Inorganic arsenic induces pyroptosis and pancreatic β cells dysfunction through stimulating the IRE1α/TNF-α pathway and protective effect of taurine

Food Chem Toxicol. 2019 Mar;125:392-402. doi: 10.1016/j.fct.2019.01.015. Epub 2019 Jan 18.

Abstract

Low-level inorganic arsenic (iAs) in drinking water is a risk factor for β cells dysfunction. Taurine (Tau) is a kind of semi-essential β amino acid, and beneficial for β cell function. However, the effects of Tau on arsenic trioxide (As2O3) induced β cells dysfunction and related mechanisms are still uncertain. Here, we found that Tau relieved As2O3-induced endoplasmic reticulum (ER) stress, inflammation and pyroptosis in rat pancreas. In INS-1 cells, with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor pretreatment, As2O3-induced activation of pyroptosis was decreased; with tumor necrosis factor-α (TNF-α) inhibitor pretreatment, As2O3-induced activation of NLRP3 inflammasome and pyroptosis were decreased; further, with the inositol-requiring enzyme 1 alpha (IRE1α) inhibitor, As2O3-induced induction of TNF-α was decreased. Tau markedly protected As2O3-induced β cells dysfunction by reducing the phosphorylation of IRE1α, production of TNF-α, activation of NLRP3 inflammasome and pyroptosis. Our results revealed that ER stress dependent inflammation and pyroptosis are critical pathogenic components of As2O3-induced β cell dysfunction. Moreover, TNF-α was a critical signaling node that linked As2O3-induced ER stress and pyroptosis. Tau was an effective supplement against As2O3-induced β cells dysfunction through the pathway as mentioned above.

Keywords: Inorganic arsenic; Pyroptosis; Taurine; Tumor necrosis factor-α; β cells dysfunction.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Arsenic Trioxide / adverse effects*
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress / drug effects
  • Endoribonucleases / metabolism
  • Female
  • Inflammasomes / drug effects
  • Inflammation / drug therapy
  • Insulin-Secreting Cells / drug effects*
  • Multienzyme Complexes / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Pregnancy
  • Protective Agents / pharmacology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyroptosis / drug effects*
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Taurine / pharmacology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Ern1 protein, rat
  • Inflammasomes
  • Multienzyme Complexes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, rat
  • Protective Agents
  • Tumor Necrosis Factor-alpha
  • Taurine
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Arsenic Trioxide