Zinc, Fe²⁺, and Fe³⁺ differentially influence IFN-γ production in human peripheral blood mononuclear cells

Iron overload is a common phenomenon in patients undergoing transfusions or organ transplantation. Clinical studies indicate that iron overload interferes with immune function. Baseless supplementation of iron leads to higher morbidity and mortality. In iron overload T-cell differentiation is skewed towards a Th2 response, with lower levels of interferon (IFN)-γ. Zinc is known for its immune balancing abilities, e.g., by induction of regulatory T cells. This study aims to investigate the interaction of iron and zinc in mixed lymphocyte cultures (MLC). MLC, peripheral blood mononuclear cells (PBMC) stimulation with phytohemagglutinin, ELISA, PCR, and ICP-MS were used as methods. Zn²⁺ supplementation leads to a significantly lower IFN-γ production in MLC compared with control (P<.03). Fe²⁺ supplementation lowers the IFN-γ production in MLC (P<.0017), too. However, Fe³⁺ has a slightly increasing effect on IFN-γ release which differs significantly from Fe²⁺ (P<.03). In 2,2-Bipyridyl-induced iron deficiency IFN-γ production is lowered (P<.0003), whereas zinc deficiency does not significantly affect IFN-γ production. Examinations of Interleukin (IL)-2 and IL-6 show comparable tendencies. The Fe²⁺ effect can be imitated by sodium sulfite. Fe³⁺ treatment increases intracellular free iron in peripheral blood mononuclear cells (PBMC) significantly compared to Fe²⁺ treatment (P<.02). Iron (II) and zinc both suppress cytokine production in MLC. Fe³⁺ shows a significantly different effect on IFN-γ production. The underlying mechanism is likely a donation of electrons by Fe²⁺ or oxidative stress. These findings provide mechanistic insights on how the oxidation state of iron differentially modulates human immune cell function and highlights the importance of iron speciation in nutritional immunology.