Zinc deficiency leads to reduced interleukin-2 production by active gene silencing due to enhanced CREMα expression in T cells

  • Veronika Kloubert
    Affiliations
    Institute of Immunology, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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  • Inga Wessels
    Affiliations
    Institute of Immunology, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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  • Jana Wolf
    Affiliations
    Institute of Immunology, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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  • Karoline Blaabjerg
    Affiliations
    Department of Animal Science – Animal Nutrition and Physiology, Aarhus University/Foulum, Blichers Allé 20, 8830, Tjele, Denmark
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  • Veerle Janssens
    Affiliations
    Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven & LKI (Leuven Cancer Institute, KU Leuven), Leuven, Belgium
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  • Jan Hapala
    Affiliations
    Helmholtz Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074, Aachen, Germany

    Institute of Biomedical Engineering, Department of Cell Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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  • Wolfgang Wagner
    Affiliations
    Helmholtz Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University, Pauwelsstr. 20, 52074, Aachen, Germany

    Institute of Biomedical Engineering, Department of Cell Biology, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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  • Lothar Rink
    Correspondence
    Corresponding author.
    Affiliations
    Institute of Immunology, Faculty of Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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Published:October 29, 2020DOI:https://doi.org/10.1016/j.clnu.2020.10.052

      Summary

      Background & aims

      The micronutrient zinc is essential for proper immune function. Consequently, zinc deficiency leads to impaired immune function, as seen in decreased secretion of interleukin (IL)-2 by T cells. Although this association has been known since the late 1980s, the underlying molecular mechanisms are still unknown. Zinc deficiency and reduced IL-2 levels are especially found in the elderly, which in turn are prone to chronic diseases. Here, we describe a new molecular link between zinc deficiency and reduced IL-2 expression in T cells.

      Methods

      The effects of zinc deficiency were first investigated in vitro in the human T cell lines Jurkat and Hut-78 and complemented by in vivo data from zinc-supplemented pigs. A short- and long-term model for zinc deficiency was established. Zinc levels were detected by flow cytometry and expression profiles were investigated on the mRNA and protein level.

      Results

      The expression of the transcription factor cAMP-responsive-element modulator α (CREMα) is increased during zinc deficiency in vitro, due to increased protein phosphatase 2A (PP2A) activity, resulting in decreased IL-2 production. Additionally, zinc supplementation in vivo reduced CREMα levels causing increased IL-2 expression. On epigenetic levels increased CREMα binding to the IL-2 promoter is mediated by histone deacetylase 1 (HDAC1). The HDAC1 activity is inhibited by zinc. Moreover, deacetylation of the activating histone mark H3K9 was increased under zinc deficiency, resulting in reduced IL-2 expression.

      Conclusions

      With the transcription factor CREMα a molecular link was uncovered, connecting zinc deficiency with reduced IL-2 production due to enhanced PP2A and HDAC1 activity.

      Graphical abstract

      Keywords

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