We are analyzing the regulation of cytokine and chemokine gene expression in lymphoid cells. We have chosen IFN-gamma gene expression as a model system for analysis of the control of gene expression in T cells and NK cells. We are continuing to dissect the regions of the human IFN-g genomic DNA to determine which regions enhance/repress gene transcription in response to extracellular signals. In particular, we are utilizing NK cell lines to elucidate the mechanisms, both transcriptional and post-transcriptional, by which interleukins 2,4,12,13,15,18 or activation of LY49 activating receptors (murine models) induce or inhibit IFN-g gene expression and effect NK cell biology. We are investigating the role of STAT, NFkB and T-bet proteins in regulating IFN-g expression and how a highly conserved element in the 3' untranslated region may affect IFN-g mRNA stability. We are also characterizing the biochemical pathways involved in the synergistic induction of IFN-g gene expression in response to IL-2 + IL-12, IL-2 + IL-18 and antibodies to the LY49 activating receptors + cytokines by both microarray and proteomic approaches. In another aspect of CMIS research, we have utilized IFN-g KO mice to identify a novel NK cell population that produces IL-13 and IL-5 in response to IL-2 and IL-18. This cytokine expression profile suggests that this NK population may play a role in influencing humoral immunity. Ongoing studies are focused on characterizing the biochemical/molecular signaling pathways utilized by these cells, determining their function in vivo and defining the pathways involved in their maturation and development. In a new aspect of our work, we have been investigating the role of the peroxisome proliferator-activated receptor-gamma in regulating NK gene expression. We have observed that the natural ligand for this receptor, 15d-PGJ2 and synthetic ligands such as ciglitazone, alter NK gene expression by both receptor dependent and independant pathways.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009283-19
Application #
6950560
Study Section
(LEI)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Khabar, Khalid S A; Young, Howard A (2007) Post-transcriptional control of the interferon system. Biochimie 89:761-9
Ortaldo, John R; Young, Howard A (2006) IL-18 as critical co-stimulatory molecules in modulating the immune response of ITAM bearing lymphocytes. Semin Immunol 18:193-6
Gonsky, R; Deem, R L; Bream, J H et al. (2006) An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells. Genes Immun 7:342-51
Young, Howard A; Ortaldo, John (2006) Cytokines as critical co-stimulatory molecules in modulating the immune response of natural killer cells. Cell Res 16:20-4
Ortaldo, John R; Winkler-Pickett, Robin; Wigginton, Jon et al. (2006) Regulation of ITAM-positive receptors: role of IL-12 and IL-18. Blood 107:1468-75
Young, Howard A (2006) Unraveling the pros and cons of interferon-gamma gene regulation. Immunity 24:506-7
Rodriguez-Galan, Maria Cecilia; Bream, Jay H; Farr, Andrew et al. (2005) Synergistic effect of IL-2, IL-12, and IL-18 on thymocyte apoptosis and Th1/Th2 cytokine expression. J Immunol 174:2796-804
Ortaldo, John R; Young, Howard A (2005) Mouse Ly49 NK receptors: balancing activation and inhibition. Mol Immunol 42:445-50
Bream, Jay H; Hodge, Deborah L; Gonsky, Rivkah et al. (2004) A distal region in the interferon-gamma gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2. J Biol Chem 279:41249-57
Gamero, Ana M; Young, Howard A; Wiltrout, Robert H (2004) Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer? Cancer Cell 5:111-2

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