Endoplasmic reticulum stress induced by lipopolysaccharide is involved in the association between inflammation and autophagy in INS‑1 cells

Mol Med Rep. 2017 Nov;16(5):5787-5792. doi: 10.3892/mmr.2017.7350. Epub 2017 Aug 24.

Abstract

Type 2 diabetes is a chronic inflammatory disease. Autophagy, the dynamic process of lysosomal degradation of damaged organelles and proteins, may protect β‑cells from destruction by inflammation in type 2 diabetes. The present study investigated the role of autophagy, inflammation and endoplasmic reticulum (ER) stress in type 2 diabetes. INS‑1 cells were incubated with lipopolysaccharide. The chemical chaperone 4‑phenylbutyric acid was used to inhibit ER stress, and 3‑methyadenine (3‑MA) was used to inhibit autophagy. Apoptosis was detected by flow cytometry and cell proliferation using Cell Counting kit‑8 solution. Light chain‑3B, interleukin (IL) 1β, caspase‑1 and C/EBP homologous protein production were assessed by western blotting, and rat activating transcription factor 4 and rat binding immunoglobulin heavy chain protein gene expression were determined by real‑time reverse transcription‑polymerase chain reaction. The results showed that inhibiting autophagy with 3‑MA unexpectedly contributed to cell death in β‑cells. This response was associated with an increase in inflammatory cytokines, including IL1β and caspase‑1. Inhibiting ER stress with 4‑phenylbutyric acid led to a decrease in cell apoptosis. These results showed that autophagy may have a protective effect by reducing inflammatory cytokines in β‑cells. In addition, the inositol‑requiring enzyme 1 pathway mediated the ER stress associated with autophagy and inflammatory cytokines (IL1β and caspase‑1). Therefore, inflammatory cytokines may be critical signalling nodes, which are associated with ER stress‑mediated β‑cell death.

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Adenine / administration & dosage
  • Adenine / analogs & derivatives
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Autophagy / genetics
  • Caspase 1 / genetics
  • Cell Count
  • Cell Proliferation / drug effects
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / genetics*
  • Gene Expression Regulation / drug effects
  • Heat-Shock Proteins / genetics
  • Humans
  • Inflammation / complications
  • Inflammation / genetics*
  • Inflammation / pathology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Interleukin-1beta / genetics
  • Lipopolysaccharides / toxicity
  • Molecular Chaperones / administration & dosage
  • Phenylbutyrates / administration & dosage
  • Rats
  • Transcription Factor CHOP / genetics

Substances

  • Atf4 protein, rat
  • GRP78 protein, rat
  • Heat-Shock Proteins
  • Interleukin-1beta
  • Lipopolysaccharides
  • Molecular Chaperones
  • Phenylbutyrates
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • 4-phenylbutyric acid
  • Caspase 1
  • Adenine