Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in activated human T cells.
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-gamma 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-gamma expression with a maximum effect at 3.1 microM. Knockdown of ZIP8 in T cells by siRNA decreased ZIP8 levels in nonactivated and activated cells and concomitantly reduced secretion of IFN-gamma 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 microM 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-gamma expression in T cells. ZIP8, through control of zinc transport from the lysosome, may provide a secondary level of IFN-gamma regulation in T cells.
Aydemir
Tolunay B
TB
Center for Nutritional Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL 32611, USA.
Liuzzi
Juan P
JP
McClellan
Steve
S
Cousins
Robert J
RJ
D000284:Administration, Oral; D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019587:Dietary Supplements; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D054353:Perforin / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D055815:Young Adult; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D027682:Cation Transport Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; C530151:SLC39A8 protein, human; D054353:Perforin; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; D015032:Zinc