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Howard A. Young, Ph.D.
Regulation of Cytokine Gene Expression
The Cellular and Molecular Immunology Section studies the control of gene expression during the development and maturation of the cellular immune system in mediating antitumor and anti-inflammatory immune responses. The general goals of this section are to use molecular approaches to: (1) investigate in detail the molecular mechanisms by which gene expression is regulated in immune effector cells; and (2) study the mechanism(s) by which tumor cell susceptibility to biological and immunological defense systems can be enhanced through the control of specific gene expression. The specific aim of the Cellular and Molecular Immunology Section is to study human and murine cell-mediated immunity, with emphasis on natural killer (NK) cell- and T cell-specific regulation of gene expression. T cells and NK cells are the two predominant cell types that express interferon-gamma (IFN-gamma), and IFN-gamma transcription occurs after stimulation of these cells with numerous exogenous stimuli, including interleukin 2 (IL-2), IL-12, IL-15, IL-18, IL-21, interferon-alpha/beta and PKC activators. We have defined regions of human IFN-gamma genomic DNA that regulate transcriptional activation of this gene in order to understand how IFN-gamma gene expression is controlled. It is our continuing goal to determine how specific extracellular signals influence the regulation of IFN-gamma gene expression.
In a new aspect of this work, we are focusing on how IFN-gamma expression may be regulated at the posttranscriptional level. We have generated a novel mouse model where a portion of the 3' untranslated region of the mRNA has been changed and this will now permit us to understand the role of this region on IFN-gamma expression. In addition we have identified a microRNA that targets the IFN-gamma gene and now have evidence that binding of the miRNA alters the secondary structure of the RNA. This binding stabilizes the IFN-gamma mRNA, resulting in increased IFN-gamma gene expression. Overall, our studies represent a molecular analysis of the regulation of cytokine gene expression in lymphoid cells and provide a basis for developing a more complete understanding of the regulation of IFN-gamma expression during the pathogenesis of cancer and infection.
We have also investigated the consequences of IL-22 receptor on lymphocytes. This receptor is normally not expressed on lymphocytes and we generated a transgenic mouse where the IL-22 receptor was expressed on T cells and B cells. These animals had circulating IL-22 in their serum and died of inflammation by 8 weeks of age. This finding prompted us to look at the role of IL-22 in Anaplastic Large Cell Lymphoma. In this lymphoma, IL-22 receptor is expressed on the lymphoma cells. We have found that serum from these patients contains IL-22 and that the appearance of IL-22 correlates with disease status. Thus we believe that IL-22 expression may be a new marker for this lymphoma.
An additional project in the lab focuses on the introduction of cytokine genes into probiotic bacteria, for the purpose of determining if intestinal inflammation or infection by gut tropic viruses can be altered by localized cytokine protein delivered by the probiotic microorganisms. This project is possible through the generous support of the NIH Office of Dietary Supplements.
Our collaborators include NCI investigators Giorgio Trinchieri, Bruce Shapiro, Stuart LeGrice, Robert Wiltrout, Frank Ruscetti, Dan McVicar, Dennis Klinman, Mary Carrington, Wyndham Wilson and David Wink. In addition we have collaborations with Dr. Stefanie Vogel, University of Maryland School of Medicine, Drs. Alan Sher, NIAID, and Drs. Rivkah Gonsky and Stephan Targan, Cedars-Sinai Medical Center, Los Angeles, CA.
This page was last updated on 2/26/2013.