Inhibition of IL-6 signaling by zinc leads to repression of memory Th17 response in humans

Abstract

Zinc is an essential trace element that plays pivotal roles in multiple facets of the immune system. Besides its catalytic and structural roles, zinc also functions as an intracellular signaling molecule, and changes in zinc levels can cause both direct and indirect modulation of immune responses. Further, cytoplasmic levels of bioavailable zinc in immune cells are largely influenced by many extracellular stimuli. Here I provide evidence that zinc alters the cytokine production profile of human memory CD4 T cells by functioning as an intracellular signaling molecule during T-cell responses. In vitro zinc treatment of CD4 T cells in the presence of activated monocytes inhibited IFN-γ- and IL-17-producing cells, but not IL-4-producing cells. Of note, production of IL-17+ cells from memory CD4 T cells, which is significantly upregulated by LPS-stimulated monocytes, was preferentially repressed by zinc. Increased cytoplasmic zinc in T cells suppressed IL-6 signaling via repression of phosphorylation of Stat3, thus leading to an inhibitory effect on Th17 responses facilitated by monocyte-derived IL-6 in humans. These finding suggest that therapeutic manipulation of zinc bioavailability may be a good means by which to modulate memory CD4 T-cell responses.