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Pathogen-Induced Interleukin-1β Processing and Secretion Is Regulated by a Biphasic Redox Response¹

Sara Tassi^2,*, Sonia Carta^2,*, Roberta Vené^*, Laura Delfino^*, Maria Rosa Ciriolo and Anna Rubartelli^3,*

*Cell Biology Unit, National Cancer Research Institute, Genova, Italy; Department Biology, University of Rome "Tor Vergata", Rome, Italy and Research Centre IRCCS San Raffaele, Via dei Bonacolsi, Rome, Italy

In this study, we show that IL-1β 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-1β. ROS production and antioxidant response are both required, because either inhibitors of NADPH oxidase and of thioredoxin reductase impair IL-1β secretion. These inhibitors also hinder cysteine release and consequently prevent reduction of the extracellular medium: addition of exogenous reducing agents restores IL-1β secretion. Not only silencing of thioredoxin, but also of the ROS scavenger superoxide dismutase 1 results in inhibition of IL-1β secretion. Thus, PAMP-induced ROS trigger an antioxidant response involving intracellular redox enzymes and release of cysteine, ultimately required for IL-1β processing and secretion.

³Address correspondence and reprint requests to Dr. Anna Rubartelli, Cell Biology Unit, National Cancer Research Institute, Largo Rosanna Benzi 10, Genova, Italy. E-mail address: anna.rubartelli{at}istge.it

¹ This work was supported in part by grants from Ministero della Salute, ISS, Compagnia San Paolo, Associazione Italiana per la Ricerca sul Cancro, Telethon.

² S.T. and S.C. contributed equally to this work.