Zinc-suppressed inflammatory cytokines by induction of A20-mediated inhibition of nuclear factor-κB

• Published in: Nutrition (Burbank, Los Angeles County, Calif.) Los Angeles County, Calif.), 2011-07, Vol.27 (7), p.816-823
• Main Authors: Prasad, Ananda S., M.D., Ph.D, Bao, Bin, M.D., Ph.D, Beck, Frances W.J., Ph.D, Sarkar, Fazlul H., Ph.D
• Format: Article
• Language: English
• Subjects: A20 protein; Biological and medical sciences; Cell Line; Cytokines - metabolism; DNA-Binding Proteins; Down-Regulation; Endothelial Cells - metabolism; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gastroenterology and Hepatology; Humans; I-kappa B Proteins - antagonists & inhibitors; Inflammation Mediators - metabolism; Interleukin-1beta - metabolism; Interleukin-1β; Intracellular Signaling Peptides and Proteins - metabolism; NF-kappa B - antagonists & inhibitors; Nuclear factor-κB; Nuclear Proteins - metabolism; Oxidative Stress - physiology; Signal Transduction; TNF Receptor-Associated Factor 1 - metabolism; Tumor Necrosis Factor alpha-Induced Protein 3; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Umbilical Veins - cytology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Zinc - metabolism; Zinc, A20
• ISSN: 0899-9007; 1873-1244
• DOI: 10.1016/j.nut.2010.08.010

Abstract Objective Chronic generation of inflammatory cytokines and reactive oxygen species are implicated in atherosclerosis, aging, cancers, and other chronic diseases. We hypothesized that zinc induces A20 in premonocytic, endothelial, and cancer cells, and A20 binds to tumor necrosis factor (TNF)-receptor associated factor, and inhibits Iκ kinase-α (IKK-α)/nuclear factor-κB (NF-κB), resulting in downregulation of TNF-α and interleukin-1β (IL-1β). Methods To test this hypothesis, we used HL-60, human umbilical vein endothelial cells, and SW480 cell lines under zinc-deficient and zinc-sufficient conditions in this study. We measured oxidative stress markers, inflammatory cytokines, A20 protein and mRNA, A20–FRAF-1 complex, and IKK-α/NF-κB signaling in stimulated zinc-deficient and zinc sufficient cells. We also conducted antisense A20 and siRNA studies to investigate the regulatory role of zinc in TNF-α and IL-1β via A20. Results We found that zinc increased A20 and A20–tumor necrosis factor-receptor associated factor-1 complex, decreased the IKK-α/NF-κB signaling pathway, oxidative stress markers, and inflammatory cytokines in these cells compared with zinc-deficient cells. We confirmed that zinc-induced A20 contributes to downregulation of TNF-α and IL-1β by antisense and short interfering RNA A20 studies. Conclusion Our studies suggest that zinc suppresses generation of NF-κB–regulated inflammatory cytokines by induction of A20.