Pathogen-induced interleukin-1beta processing and secretion is regulated by a biphasic redox response.
In this study, we show that IL-1beta processing and secretion induced by pathogen-associated molecular pattern (PAMP) molecules in human monocytes is regulated by a biphasic redox event including a prompt oxidative stress and a delayed antioxidant response. Namely, PAMPs induce an early generation of reactive oxygen species (ROS) followed by increase of intracellular thioredoxin and release of reduced cysteine: this antioxidant phase is paralleled by secretion of mature IL-1beta. ROS production and antioxidant response are both required, because either inhibitors of NADPH oxidase and of thioredoxin reductase impair IL-1beta secretion. These inhibitors also hinder cysteine release and consequently prevent reduction of the extracellular medium: addition of exogenous reducing agents restores IL-1beta secretion. Not only silencing of thioredoxin, but also of the ROS scavenger superoxide dismutase 1 results in inhibition of IL-1beta secretion. Thus, PAMP-induced ROS trigger an antioxidant response involving intracellular redox enzymes and release of cysteine, ultimately required for IL-1beta processing and secretion.
Tassi
Sara
S
Cell Biology Unit, National Cancer Research Institute, Genova, Italy.
Carta
Sonia
S
Vené
Roberta
R
Delfino
Laura
L
Ciriolo
Maria Rosa
MR
Rubartelli
Anna
A
D001426:Bacterial Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011135:Polysaccharides, Bacterial / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism
D001426:Bacterial Proteins; D053583:Interleukin-1beta; D011135:Polysaccharides, Bacterial; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D019255:NADPH Oxidases; D003545:Cysteine