title: Tissue-Specific Induction of Mouse ZIP8 and ZIP14 Divalent Cation/Bicarbonate Symporters by, and Cytokine Response to, Inflammatory Signals.
abstract: Mouse Slc39a8 and Slc39a14 genes encode ZIP8 and ZIP14, respectively, which are ubiquitous divalent cation/(HCO3-)2symporters responsible for uptake of Zn2+, Fe2+, and Mn2+into cells. Cd2+and other toxic nonessential metals can displace essential cations, thereby entering vertebrate cells. Whereas Slc39a8 encodes a single protein, Slc39a14 has 2 exons 4 which, via alternative splicing, give rise to ZIP14A and ZIP14B; why differences exist in cell type-specific expression of ZIP14A and ZIP14B remains unknown. Inflammatory stimuli have been associated with upregulation of ZIP8 and ZIP14, but a systematic study of many tissues simultaneously in a laboratory animal following inflammatory cytokine exposure has not yet been reported. Herein, we show that C57BL/6J male mice--treated intraperitoneally with lipopolysaccharide or the proinflammatory cytokines tumor necrosis factor (TNF) or interleukin-6 (IL6)--exhibited quantatively very different, highly tissue-specific, and markedly time-dependent up- and downregulation of ZIP8, ZIP14A, and ZIP14B messenger RNA (mRNA) levels in 12 tissues. The magnitude of inflammatory response was confirmed by measuring the proinflammatory cytokine TNF, IL6, and interleukin-1β mRNA levels in the same tissues of these animals. Our data suggest that most if not all tissues use ZIP8, ZIP14A, and/or ZIP14B for Zn2+uptake, some tissues under basal conditions and others moreso when inflammatory stressors are present; collectively, this might lead to substantial alterations in plasma Zn2+levels due to Zn2+redistribution not just in liver but across many vital organs. In the context of cadmium-mediated toxicity, our data suggest that tissues other than liver, kidney, and lung should also be considered.
authors.affiliation: Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA.|Present address: Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Gálvez-Peralta
authors.affiliation: Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA.|Present address: Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: David Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA.
authors.forename: Shengying
authors.initials: S
authors.lastname: Bao
authors.affiliation: David Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA.
authors.forename: Daren L
authors.initials: DL
authors.lastname: Knoell
authors.affiliation: Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA dan.nebert@uc.edu.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D019446:Endotoxemia / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D015032:Zinc / Q000097:blood / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D016207:Cytokines; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C500556:SLC39A14 protein, mouse; C499256:Slc39a8 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D015032:Zinc
keywords: ZIP transporter gene family; ZIP14 Zn2+/(HCO3
                 –)2 symporter; ZIP8 Zn2+/(HCO3
                 –)2 symporter; inflammation; interleukin-6; lipopolysaccharide; mouse Slc39 gene family; tumor necrosis factor
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