Activation of interleukin-6 and -8 expressions by methylmercury in human U937 macrophages involves RelA and p50

Area of Science:

• Neuroscience
• Toxicology
• Immunology

Background:

• Macrophages accumulate around brain lesions in Minamata disease patients.
• Mercury is detected in brain macrophages, but its role in methylmercury (MeHg) neurotoxicity is unclear.
• The molecular mechanisms of macrophage response to MeHg exposure require elucidation.

Purpose of the Study:

• To investigate how MeHg affects the expression of proinflammatory cytokines, specifically interleukin (IL)-6 and IL-8, in cultured human U937 macrophages.
• To explore the molecular pathways involved in MeHg-induced cytokine activation.
• To assess the potential therapeutic effect of N-acetyl-l-cysteine on MeHg-induced inflammation.

Main Methods:

• Treatment of cultured human U937 macrophages and U-87 MG cells with varying concentrations of MeHg.
• Quantification of IL-6 and IL-8 mRNA and protein expression.
• Luciferase reporter assays to assess nuclear factor kappa B (NF-κB) activation.
• siRNA knockdown experiments to confirm the role of NF-κB subunits.
• Treatment with N-acetyl-l-cysteine to evaluate its suppressive effects.

Main Results:

• MeHg significantly induced IL-6 and IL-8 mRNA and protein expression in U937 macrophages.
• NF-κB activation, involving subunits RelA and p50, was identified as a key mechanism in MeHg-induced IL-6 and IL-8 production.
• MeHg also induced IL-8 expression in U-87 MG cells, suggesting a general response across cell types.
• N-acetyl-l-cysteine suppressed MeHg-induced IL-6 and IL-8 mRNA expression.

Conclusions:

• MeHg exposure triggers an early inflammatory response involving IL-6 and IL-8 expression in macrophages.
• NF-κB pathway activation is crucial for MeHg-induced pro-inflammatory cytokine production.
• These findings suggest a potential role for inflammation in MeHg pathogenesis.
• N-acetyl-l-cysteine demonstrates therapeutic potential for mitigating MeHg-induced inflammation.