Ni(II) activates the Nrf2 signaling pathway in human monocytic cells.
Nickel is a component of biomedical alloys that is released during corrosion and causes inflammation in tissues by as yet unknown mechanisms. Recent data show that Ni(II) at concentrations of 10-50 microM amplifies lipopolysaccharide-triggered, NFkappaB-mediated cytokine secretion from monocytes. In the current study, we tested the hypothesis that Ni(II) amplifies cytokine secretion by activating the Nrf2 antioxidant pathway rather than by enhancing activity of the NFkappaB signaling pathway. Human THP1 monocytes were exposed to Ni(II) concentrations of 10-30 microM for 6-72 h, then immunoblots of whole-cell lysates or cytosolic and nuclear proteins were used to detect changes in Nrf2 or NFkappaB signaling. Our results show that Ni(II) increased (by 1-2 fold) whole-cell Nrf2 levels and nuclear translocation of Nrf2, and amplified lipopolysaccharide (LPS)-induction of Nrf2 (by 3-5 fold), but had no detectable effect on the initial activation or nuclear translocation of NFkappaB. Because Nrf2 target gene products are known regulators of NFkappaB nuclear activity, our results suggest that Ni(II) may affect cytokine secretion indirectly via modulation of the Nrf2 pathway.
Lewis
Jill B
JB
Department of Oral Biology and Maxillofacial Pathology, AD1417, Medical College of Georgia, Augusta, GA 30912-1126, USA.
Messer
Regina L
RL
McCloud
Veronica V
VV
Lockwood
Petra E
PE
Hsu
Stephen D
SD
Wataha
John C
JC
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009532:Nickel / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D009532:Nickel