title: Inhibition of interleukin-1β-mediated interleukin-1 receptor-associated kinase 4 phosphorylation by zinc leads to repression of memory T helper type 17 response in humans.
abstract: Zinc is an essential trace element that plays pivotal roles in multiple facets of the immune system. Besides its catalytic and structural roles, zinc also functions as an intracellular signalling molecule, and changes in zinc levels can cause both direct and indirect modulation of immune responses. Further, cytoplasmic levels of bioavailable zinc in immune cells are largely influenced by many extracellular stimuli. Here we provide evidence that zinc represses memory T helper type 17 responses in humans by inhibiting interleukin-1β (IL-1β)-mediated signal. In vitro zinc treatment of CD4(+) T cells in the presence of activated monocytes inhibited interferon-γ-producing cells and IL-17-producing cells, but not IL-4-producing cells. Of note, production of IL-17(+) cells from memory CD4(+) T cells, which is significantly up-regulated by lipopolysaccharide-stimulated monocytes, was preferentially repressed by zinc. Increased cytoplasmic zinc in T cells suppressed IL-1β signalling through repression of phosphorylation of IL-1 receptor-associated kinase 4 (IRAK4), so leading to an inhibitory effect on T helper type 17 responses facilitated by monocyte-derived IL-1β in humans. These findings suggest that extracellular zinc bioavailability may affect memory CD4(+) T-cell responses by modulating the zinc-mediated signalling pathway.
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul.|Cancer Research Institute, Seoul National University, Seoul.|BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Lee
authors.affiliation: BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul.
authors.forename: Bonah
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul.|Cancer Research Institute, Seoul National University, Seoul.
authors.forename: Yeon Ho
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul.|BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Hwang
authors.affiliation: BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul.|Cancer Research Institute, Seoul National University, Seoul.
authors.forename: Sunjung
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul.
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Hong
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul.|Cancer Research Institute, Seoul National University, Seoul.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul.|Ischaemic/Hypoxic Disease Institute and Institute of Infectious Diseases, Seoul National University College of Medicine and Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea.
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D053592:Interleukin-1 Receptor-Associated Kinases; D015032:Zinc
keywords: T helper type 17; interleukin-1 receptor-associated kinase 4; interleukin-1β; monocytes; zinc