In humans, zinc deficiency may lead to the generation of new CD4+ T cells, produced in the thymus. Because IL-2 production (Th(1) cytokine) is decreased, this causes decreased activity of natural-killer-cell (NK cell) and T cytolytic cells, normally involved in killing viruses, bacteria, and malignant cells. The change of Th(1) to Th(2) function leads to cell-mediated immune dysfunction. T-helper 1 (Th(1)) cytokines are decreased but T-helper 2 (Th(2)) cytokines are not affected by zinc deficiency in humans. Zinc deficiency in humans decreases the activity of serum thymulin (a hormone of the thymus), which is necessary for the maturation of T-helper cells. Cochrane researchers examined the evidence available up to 30 September 2016. Various mechanisms are specific to the gastrointestinal system: zinc restores mucosal barrier integrity and enterocyte brush-border enzyme activity, it promotes the production of antibodies and circulating lymphocytes against intestinal pathogens, and has a direct effect on ion channels, acting as a potassium channel blocker of adenosine 3-5-cyclic monophosphate-mediated chlorine secretion. There are several mechanisms of action of zinc on acute diarrhea. In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the up-regulation of A20 mRNA, which, via TRAF pathway, decreases NF-kappaB activation, leading to decreased gene expression and generation of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-8. Zinc promotes resistance to epithelial apoptosis through cell protection (cytoprotection) against reactive oxygen species and bacterial toxins, likely through the antioxidant activity of the cysteine-rich metallothioneins. It is implicated in numerous cellular processes as a cofactor for approximately 3000 human proteins including enzymes, nuclear factors, and hormones. For example, zinc is a structural constituent in numerous proteins, inclusive of growth factors, cytokines, receptors, enzymes, and transcription factors for different cellular signaling pathways. The catalytic and structural role of zinc is well established, and there are various noteworthy reviews on these functions. Zinc has three primary biological roles: catalytic, structural, and regulatory.
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