title: Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition.
abstract: Two vital functions of the innate immune system are to initiate inflammation and redistribute micronutrients in favor of the host. Zinc is an essential micronutrient used in host defense. The zinc importer ZIP8 is uniquely induced through stimulation of the NF-κB pathway by LPS in monocytes and functions to regulate inflammation in a zinc-dependent manner. Herein we determined the impact of zinc metabolism following LPS-induced inflammation in human macrophages. We observed that ZIP8 is constitutively expressed in resting macrophages and strikingly elevated following LPS exposure, a response that is unique compared to the 13 other known zinc import proteins. During LPS exposure, extracellular zinc concentrations within the physiological range markedly reduced IL-10 mRNA expression and protein release but increased mRNA expression of TNFα, IL-8, and IL-6. ZIP8 knockdown inhibited LPS-driven cellular accumulation of zinc and prevented zinc-dependent reduction of IL-10 release. Further, zinc supplementation reduced nuclear localization and activity of C/EBPβ, a transcription factor known to drive IL-10 expression. These studies demonstrate for the first time that zinc regulates LPS-mediated immune activation of human macrophages in a ZIP8-dependent manner, reducing IL-10. Based on these findings we predict that macrophage zinc metabolism is important in host defense against pathogens.
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Charlie J
authors.initials: CJ
authors.lastname: Pyle
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Saife
authors.initials: S
authors.lastname: Akhter
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.|College of Pharmacy, The University of Nebraska Medical Center College of Pharmacy, Omaha, Nebraska United States of America.
authors.forename: ShengYing
authors.initials: S
authors.lastname: Bao
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, United States of America.|Department of Microbiology, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Dodd
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.|Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.|College of Pharmacy, The University of Nebraska Medical Center College of Pharmacy, Omaha, Nebraska United States of America.
authors.forename: Daren L
authors.identifier: http://orcid.org/0000-0002-0443-1866
authors.initials: DL
authors.lastname: Knoell
mesh_terms: D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D018613:Microscopy, Confocal; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013054:Spectrophotometry, Atomic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D027682:Cation Transport Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C530151:SLC39A8 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015032:Zinc