Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Hence, many of its toxic effects are in fact due to copper deficiency. While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells. Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families. One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. Rather than being a toxic metal ion, zinc is an essential trace element. Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal. Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.

https://www.mdpi.com/1660-4601/7/4/1342/pdf

The Essential Toxin: Impact of Zinc on Human Health

Zinc requirements and the risks and benefits of zinc supplementation

Immune support by micronutrients is historically based on vitamin C deficiency and supplementation in scurvy in early times. It has since been established that the complex, integrated immune system needs multiple specific micronutrients, including vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium, which play vital, often synergistic roles at every stage of the immune response. Adequate amounts are essential to ensure the proper function of physical barriers and immune cells; however, daily micronutrient intakes necessary to support immune function may be higher than current recommended dietary allowances. Certain populations have inadequate dietary micronutrient intakes, and situations with increased requirements (e.g., infection, stress, and pollution) further decrease stores within the body. Several micronutrients may be deficient, and even marginal deficiency may impair immunity. Although contradictory data exist, available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection. Micronutrients with the strongest evidence for immune support are vitamins C and D and zinc. Better design of human clinical studies addressing dosage and combinations of micronutrients in different populations are required to substantiate the benefits of micronutrient supplementation against infection.

A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection

Although the essentiality of zinc for plants and animals has been known for many decades, the essentiality of zinc for humans was recognized only 40 years ago in the Middle East. The zinc-deficient patients had severe immune dysfunctions, inasmuch as they died of intercurrent infections by the time they were 25 years of age. In our studies in an experimental human model of zinc deficiency, we documented decreased serum testosterone level, oligospermia, severe immune dysfunctions mainly affecting T helper cells, hyperammonemia, neurosensory disorders, and decreased lean body mass. It appears that zinc deficiency is prevalent in the developing world and as many as two billion subjects may be growth retarded due to zinc deficiency. Besides growth retardation and immune dysfunctions, cognitive impairment due to zinc deficiency also has been reported recently. Our studies in the cell culture models showed that the activation of many zinc-dependent enzymes and transcription factors were adversely affected due to zinc deficiency. In HUT-78 (T helper 0 (Th0) cell line), we showed that a decrease in gene expression of interleukin-2 (IL-2) and IL-2 receptor α (IL-2Rα) were due to decreased activation of nuclear factor-κB (NF-κB) in zinc deficient cells. Decreased NF-κB activation in HUT-78 due to zinc deficiency was due to decreased binding of NF-κB to DNA, decreased level of NF-κB p105 (the precursor of NF-κB p50) mRNA, decreased κB inhibitory protein (IκB) phosphorylation, and decreased Iκκ. These effects of zinc were cell specific. Zinc also is an antioxidant and has anti-inflammatory actions. The therapeutic roles of zinc in acute infantile diarrhea, acrodermatitis enteropathica, prevention of blindness in patients with age-related macular degeneration, and treatment of common cold with zinc have been reported. In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the up-regulation of A20 mRNA, which, via TRAF pathway, decreases NF-κB activation, leading to decreased gene expression and generation of tumor necrosis factor-α (TNF-α), IL-1β, and IL-8. We have reported recently that in both young adults and elderly subjects, zinc supplementation decreased oxidative stress markers and generation of inflammatory cytokines.

Zinc in human health: effect of zinc on immune cells.

Adequate intakes of vitamins and trace elements are required for the immune system to function efficiently. Micronutrient deficiency suppresses immune functions by affecting the innate T-cell-mediated

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Contribution of Selected Vitamins and Trace Elements to Immune Function

Zinc is known to be essential for all highly proliferating cells in the human body, especially the immune system. A variety of in vivo and in vitro effects of zinc on immune cells mainly depend on the zinc concentration. All kinds of immune cells show decreased function after zinc depletion. In monocytes, all functions are impaired, whereas in natural killer cells, cytotoxicity is decreased, and in neutrophil granulocytes, phagocytosis is reduced. The normal functions of T cells are impaired, but autoreactivity and alloreactivity are increased. B cells undergo apoptosis. Impaired immune functions due to zinc deficiency are shown to be reversed by an adequate zinc supplementation, which must be adapted to the actual requirements of the patient. High dosages of zinc evoke negative effects on immune cells and show alterations that are similar to those observed with zinc deficiency. Furthermore, when peripheral blood mononuclear cells are incubated with zinc in vitro, the release of cytokines such as interleukins (IL)-1 and -6, tumor necrosis factor-alpha, soluble IL-2R and interferon-gamma is induced. In a concentration of 100 micro mol/L, zinc suppresses natural killer cell killing and T-cell functions whereas monocytes are activated directly, and in a concentration of 500 micro mol/L, zinc evokes a direct chemotactic activation of neutrophil granulocytes. All of these effects are discussed in this short overview.

/pdf/zinc-altered-immune-function-2um5zidhyu.pdf

Zinc-Altered Immune Function

Zinc is an essential trace element for the immune system. Previously it was shown that zinc inhibits alloreactivity. In our present in vitro experiments, it is shown that zinc maintains the antigenic potency of the host while blocking the allogeneic response. These results were observed in experiments using tetanus toxoid as a well-established recall antigen and the mixed lymphocyte culture as an in vitro model for allogeneic reaction. To prove the in vivo relevance, an ex vivo experimental setup was established. This involved participants taking zinc orally for 1 week. Here it is shown that in vivo zinc application induced the same effect of blocking the mixed lymphocyte culture without influencing tetanus toxoid stimulation. So far, no clinical application studies have been performed, but the observed selective suppression of allogeneic reaction by zinc is the first step towards a new generation of immunosuppressants.

Klaus-Helge Ibs

Papers

Zinc-Altered Immune Function

Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response.

Zinc and the immune system of elderly

Die Bedeutung von Zinkionen für mononucleäre Leukocyten