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

Toxicology. 2018 Feb 15;395:45-53. doi: 10.1016/j.tox.2018.01.006. Epub 2018 Jan 31.


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.

Keywords: HIF-1α; HIF-1β; HSP90; Interleukin 8; Nickel; THP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cobalt / metabolism
  • Cobalt / pharmacology
  • HSP90 Heat-Shock Proteins / drug effects
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / drug effects
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Interleukin-8 / biosynthesis*
  • Monocytes / metabolism
  • Mustard Compounds / pharmacology
  • Nickel / metabolism*
  • Nickel / pharmacology*
  • Phenylpropionates / pharmacology
  • Protein Binding
  • Toll-Like Receptor 4 / drug effects
  • Toll-Like Receptor 4 / metabolism


  • 2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
  • CXCL8 protein, human
  • HIF1A protein, human
  • HSP90 Heat-Shock Proteins
  • HSP90AB1 protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-8
  • Mustard Compounds
  • Phenylpropionates
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Cobalt
  • nickel chloride
  • Nickel
  • cobaltous chloride