Arsenic-induced dose-dependent modulation of the NF-kappa B/IL-6 axis in thymocytes triggers differential immune responses

作者：Choudhury Sreetama; Gupta Payal; Ghosh Sayan; Mukherjee Sudeshna; Chakraborty Priyanka; Chatterji Urmi; Chattopadhyay Sreya^*

来源：Toxicology, 2016, 357: 85-96.

DOI：10.1016/j.tox.2016.06.005

• Arsenic
• Thymus
• Oxidative stress
• Apoptosis
• NF-kappa B/IL-6/STAT3
• nTreg

Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30 days. Detailed study of the thymus, a primary immune organ, revealed arsenic mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-kappa B/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-kappa B activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune-suppression. Our study establishes a novel role of arsenic in regulating immune homeostasis in context to its dose, where, at higher doses, arsenic related upregulation of NF-kappa B cascade takes on an alternative role that is correlated with increased immune-suppression.

• 出版日期2016-5-16