Tunicamycin aggravates endoplasmic reticulum stress and airway inflammation via PERK-ATF4-CHOP signaling in a murine model of neutrophilic asthma

J Asthma. 2017 Mar;54(2):125-133. doi: 10.1080/02770903.2016.1205085. Epub 2016 Jul 6.

Abstract

Introduction: Endoplasmic reticulum (ER) stress has been considered to be an important regulator of airway inflammation in the pathogenesis of bronchial asthma, but the mechanism of ER stress involved in neutrophilic asthma remain not fully understood.

Methods: Tunicamycin is a mixture of homologous nucleoside antibiotics, which is used to induce ER stress. In the present study, Tunicamycin was administered to mouse bronchial epithelial cells and a neutrophilic asthma model (OVALPS-OVA mice), and ER stress indicators and inflammatory cytokines were measured by Western blotting and Elisa.

Results: Tunicamycin not only induced ER stress in mouse bronchial epithelial cells, but also increased expression of inflammation indicators such as IL-6, IL-8, and TNF-α via PERK-ATF4-CHOP signaling. Additionally, the phosphorylation of PERK and the expression levels of ATF4 and CHOP proteins and inflammatory cytokines (IL-6, IL-8 and TNF-α) were elevated in the lung tissue of OVALPS-OVA mice. Administering tunicamycin further increased protein expression levels of ER stress indicators and inflammatory cytokines, and resulted in more severe asthma phenotypes in OVALPS-OVA mice, suggesting that PERK-ATF4-CHOP signaling is associated with airway inflammation in neutrophil-dominant asthma.

Conclusions: These data support the emerging notion that regulation of ER stress could be strongly associated with the development of neutrophilic asthma.

Keywords: Airway inflammation; ER stress; PERK-ATF4-CHOP signaling; inflammatory cytokine; neutrophilic asthma; tunicamycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / drug effects
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Asthma / physiopathology*
  • Bronchi / drug effects
  • Bronchi / metabolism
  • Bronchoalveolar Lavage Fluid / cytology
  • Cells, Cultured
  • Cytokines / drug effects
  • Cytokines / metabolism
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Inflammation Mediators / metabolism*
  • Interleukin-6 / biosynthesis
  • Interleukin-8 / biosynthesis
  • Mice
  • Signal Transduction / drug effects
  • Transcription Factor CHOP / drug effects
  • Transcription Factor CHOP / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tunicamycin / pharmacology*
  • eIF-2 Kinase / drug effects
  • eIF-2 Kinase / metabolism

Substances

  • Cytokines
  • Inflammation Mediators
  • Interleukin-6
  • Interleukin-8
  • Tumor Necrosis Factor-alpha
  • Tunicamycin
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • PERK kinase
  • eIF-2 Kinase