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.