Dataset Information

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-)2 symporters 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-1? 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.

SUBMITTER: Galvez-Peralta M

PROVIDER: S-EPMC4193950 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tissue-Specific Induction of Mouse ZIP8 and ZIP14 Divalent Cation/Bicarbonate Symporters by, and Cytokine Response to, Inflammatory Signals.

Gálvez-Peralta Marina M Wang Zhifang Z Bao Shengying S Knoell Daren L DL Nebert Daniel W DW

International journal of toxicology 20140410 3

Mouse Slc39a8 and Slc39a14 genes encode ZIP8 and ZIP14, respectively, which are ubiquitous divalent cation/(HCO3-)2 symporters 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; ...[more]

PMID: 24728862

Similar Datasets

Project description:Manganese (Mn) and Zinc (Zn) are essential micronutrients whose concentration and location within cells are tightly regulated at the onset of infection. Two families of Zn transporters (ZIPs and ZnTs) are largely responsible for regulation of cytosolic Zn levels and to a certain extent, Mn levels, although much less is known regarding Mn. The capacity of pathogens to persevere also depends on access to micronutrients, yet a fundamental gap in knowledge remains regarding the importance of metal exchange at the host interface, often referred to as nutritional immunity. ZIP8, one of 14 ZIPs, is a pivotal importer of both Zn and Mn, yet much remains to be known. Dietary Zn deficiency is common and commonly occurring polymorphic variants of ZIP8 that decrease cellular metal uptake (Zn and Mn), are associated with increased susceptibility to infection. Strikingly, ZIP8 is the only Zn transporter that is highly induced following bacterial exposure in key immune cells involved with host defense against leading pathogens. We postulate that mobilization of Zn and Mn into key cells orchestrates the innate immune response through regulation of fundamental defense mechanisms that include phagocytosis, signal transduction, and production of soluble host defense factors including cytokines and chemokines. New evidence also suggests that host metal uptake may have long-term consequences by influencing the adaptive immune response. Given that activation of ZIP8 expression by pathogens has been shown to influence parenchymal, myeloid, and lymphoid cells, the impact applies to all mucosal surfaces and tissue compartments that are vulnerable to infection. We also predict that perturbations in metal homeostasis, either genetic- or dietary-induced, has the potential to impact bacterial communities in the host thereby adversely impacting microbiome composition. This review will focus on Zn and Mn transport via ZIP8, and how this vital metal transporter serves as a "go to" conductor of metal uptake that bolsters host defense against pathogens. We will also leverage past studies to underscore areas for future research to better understand the Zn-, Mn- and ZIP8-dependent host response to infection to foster new micronutrient-based intervention strategies to improve our ability to prevent or treat commonly occurring infectious disease.

Project description:Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is characterized by the progressive loss of oligodendrocytes and myelin and is associated with thalamic dysfunction. Cuprizone (CPZ)-induced general demyelination in rodents is a valuable model for studying different aspects of MS pathology. CPZ feeding is associated with the altered distribution and expression of different ion channels along neuronal somata and axons. However, it is largely unknown whether the copper chelator CPZ directly influences ion channels. Therefore, we assessed the effects of different divalent cations (copper; zinc) and trace metal chelators (EDTA; Tricine; the water-soluble derivative of CPZ, BiMPi) on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that are major mediators of thalamic function and pathology. In addition, alterations of HCN channels induced by CPZ treatment and MS-related proinflammatory cytokines (IL-1β; IL-6; INF-α; INF-β) were characterized in C57Bl/6J mice. Thus, the hyperpolarization-activated inward current (Ih) was recorded in thalamocortical (TC) neurons and heterologous expression systems (mHCN2 expressing HEK cells; hHCN4 expressing oocytes). A number of electrophysiological characteristics of Ih (potential of half-maximal activation (V0.5); current density; activation kinetics) were unchanged following the extracellular application of trace metals and divalent cation chelators to native neurons, cell cultures or oocytes. Mice were fed a diet containing 0.2% CPZ for 35 days, resulting in general demyelination in the brain. Withdrawal of CPZ from the diet resulted in rapid remyelination, the effects of which were assessed at three time points after stopping CPZ feeding (Day1, Day7, Day25). In TC neurons, Ih was decreased on Day1 and Day25 and revealed a transient increased availability on Day7. In addition, we challenged naive TC neurons with INF-α and IL-1β. It was found that Ih parameters were differentially altered by the application of the two cytokines to thalamic cells, while IL-1β increased the availability of HCN channels (depolarized V0.5; increased current density) and the excitability of TC neurons (depolarized resting membrane potential (RMP); increased the number of action potentials (APs); produced a larger voltage sag; promoted higher input resistance; increased the number of burst spikes; hyperpolarized the AP threshold), INF-α mediated contrary effects. The effect of cytokine modulation on thalamic bursting was further assessed in horizontal slices and a computational model of slow thalamic oscillations. Here, IL-1β and INF-α increased and reduced oscillatory bursting, respectively. We conclude that HCN channels are not directly modulated by trace metals and divalent cation chelators but are subject to modulation by different MS-related cytokines.

Dataset Information

Tissue-Specific Induction of Mouse ZIP8 and ZIP14 Divalent Cation/Bicarbonate Symporters by, and Cytokine Response to, Inflammatory Signals.

Publications

Tissue-Specific Induction of Mouse ZIP8 and ZIP14 Divalent Cation/Bicarbonate Symporters by, and Cytokine Response to, Inflammatory Signals.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets