Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-γ expression in activated human T cells
Open Access
- 28 April 2009
- journal article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 86 (2), 337-348
- https://doi.org/10.1189/jlb.1208759
Abstract
Dietary zinc supplement increases production of the tumor/infection-fighting cytokine IFN-γ in T cells by increasing zinc transport from the lysosomes to the cell cytoplasm. The zinc transporter ZIP8 is highly expressed in T cells derived from human subjects. T cell ZIP8 expression was markedly up-regulated upon in vitro activation. T cells collected from human subjects who had received oral zinc supplementation (15 mg/day) had higher expression of the activation marker IFN-γ upon in vitro activation, indicating a potentiating effect of zinc on T cell activation. Similarly, in vitro zinc treatment of T cells along with activation resulted in increased IFN-γ expression with a maximum effect at 3.1 μM. Knockdown of ZIP8 in T cells by siRNA decreased ZIP8 levels in nonactivated and activated cells and concomitantly reduced secretion of IFN-γ and perforin, both signatures of activation. Overexpression of ZIP8 by transient transfection caused T cells to exhibit enhanced activation. Confocal microscopy established that ZIP8 is localized to the lysosome where ZIP8 abundance is increased upon activation. Loss of lysosomal labile zinc in response to activation was measured by flow cytometry using a zinc fluorophore. Zinc between 0.8 and 3.1 μM reduced CN phosphatase activity. CN was also inhibited by the CN inhibitor FK506 and ZIP8 overexpression. The results suggest that zinc at low concentrations, through inhibition of CN, sustains phosphorylation of the transcription factor CREB, yielding greater IFN-γ expression in T cells. ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN-γ regulation in T cells.Keywords
Funding Information
- National Institutes of Health (DK 31127)
- Boston Family Endowment Funds
- Interdisciplinary Center for Biotechnology Research
- Bankhead-Coley Cancer Research Program
- National Institutes of Health (DK 31127)
- Boston Family Endowment Funds
- Interdisciplinary Center for Biotechnology Research
- Bankhead-Coley Cancer Research Program
This publication has 48 references indexed in Scilit:
- Zinc Transporters ZnT1 (Slc30a1), Zip8 (Slc39a8), and Zip10 (Slc39a10) in Mouse Red Blood Cells Are Differentially Regulated during Erythroid Development and by Dietary Zinc DeficiencyJournal of Nutrition, 2008
- The human zinc transporter SLC39A8 (Zip8) is critical in zinc-mediated cytoprotection in lung epitheliaAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2008
- Zinc is a novel intracellular second messengerThe Journal of cell biology, 2007
- Signal transduction in monocytes: the role of zinc ionsBioMetals, 2007
- Zinc homeostasis and immunityTrends in Immunology, 2007
- Zinc ions suppress mitogen-activated interleukin-2 production in Jurkat cellsBiochemical and Biophysical Research Communications, 2005
- Zip3 plays a major role in zinc uptake into mammary epithelial cells and is regulated by prolactinAmerican Journal of Physiology-Cell Physiology, 2005
- Zinc Inhibition of cAMP SignalingPublished by Elsevier BV ,2002
- Transcriptional regulation by the phosphorylation-dependent factor CREBNature Reviews Molecular Cell Biology, 2001
- Nitric oxide selectively releases metals from theN‐terminal domain of metallothioneins: potential role at inflammatory sitesThe FASEB Journal, 2001