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

Nickel ions (Ni²⁺) are eluted from various metallic materials, such as medical devices implanted in human tissues. Previous studies have shown that Ni²⁺ enters inflammatory cells inducing inflammation. However, the regulation of Ni²⁺ uptake in cells has not yet been reported in detail. In the present study, we investigated the effects of various divalent cations on Ni²⁺ uptake and Ni²⁺-induced interleukin (IL)-8 production in the human monocytic cell line, THP-1. We demonstrated that ZnCl_2, MnCl₂, and CoCl₂ inhibited the Ni²⁺ uptake, while CuCl₂, FeCl₂, MgCl₂, and divalent metal transporter (DMT)-1 inhibitor, Chlorazol Black, did not. Furthermore, ZnCl₂ inhibited Ni²⁺-induced IL-8 production, correlating with the inhibition of Ni²⁺ uptake. These results suggested that Ni²⁺ uptake occurred through Zn²⁺, Mn²⁺, and Co²⁺-sensitive transporters and that the inhibition of Ni²⁺ 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 Zn²⁺ modulates Ni²⁺ uptake by inflammatory cells, and a Zn deficient state might increase sensitivity to Ni.