生物活性的IL-12。然而，在这方面， 在某些病理条件下，IL-12失调，导致 要么是缺乏对微生物感染的抵抗力， 肿瘤生长或破坏性炎症。我们假设 IL-12产生的短暂或不可逆的失调反映了 病原体/肿瘤细胞诱导的高度协调的 p40和p35基因的表达。本建议旨在：（1） 识别和表征激活转录因子的转录因子， 激活IL-12 p40基因表达的因子 病原刺激;（2）研究致病的分子机制 IL-12 p40基因表达对致病性刺激的响应;（2） 探讨IL-12 p40基因在T细胞中表达的分子机制， B和单核细胞的抑制作用;（3）分析抑制的分子基础 IL-12基因的表达。的理解 调控IL-12 p40表达的分子机制， p35基因在病原体与宿主细胞相互作用中的作用 免疫系统将大大有利于我们的努力， 治疗传染病和恶性疾病的治疗策略。

Interleukin-12 is a pivotal cytokine representing the link between the cellular and humoral branches of an effective host immune defense apparatus. It is a key factor in the induction of T-cell dependent and independent activation of macrophages, generation of T helped type 1 and cytotoxic T cells, resistance to bacterial and parasitic infections, and elimination of tumors. IL-12 is a heterodimer consisted to two subunits, p40 and p35 that are encoded on different human chromosomes. The expression of these two genes are highly coordinated to form the biologically active IL-12 during an effective immune response. However, under some pathological conditions IL-12 is dysregulated, resulting either in a lack of resistance to microbial infection and uncontrolled tumor growth, or in destructive inflammation. We hypothesize that a transient or irreversible dysregulation of IL-12 production reflects a pathogen/tumor cell-induced disruption in the highly coordinated expression of p40 and p35 genes. This proposal is aimed at: (1) identifying and characterizing the transcription factors which activate factors which activate IL-12 p40 gene expression in response to pathogenic stimulation; (2) investigating the molecular mechanisms of IL-12 p40 gene expression in response to pathogenic stimulation; (2) investigating the molecular mechanism of IL-12 p40 gene expression in T, B and monocytic cells; (3) analyzing the molecular basis of inhibition of IL-12 gene expression by immunosuppressive agents. The understanding of the molecular mechanisms governing the expression of IL-12 p40 and p35 genes in the context of interactions between pathogens and the immune system will benefit significantly our efforts in designing therapeutic strategies to treat infectious and malignant diseases.