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

Nickel ions (Ni) eluted from biomedical devices cause inflammation and Ni allergy. Although Ni and Co elicit common effects, Ni induces a generally stronger inflammatory reaction. However, the molecular mechanism by which Ni and Co induce such different responses remains to be elucidated. In the present study, we compared the effects of Ni and Co on the expression of interleukin (IL)-8 in human monocyte THP-1 cells. We report that NiCl but not CoCl induced the expression of IL-8; in contrast, CoCl elicited a higher expression of hypoxia-inducible factor-1α (HIF-1α). The NiCl-induced expression of IL-8 in late phase was blocked by a HIF-1α inhibitor, PX-478, indicating that NiCl 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, Ni 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 Ni could bind to the linker domain on HSP90β. These results suggest that HSP90β plays important roles in Ni-induced production of IL-8 and could be a potential target for the regulation of Ni-induced inflammation.