A novel pathway for nickel-induced interleukin-8 expression.

Area of Science:

• Environmental toxicology
• Cellular and molecular biology
• Respiratory medicine

Background:

• Inhalation of nickel subsulfide (Ni3S2) is linked to lung inflammation and fibrosis.
• The precise molecular mechanisms underlying Ni3S2-induced lung injury remain unclear.

Purpose of the Study:

• To investigate the cellular response of human airway epithelial cells to Ni3S2 exposure.
• To determine if Ni3S2 induces the expression of inflammatory cytokines, specifically interleukin-8 (IL-8).

Main Methods:

• BEAS-2B human airway epithelial cells were exposed to non-cytotoxic levels of Ni3S2.
• IL-8 protein and mRNA levels were quantified using various techniques.
• IL-8 promoter activity was assessed using luciferase reporter constructs.
• Key signaling pathways and transcription factors were inhibited or mutated to identify their role.

Main Results:

• Ni3S2 exposure for 48 hours significantly increased IL-8 protein levels, preceded by increased IL-8 mRNA transcription.
• Nickel-induced IL-8 transcription required a specific region (-272 bp) of the IL-8 promoter.
• The transcription factor AP-1, along with GATA and C/EBP sites, was crucial for nickel-induced IL-8 expression.
• Inhibition of ERK and phosphatidylinositol 3-kinase pathways attenuated Ni3S2-induced IL-8 production.

Conclusions:

• Ni3S2 exposure induces IL-8 expression in airway epithelial cells via transcriptional activation.
• A novel pathway involving AP-1 and non-traditional transcription factors mediates nickel-induced IL-8 transcription.
• These findings provide insights into the molecular mechanisms of nickel-induced lung inflammation.