Medicine and Health Sciences Commons^™

Translational Repression Of Pre-Formed Cytokine-Encoding Mrna Prevents Chronic Activation Of Memory T Cells, Fiamma Salerno, Sander Engels, Maartje Van Den Biggelaar, Floris P.J. Van Alphen, Aurelie Guislain, Wanqi Zhao, Deborah L. Hodge, Sarah E. Bell, Jan Paul Medema, Marieke Von Lindern, Martin Turner, Howard A. Young, Monika C. Wolkers

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Memory T cells are critical for the immune response to recurring infections. Their instantaneous reactivity to pathogens is empowered by the persistent expression of cytokine-encoding mRNAs. How the translation of proteins from pre-formed cytokine-encoding mRNAs is prevented in the absence of infection has remained unclear. Here we found that protein production in memory T cells was blocked via a 3′ untranslated region (3′ UTR)-mediated process. Germline deletion of AU-rich elements (AREs) in the Ifng-3′ UTR led to chronic cytokine production in memory T cells. This aberrant protein production did not result from increased expression and/or half-life of the mRNA. Instead, …

Interferon-Gamma Impairs Maintenance And Alters Hematopoietic Support Of Bone Marrow Mesenchymal Stromal Cells, Marieke Goedhart, Anne S. Cornelissen, Carlijn Kuijk, Sulima Geerman, Marion Kleijer, Jaap D. Van Buul, Stephan Huveneers, Marc H.G.P. Raaijmakers, Howard A. Young, Monika C. Wolkers, Carlijn Voermans, Martijn A. Nolte

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Bone marrow (BM) mesenchymal stromal cells (MSCs) provide microenvironmental support to hematopoietic stem and progenitor cells (HSPCs). Culture-expanded MSCs are interesting candidates for cellular therapies due to their immunosuppressive and regenerative potential which can be further enhanced by pretreatment with interferon-gamma (IFN-γ). However, it remains unknown whether IFN-γ can also influence hematopoietic support by BM-MSCs. In this study, we elucidate the impact of IFN-γ on the hematopoietic support of BM-MSCs. We found that IFN-γ increases expression of interleukin (IL)-6 and stem cell factor by human BM-MSCs. IFN-γ-treated BM-MSCs drive HSPCs toward myeloid commitment in vitro, but impair subsequent differentiation of …

Tipsheet: Student Mental Health And Resources, Unl Office Of The Executive Vice Chancellor

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Stress, depression, anxiety, alcohol abuse, eating disorders, and other mental health challenges affect at least 1 in 5 college students*. Faculty can be an important source of support for UNL students. Here are some strategies for supporting student mental health:

1. Communicate the importance of mental health. Mental health is just as important as physical health. When someone breaks a leg they go to the hospital. Mental illness is the same thing. If someone is feeling depressed they should seek treatment. Normalize mental health by talking about getting support if you notice your students struggling with stress, depression, anxiety, etc. …

The Interplay Of Type I And Type Ii Interferons In Murine Autoimmune Cholangitis As A Basis For Sex-Biased Autoimmunity, Heekyong R. Bae, Deborah L. Hodge, Guo Xiang Yang, Patrick S.C. Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M E. Gershwin, Howard A. Young

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We have reported on a murine model of autoimmune cholangitis, generated by altering the AU-rich element (ARE) by deletion of the interferon gamma (IFN-γ) 3' untranslated region (coined ARE-Del−/−), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the sex bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del−/− …

Early Tcr Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions, Ashley V. Menk, Nicole E. Scharping, Rebecca S. Moreci, Xue Zeng, Cliff Guy, Sonia Salvatore, Heekyong Bae, Jianxin Xie, Howard A. Young, Stacy Gelhaus Wendell, Greg M. Delgoffe

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To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for …

Therapeutic And Immunological Interventions In Primary Biliary Cholangitis: From Mouse Models To Humans, Atsushi Tanaka, Patrick S.C. Leung, Howard A. Young, M. Eric Gershwin

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Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that predominantly affects women in their fifth and sixth decades. The diagnostic hallmarks of PBC are detection of anti-mitochondrial antibodies (AMAs) and chronic non-suppurative destructive cholangitis (CNSDC) of small- and medium-sized intrahepatic bile ducts in liver histological examination [1, 2]. A significant amount of data suggests that immunological activity against small biliary epithelial cells (BECs), found histologically as portal inflammation, leads to clinical disease. In PBC, as with other autoimmune diseases, both genetic and environmental factors contribute to the development of pathology [3–8]. The first-line therapy of PBC is ursodeoxycholic …