Nickel ions bind to HSP90β and enhance HIF-1α-mediated IL-8 expression

Nickel ions (Ni²⁺) eluted from biomedical devices cause inflammation and Ni allergy. Although Ni²⁺ and Co²⁺ elicit common effects, Ni²⁺ induces a generally stronger inflammatory reaction. However, the molecular mechanism by which Ni²⁺ and Co²⁺ induce such different responses remains to be elucidated. In the present study, we compared the effects of Ni²⁺ and Co²⁺ on the expression of interleukin (IL)-8 in human monocyte THP-1 cells. We report that NiCl₂ but not CoCl₂ induced the expression of IL-8; in contrast, CoCl₂ elicited a higher expression of hypoxia-inducible factor-1α (HIF-1α). The NiCl₂-induced expression of IL-8 in late phase was blocked by a HIF-1α inhibitor, PX-478, indicating that NiCl₂ targets additional factors responsible for activating HIF-1α. To identify such targets, proteins that bound preferentially to Ni-NTA beads were analyzed by LC/MS/MS. The analysis yielded heat shock protein 90β (HSP90β) as a possible candidate. Furthermore, Ni²⁺ reduced the interaction of HSP90β with HIF-1α, and instead promoted the interaction between HIF-1α and HIF-1β, as well as the nuclear localization of HIF-1α. Using various deletion variants, we showed that Ni²⁺ could bind to the linker domain on HSP90β. These results suggest that HSP90β plays important roles in Ni²⁺-induced production of IL-8 and could be a potential target for the regulation of Ni²⁺-induced inflammation.