Zinc inhibits interleukin-1-dependent T cell stimulation.
Zinc is a trace element which is essential for immune functions. It directly induces monokine secretion by monocytes; however, effects of zinc on T cells appear contradictory. Apart from enhanced lymphocyte proliferation in peripheral blood mononuclear cells (PBMC), inhibitory properties of high zinc dosages have also been described. In this study, PBMC failed to produce lymphokines like interferon (IFN)-gamma after stimulation with zinc in a serum- and LPS-free cell culture system, whereas monokine secretion [interleukin (IL)-1 beta] occurred. Zinc-uptake studies with the zinc-specific fluorescent probe zinquin revealed that zinc is taken up by PBMC within a few minutes, reaching nearly equal levels in PBMC, isolated monocytes, and T cells. However, if zinc was depleted 1 h after monocyte induction, zinc-free pre-cultured T cells were stimulated to secrete IFN-gamma by zinc-induced monokines. Furthermore, the necessity for a cell-cell interaction between monocytes and T cells for IFN-gamma induction was elucidated. Zinc ions inhibited the proliferation of the IL-1-dependent T cell line D 10N in a dose-dependent manner, suggesting a direct inhibitory effect of zinc. By immunoprecipitation we revealed a specific inhibition of IL-1 receptor-associated protein kinase (IRAK) by zinc ions. Therefore, in contrast to an indirect stimulation of T cells due to zinc-induced monokines, higher concentrations of zinc directly inhibit T cell functions by means of specific inhibition of IRAK and subsequent signaling events such as NF kappa B activation. The divergent effects of zinc on different cell populations, depending on the zinc concentration, could explain contradictory results of zinc stimulation. Furthermore, our data suggest new strategies of specific zinc-mediated immune modulation.
Wellinghausen
N
N
Institute of Immunology and Transfusion Medicine, University of Lübeck School of Medicine, Germany.
Martin
M
M
Rink
L
L
D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D008213:Lymphocyte Activation / Q000187:drug effects*; D008223:Lymphoma / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D015363:Quinolones / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014105:Tosyl Compounds / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D014105:Tosyl Compounds; D007371:Interferon-gamma; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D015032:Zinc; C084731:zinquin