Zinc is an Antioxidant and Anti-Inflammatory Agent: Its Role in Human Health

Abstract

Zinc supplementation trials in the elderly showed that the incidence of infections was decreased by approximately 66% in the zinc group. Zinc supplementation also decreased oxidative stress biomarkers and decreased inflammatory cytokines in the elderly. In our studies in the experimental model of zinc deficiency in humans, we showed that zinc deficiency per se increased the generation of IL-1β and its mRNA in human mononuclear cells following LPS stimulation. Zinc supplementation upregulated A20, a zinc transcription factor, which inhibited the activation of NF-κB, resulting in decreased generation of inflammatory cytokines. Oxidative stress and chronic inflammation are important contributing factors for several chronic diseases attributed to aging, such as atherosclerosis and related cardiac disorders, cancer, neurodegeneration, immunologic disorders and the aging process itself. Zinc is very effective in decreasing reactive oxygen species (ROS). In this review, the mechanism of zinc actions on oxidative stress and generation of inflammatory cytokines and its impact on health in humans will be presented.

Keywords: anti-inflammatory agent; antioxidant agent; inflammatory cytokines; oxidative stress; zinc.

Figures

Figure 1

A picture of four dwarfs from Iran. From left to right (i) Age 21 years, height 4 ft, 11 (1/2″); (ii) age 18 years, height 4 ft 9″; (iii) age 18 years, height 4 ft 7″; (iv) age 21 years, height 4 ft 7″ Staff physician at left is 6 ft in height (1).

Figure 2

Zinc is an integral part of a thymic hormone molecule, thymulin. Thymulin is required for maturation of T cells. Zinc deficiency-induced decrease in thymulin activity is associated with decreased maturation of T cells and Th1 production of IL-2 and INF-γ. Decreased IL-2 leads to decreased NK and T cytolytic cell activities. Macrophages–monocytes produce IL-12 (a zinc-dependent cytokine), which along with INF-γ kills parasites, viruses, and bacteria. Th2 cytokines, in general are not affected by zinc deficiency except IL-10, which may be increased in zinc-deficient elderly individuals. Increased IL-10 from Th2 cells further affects Th1 functions adversely. Thus, in zinc deficiency there is a shift from Th1 to Th2 functions and cell-mediated immune functions are impaired. Zinc deficiency also leads to stress and activation of macrophages–monocytes, resulting in increased generation of inflammatory cytokines, IL-1β, IL-6, IL-8, and TNF-α. Solid lines indicate pathways leading to generation of selected cytokines and dotted lines represent pathways, which lead to inhibition of cytokine generation. NK represent natural-killer cells; Th1 represent activated Th1 type T cells and secreted cytokines (small triangles); Th2 represents activated Th2 type T cells and secreted cytokines (small rounds); B-cell represents B-cell lineages and associated immunoglobulins (triangles). (Prasad, AS. Zinc: role in immunity, oxidative stress and chronic inflammation. Current Opinion in Clin Nutr and Metab Care, 12:646–652, 2009)

Figure 3

Signaling pathway for zinc prevention of atherosclerosis in monocytes/macrophages and vascular endothelial cells: a proposed hypothesis. Reactive oxygen species (ROS) induced by many stimuli modifies LDL into oxidized LDL (ox-LDL) in macrophages and vascular endothelial cells. ox-LDL or ROS can activate the apoptotic pathway via activation of proapoptotic enzymes and the nuclear transcription factor κB (NF-κB) pathway via NF-κB inducible kinase (NIK) activation, which eventually results in the development and progression of atherosclerosis. Zinc might have an atheroprotective function by the following mechanisms: (1) inhibition of ROS generation via metallothionein (MT), superoxide dismutase (SOD), and NADPH, and (2) down-regulation of atherosclerotic cytokines/molecules such as inflammatory cytokines, adhesion molecules, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), fibrinogen, and tissue factor (TF) through inhibition of NF-κB activation by A20-mediating tumor necrosis factor (TNF)-receptor associated factor (TRAF) signaling and peroxisome proliferator-activated receptor a (PPAR-a)-mediating crosstalk signaling. The black arrows indicate up-regulation; arrows with a broken line indicate down-regulation or the inhibitory pathway. IKK, I-κB kinase; IL, interleukin; MCP-1, macrophage chemoattractant protein 1; CRP, C-reactive protein; ICAM-1, intercell adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1 (14).