A novel pathway for nickel-induced interleukin-8 expression.
Inhalation of particulate nickel subsulfide (Ni3S2) causes chronic active inflammation and fibrosis of the lungs. However, the mechanisms for these effects are not well understood. Therefore, cell culture experiments with BEAS-2B human airway epithelial cells were conducted to test the hypothesis that exposure to non-cytotoxic levels of Ni3S2 induces expression of inflammatory cytokines such as interleukin-8 (IL-8). Exposure to Ni3S2 for 48 h was required to significantly increase IL-8 protein levels. Transcriptional stimulation of IL-8 mRNA levels preceded the increase in protein. Transient exposure to soluble nickel sulfate failed to increase IL-8 mRNA. Transfection with truncated IL-8 promoter constructs linked to the luciferase gene demonstrated that nickel-induced IL-8 transcription required -272 bp of the promoter relative to the transcriptional start site. A -133-bp construct, containing cytokine and hypoxia-sensitive AP-1, NF-IL6, and NF-kappaB sites, was insufficient for induction by nickel. Transfection with a dominant negative AP-1 construct or mutation of the AP-1, GATA, or C/EBP sites in the -272-bp IL-8 promoter construct blocked induction by nickel. Inhibiting ERK, phosphatidylinositol 3-kinase, but not p38 kinase, diacylglycerol kinase, or hypoxia-inducible factor-1alpha, attenuated nickel induction of IL-8. These studies indicate that nickel induced IL-8 transcription through a novel pathway that requires both AP-1 and non-traditional transcription factors.
Barchowsky
Aaron
A
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Soucy
Nicole V
NV
O'Hara
Kimberley A
KA
Hwa
John
J
Noreault
Trisha L
TL
Andrew
Angeline S
AS
D001980:Bronchi; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D009532:Nickel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D022762:CCAAT-Enhancer-Binding Proteins; D016209:Interleukin-8; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D009532:Nickel; C017557:nickel subsulfide