Department of Internal Medicine, Division of Hematology/Oncology, Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, Michigan, USA.
Nutrition. 2011 Jul-Aug;27(7-8):816-23. doi: 10.1016/j.nut.2010.08.010. Epub 2010 Oct 29.
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).
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.
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.
Our studies suggest that zinc suppresses generation of NF-κB-regulated inflammatory cytokines by induction of A20.
慢性产生的炎症细胞因子和活性氧在动脉粥样硬化、衰老、癌症和其他慢性疾病中起作用。我们假设锌诱导前单核细胞、内皮细胞和癌细胞中的 A20，A20 与肿瘤坏死因子（TNF）-受体相关因子结合，并抑制 Iκ 激酶-α（IKK-α）/核因子-κB（NF-κB），导致 TNF-α和白细胞介素-1β（IL-1β）下调。
为了验证这一假设，我们在这项研究中使用了 HL-60、人脐静脉内皮细胞和 SW480 细胞系，在缺锌和锌充足的条件下进行实验。我们测量了刺激缺锌和锌充足细胞后的氧化应激标志物、炎症细胞因子、A20 蛋白和 mRNA、A20-FRAF-1 复合物和 IKK-α/NF-κB 信号通路。我们还进行了反义 A20 和 siRNA 研究，以调查锌通过 A20 对 TNF-α和 IL-1β的调节作用。
与缺锌细胞相比，我们发现锌增加了 A20 和 A20-肿瘤坏死因子受体相关因子-1 复合物，减少了这些细胞中的 IKK-α/NF-κB 信号通路、氧化应激标志物和炎症细胞因子。我们通过反义 A20 和 siRNA A20 研究证实，锌诱导的 A20 有助于下调 TNF-α和 IL-1β。
我们的研究表明，锌通过诱导 A20 抑制 NF-κB 调节的炎症细胞因子的产生。
