Chemioxyexcitation (ΔpO2/ROS)-dependent release of IL-1β, IL-6 and TNF-α: Evidence of cytokines as oxygen-sensitive mediators in the alveolar epithelium

John J. E. Haddad (Lead / Corresponding author), Bared Safieh-Garabedian, Nayef E. Saadé, Salim A. Kanaan, Stephen C. Land

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

The signalling mechanisms in oxidative stress mediated by cytokines in the perinatal alveolar epithelium are not well known. In an in vitro model of fetal alveolar type II epithelial cells, we investigated the profile of cytokines in response to ascending ΔpO2 regimen (oxyexcitation). The peak of TNF-α (4 h) preceded IL-1β and IL-6 (6-9 h), indicating a positive feedback autocrine loop confirmed by exogenous rmTNF-α. Reactive oxygen species (ROS) induced a dose-dependent release of cytokines, an effect specifically obliterated by selective antioxidants of the hydroxyl radical (·OH) and superoxide anion (O2 -). Actinomycin and cycloheximide blocked the induced production of cytokines, implicating transcriptional and translational control. Whilst the dismutating enzymes superoxide dismutase (SOD) and catalase were ineffective in reducing ROS-induced cytokines, MnP, a cell-permeating SOD mimetic, abrogated xanthine/xanthine oxidase-dependent cytokine release. Desferrioxamine mesylate, which inhibits the iron-catalysed generation of OH via the Fenton reaction, exhibited a mild effect on the release of cytokines. Dynamic variation in alveolar pO2 constitutes a potential signalling mechanism within the perinatal lung allowing upregulation of cytokines in an ROS-dependent manner.

Original languageEnglish
Pages (from-to)138-147
Number of pages10
JournalCytokine
Volume13
Issue number3
DOIs
Publication statusPublished - 7 Feb 2001

Keywords

  • Antioxidant
  • Bronchopulmonary dysplasia
  • Cytokine
  • Development
  • Pathophysiology
  • Reactive oxygen species
  • Redox equilibrium

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