Gálvez-Peralta Marina, Wang Zhifang, Bao Shengying, Knoell Daren L, Nebert Daniel W
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.
Int J Toxicol. 2014 May;33(3):246-258. doi: 10.1177/1091581814529310. Epub 2014 Apr 10.
Mouse Slc39a8 and Slc39a14 genes encode ZIP8 and ZIP14, respectively, which are ubiquitous divalent cation/(HCO) symporters responsible for uptake of Zn, Fe, and Mn into cells. Cd 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 Zn uptake, some tissues under basal conditions and others moreso when inflammatory stressors are present; collectively, this might lead to substantial alterations in plasma Zn levels due to Zn 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.
小鼠的Slc39a8和Slc39a14基因分别编码ZIP8和ZIP14，它们是普遍存在的二价阳离子/（HCO）同向转运体，负责将锌、铁和锰摄入细胞。镉和其他有毒的非必需金属可以取代必需阳离子，从而进入脊椎动物细胞。虽然Slc39a8编码一种单一蛋白质，但Slc39a14有2个外显子，通过可变剪接产生ZIP14A和ZIP14B；ZIP14A和ZIP14B在细胞类型特异性表达上存在差异的原因尚不清楚。炎症刺激与ZIP8和ZIP14的上调有关，但尚未有关于实验室动物在暴露于炎症细胞因子后同时对许多组织进行系统研究的报道。在此，我们表明，经腹腔注射脂多糖或促炎细胞因子肿瘤坏死因子（TNF）或白细胞介素-6（IL6）处理的C57BL/6J雄性小鼠，在12个组织中ZIP8、ZIP14A和ZIP14B信使核糖核酸（mRNA）水平呈现出数量上非常不同、高度组织特异性且明显随时间变化的上调和下调。通过测量这些动物相同组织中促炎细胞因子TNF、IL6和白细胞介素-1β的mRNA水平，证实了炎症反应的程度。我们的数据表明，大多数（如果不是全部）组织利用ZIP8、ZIP14A和/或ZIP14B摄取锌，一些组织在基础条件下如此，其他组织在存在炎症应激源时摄取更多；总的来说，这可能不仅导致肝脏，而且导致许多重要器官的锌重新分布，从而使血浆锌水平发生实质性改变。在镉介导的毒性背景下，我们的数据表明，除肝脏、肾脏和肺之外的其他组织也应予以考虑。
