MOLECULAR REGULATION OF INTERLEUKIN 12 GENE EXPRESSION

点击翻译按钮获取中文摘要

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.