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

Toxicology. 2016 May 16;357-358:85-96. doi: 10.1016/j.tox.2016.06.005. Epub 2016 Jun 8.

Abstract

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 30days. 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-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB 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-κB cascade takes on an alternative role that is correlated with increased immune-suppression.

Keywords: Apoptosis; Arsenic; NF-κB/IL-6/STAT3; Oxidative stress; Thymus; nTreg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Arsenic / administration & dosage
  • Arsenic / toxicity*
  • Cytokines
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drinking Water / chemistry
  • Immune System / drug effects
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Microscopy, Electron, Scanning
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects*
  • Thymocytes / drug effects*
  • Thymocytes / immunology
  • Thymus Gland / drug effects
  • Thymus Gland / immunology
  • Water Pollutants, Chemical / administration & dosage
  • Water Pollutants, Chemical / toxicity*

Substances

  • Cytokines
  • Drinking Water
  • Interleukin-6
  • NF-kappa B
  • Water Pollutants, Chemical
  • Arsenic