Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition
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 func...
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| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0169531 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0169531</identifier><identifier>PMID: 28056086</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Biology ; Biology and Life Sciences ; Blotting, Western ; Cation Transport Proteins - metabolism ; CCAAT-Enhancer-Binding Protein-beta - metabolism ; Cell activation ; Cells, Cultured ; Cytokines ; Enzyme-Linked Immunosorbent Assay ; Exposure ; Gene expression ; Heart ; Humans ; Immune response ; Immune system ; Infections ; Inflammation ; Innate immunity ; Interleukin 10 ; Interleukin 6 ; Interleukin 8 ; Interleukin-10 - metabolism ; Interleukin-6 - metabolism ; Interleukin-8 - metabolism ; Kinases ; Lipopolysaccharides ; Lipopolysaccharides - toxicity ; Localization ; Macrophages ; Macrophages - drug effects ; Macrophages - metabolism ; Medicine and Health Sciences ; Metabolism ; Micronutrients ; MicroRNAs ; Microscopy, Confocal ; Monocytes ; Monocytes - cytology ; Monocytes - drug effects ; Monocytes - metabolism ; NF-κB protein ; Pathogens ; Pharmacy ; Phosphorylation ; Physical Sciences ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger ; Rodents ; Spectrophotometry, Atomic ; Supplementation ; Supplements ; Transcription factors ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α ; Zinc ; Zinc - pharmacology</subject><ispartof>PloS one, 2017-01, Vol.12 (1), p.e0169531</ispartof><rights>2017 Pyle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Pyle et al 2017 Pyle et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-4d65062ed405b7520c10be5b3d35fbee94e6ae7ad217dd9c5634a520472ebcc93</citedby><cites>FETCH-LOGICAL-c526t-4d65062ed405b7520c10be5b3d35fbee94e6ae7ad217dd9c5634a520472ebcc93</cites><orcidid>0000-0002-0443-1866</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215883/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215883/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28056086$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pyle, Charlie J</creatorcontrib><creatorcontrib>Akhter, Saife</creatorcontrib><creatorcontrib>Bao, ShengYing</creatorcontrib><creatorcontrib>Dodd, Claire E</creatorcontrib><creatorcontrib>Schlesinger, Larry S</creatorcontrib><creatorcontrib>Knoell, Daren L</creatorcontrib><title>Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Blotting, Western</subject><subject>Cation Transport Proteins - metabolism</subject><subject>CCAAT-Enhancer-Binding Protein-beta - metabolism</subject><subject>Cell activation</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Exposure</subject><subject>Gene expression</subject><subject>Heart</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Innate immunity</subject><subject>Interleukin 10</subject><subject>Interleukin 6</subject><subject>Interleukin 8</subject><subject>Interleukin-10 - metabolism</subject><subject>Interleukin-6 - metabolism</subject><subject>Interleukin-8 - metabolism</subject><subject>Kinases</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - toxicity</subject><subject>Localization</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Micronutrients</subject><subject>MicroRNAs</subject><subject>Microscopy, Confocal</subject><subject>Monocytes</subject><subject>Monocytes - cytology</subject><subject>Monocytes - drug effects</subject><subject>Monocytes - metabolism</subject><subject>NF-κB protein</subject><subject>Pathogens</subject><subject>Pharmacy</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Proteins</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger</subject><subject>Rodents</subject><subject>Spectrophotometry, Atomic</subject><subject>Supplementation</subject><subject>Supplements</subject><subject>Transcription factors</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumor necrosis factor-α</subject><subject>Zinc</subject><subject>Zinc - 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metabolism</topic><topic>CCAAT-Enhancer-Binding Protein-beta - metabolism</topic><topic>Cell activation</topic><topic>Cells, Cultured</topic><topic>Cytokines</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Exposure</topic><topic>Gene expression</topic><topic>Heart</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Infections</topic><topic>Inflammation</topic><topic>Innate immunity</topic><topic>Interleukin 10</topic><topic>Interleukin 6</topic><topic>Interleukin 8</topic><topic>Interleukin-10 - metabolism</topic><topic>Interleukin-6 - metabolism</topic><topic>Interleukin-8 - metabolism</topic><topic>Kinases</topic><topic>Lipopolysaccharides</topic><topic>Lipopolysaccharides - toxicity</topic><topic>Localization</topic><topic>Macrophages</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Micronutrients</topic><topic>MicroRNAs</topic><topic>Microscopy, Confocal</topic><topic>Monocytes</topic><topic>Monocytes - cytology</topic><topic>Monocytes - drug effects</topic><topic>Monocytes - metabolism</topic><topic>NF-κB protein</topic><topic>Pathogens</topic><topic>Pharmacy</topic><topic>Phosphorylation</topic><topic>Physical Sciences</topic><topic>Proteins</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger</topic><topic>Rodents</topic><topic>Spectrophotometry, Atomic</topic><topic>Supplementation</topic><topic>Supplements</topic><topic>Transcription factors</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-TNF</topic><topic>Tumor necrosis factor-α</topic><topic>Zinc</topic><topic>Zinc - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pyle, Charlie J</creatorcontrib><creatorcontrib>Akhter, Saife</creatorcontrib><creatorcontrib>Bao, ShengYing</creatorcontrib><creatorcontrib>Dodd, Claire E</creatorcontrib><creatorcontrib>Schlesinger, Larry S</creatorcontrib><creatorcontrib>Knoell, Daren L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28056086</pmid><doi>10.1371/journal.pone.0169531</doi><orcidid>https://orcid.org/0000-0002-0443-1866</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Biology Biology and Life Sciences Blotting, Western Cation Transport Proteins - metabolism CCAAT-Enhancer-Binding Protein-beta - metabolism Cell activation Cells, Cultured Cytokines Enzyme-Linked Immunosorbent Assay Exposure Gene expression Heart Humans Immune response Immune system Infections Inflammation Innate immunity Interleukin 10 Interleukin 6 Interleukin 8 Interleukin-10 - metabolism Interleukin-6 - metabolism Interleukin-8 - metabolism Kinases Lipopolysaccharides Lipopolysaccharides - toxicity Localization Macrophages Macrophages - drug effects Macrophages - metabolism Medicine and Health Sciences Metabolism Micronutrients MicroRNAs Microscopy, Confocal Monocytes Monocytes - cytology Monocytes - drug effects Monocytes - metabolism NF-κB protein Pathogens Pharmacy Phosphorylation Physical Sciences Proteins Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Rodents Spectrophotometry, Atomic Supplementation Supplements Transcription factors Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF Tumor necrosis factor-α Zinc Zinc - pharmacology |
| title | Zinc Modulates Endotoxin-Induced Human Macrophage Inflammation through ZIP8 Induction and C/EBPβ Inhibition |
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