Chemioxyexcitation (delta pO2/ROS)-dependent release of IL-1 beta, IL-6 and TNF-alpha: evidence of cytokines as oxygen-sensitive mediators in the alveolar epithelium.
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 Deltap O(2)regimen (oxyexcitation). The peak of TNF-alpha (4 h) preceded IL-1beta and IL-6 (6-9 h), indicating a positive feedback autocrine loop confirmed by exogenous rmTNF-alpha. 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 (O(2)-). 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 p O(2)constitutes a potential signalling mechanism within the perinatal lung allowing upregulation of cytokines in an ROS-dependent manner.
Haddad
J J
JJ
Oxygen Signalling Group, Center for Research into Human Development, Tayside Institute of Child Health, Faculty of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK. j.j.haddad@dundee.ac.uk
Safieh-Garabedian
B
B
Saadé
N E
NE
Kanaan
S A
SA
Land
S C
SC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism* / Q000502:physiology; D015850:Interleukin-6 / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010100:Oxygen / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000502:physiology; D020545:Respiratory Mucosa / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D013482:Superoxide Dismutase / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology
D000975:Antioxidants; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D017665:Hydroxyl Radical; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D010100:Oxygen