Nickel Ions Bind To Hsp90 Beta And Enhance Hif-1 Alpha-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-1 alpha (HIF-1 alpha). The NiCl2-induced expression of IL-8 in late phase was blocked by a HIF-1 alpha inhibitor, PX-478, indicating that NiCl2 targets additional factors responsible for activating HIF-1 alpha. To identify such targets, proteins that bound preferentially to Ni-NTA beads were analyzed by LC/MS/MS. The analysis yielded heat shock protein 90 beta (HSP90 beta) as a possible candidate. Furthermore, Ni2+ reduced the interaction of HSP90 beta with HIF-1 alpha, and instead promoted the interaction between HIF-1 alpha and HIF-1 beta, as well as the nuclear localization of HIF-1 alpha. Using various deletion variants, we showed that Ni2+ could bind to the linker domain on HSP90 beta. These results suggest that HSP90 beta plays important roles in Ni2+ -induced production of IL-8 and could be a potential target for the regulation of Ni2+ -induced inflammation.