We are analyzing the regulation of cytokine and chemokine gene expression in lymphoid cells. We have chosen interferon-gamma (IFN-gamma) gene expression as a model system for analysis of the control of gene expression. We are continuing to dissect the regions of the human interferon-gamma gene to determine which regions enhance/repress gene transcription in response to extracellular signals. We have used a bioinformatics approach to identify conserved regions of the 3'untranslated portion of the interferon-gamma mRNA. It is believed that these conserved regions represent important regulatory elements in the gene structure as there would be no inherent region for conservation through evolution unless the non-coding regions of the mRNA provided some evolutionary advantage. Based on this analysis, we have targeted a 160-bp region of the murine interferon-gamma 3'untranslated region for deletion, as this region is rich in AUUA sequences and such regions have been previously shown to be important in the regulation of cytokine gene expression. The knockout (KO) mouse has been successfully created and our data indicates that this mouse produces significantly more interferon-gamma upon treatment with IL-12. In addition, low levels of interferon-gamma are detected in the serum of knockout mice but not wild type control mice. Furthermore, the architecture of lymph nodes, spleen and thymus is disrupted and the liver exhibits signs of chronic inflammation. T cell homeostasis has been disrupted as increased CD4+ and CD8+ T cells are present and the T reg cells in the mouse have more potent suppressor activity. There is also an increased TH1 response and a decreased TH2 response to antigenic stimulation. The B cell population is also altered and baseline antibody production is skewed. B cells are also observed in the thymus at increased frequency, thus indicating that IFN-gamma may alter B cell trafficking. In addition to the phenotypic consequences, the B cell response to antigen is also disrupted as increased IgM and Ig2a ab responses are seen with a decrease in the IgG1 response. Strong anti-DNA and anti-nuclear antigen antibody responses are also observed, suggesting that chronic IFN-gamma expression may play a role in the development of lupus. Curiously, lupus like symptoms are not seen in the Balb/c where the 160 bp deletion has also been generated. These mice have increased spleen sizes and an apparent defect in lymphocyte trafficking to the lymph nodes. The basis for these differences is under investigation. Surprisingly Balb/c mice with the deletion appear to be more resistant to challenge with the renal carcinoma line, RENCA. In summary, our approaches towards elucidating the multiple mechanisms involved in the regulation of interferon-gamma demonstrates the complexity by which interferon-gamma gene expression is regulated in immune effector cells. Furthermore we now have developed a mouse model for understanding and elucidating the systems biology effects of long term, chronic IFN-gamma gene expression.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Goedhart, Marieke; Cornelissen, Anne S; Kuijk, Carlijn et al. (2018) Interferon-Gamma Impairs Maintenance and Alters Hematopoietic Support of Bone Marrow Mesenchymal Stromal Cells. Stem Cells Dev 27:579-589
Menk, Ashley V; Scharping, Nicole E; Moreci, Rebecca S et al. (2018) Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions. Cell Rep 22:1509-1521
Sallin, Michelle A; Sakai, Shunsuke; Kauffman, Keith D et al. (2017) Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis. Cell Rep 18:3091-3104
Green, Daniel S; Young, Howard A; Valencia, Julio C (2017) Current prospects of type II interferon ? signaling and autoimmunity. J Biol Chem 292:13925-13933
Tanakaa, Atsushi; Leung, Patrick Sc; Young, Howard A et al. (2017) Toward solving the etiological mystery of primary biliary cholangitis. Hepatol Commun 1:275-287
Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako et al. (2016) Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers. J Immunol 196:3385-97
Sakai, Shunsuke; Kauffman, Keith D; Sallin, Michelle A et al. (2016) CD4 T Cell-Derived IFN-? Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease. PLoS Pathog 12:e1005667
Bae, Heekyong R; Leung, Patrick S C; Tsuneyama, Koichi et al. (2016) Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology 64:1189-201
Carvalheiro, Tiago; Gomes, Diane; Pinto, Ligia A et al. (2015) Sera from patients with active systemic lupus erythematosus patients enhance the toll-like receptor 4 response in monocyte subsets. J Inflamm (Lond) 12:38
Ridnour, Lisa A; Cheng, Robert Y S; Weiss, Jonathan M et al. (2015) NOS Inhibition Modulates Immune Polarization and Improves Radiation-Induced Tumor Growth Delay. Cancer Res 75:2788-99

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