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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Scientist Development Award - Research & Training (K01)
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Subcommittee G - Education (NCI)
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Eckstein, David J
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Liu, Jianguo; Guan, Xiuqin; Tamura, Tomohiko et al. (2004) Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. J Biol Chem 279:55609-17
Shi, Xiaoyan; Cao, Shanjin; Mitsuhashi, Maki et al. (2004) Genome-wide analysis of molecular changes in IL-12-induced control of mammary carcinoma via IFN-gamma-independent mechanisms. J Immunol 172:4111-22
Liu, Jianguo; Xiang, Zhaoying; Ma, Xiaojing (2004) Role of IFN regulatory factor-1 and IL-12 in immunological resistance to pathogenesis of N-methyl-N-nitrosourea-induced T lymphoma. J Immunol 173:1184-93
Xiang, Zhaoying; Yang, Yaning; Ma, Xiaojing et al. (2003) Microarray expression profiling: analysis and applications. Curr Opin Drug Discov Devel 6:384-95
Liu, Jianguo; Cao, Shanjin; Herman, Lisa M et al. (2003) Differential regulation of interleukin (IL)-12 p35 and p40 gene expression and interferon (IFN)-gamma-primed IL-12 production by IFN regulatory factor 1. J Exp Med 198:1265-76
Cao, Shanjin; Liu, Jianguo; Chesi, Marta et al. (2002) Differential regulation of IL-12 and IL-10 gene expression in macrophages by the basic leucine zipper transcription factor c-Maf fibrosarcoma. J Immunol 169:5715-25
Grazia Cappiello, M; Sutterwala, F S; Trinchieri, G et al. (2001) Suppression of Il-12 transcription in macrophages following Fc gamma receptor ligation. J Immunol 166:4498-506
Ma, X (2001) TNF-alpha and IL-12: a balancing act in macrophage functioning. Microbes Infect 3:121-9
Ma, X; Montaner, L J (2000) Proinflammatory response and IL-12 expression in HIV-1 infection. J Leukoc Biol 68:383-90