Zinc ions have a potential to attenuate both Ni ion uptake and Ni ion-induced inflammation

Nickel ions (Ni(2+)) are eluted from various metallic materials, such as medical devices implanted in human tissues. Previous studies have shown that Ni(2+) enters inflammatory cells inducing inflammation. However, the regulation of Ni(2+) uptake in cells has not yet been reported in detail. In the present study, we investigated the effects of various divalent cations on Ni(2+) uptake and Ni(2+)-induced interleukin (IL)-8 production in the human monocytic cell line, THP-1. We demonstrated that ZnCl(2,) MnCl(2), and CoCl(2) inhibited the Ni(2+) uptake, while CuCl(2), FeCl(2), MgCl(2), and divalent metal transporter (DMT)-1 inhibitor, Chlorazol Black, did not. Furthermore, ZnCl(2) inhibited Ni(2+)-induced IL-8 production, correlating with the inhibition of Ni(2+) uptake. These results suggested that Ni(2+) uptake occurred through Zn(2+), Mn(2+), and Co(2+)-sensitive transporters and that the inhibition of Ni(2+) uptake resulted in the inhibition of IL-8 production. Furthermore, using an Ni wire-implanted mouse model, we found that Ni wire-induced expression of mouse macrophage inflammatory protein-2 (MIP-2) and cyclooxygenase-2 (COX-2) mRNA in the skin tissue surrounding the wire were enhanced by low Zn conditions. These results suggested that the physiological concentration of Zn(2+) modulates Ni(2+) uptake by inflammatory cells, and a Zn deficient state might increase sensitivity to Ni.