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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; and 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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.

³ Address 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

⁴ Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern molecule; NOD, nucleotide oligomerization domain; ROS, reactive oxygen species; Trx, thioredoxin; SOD1, superoxide dismutase 1; GSH, glutathione; NPSH, non protein thiol; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; BSO, L-buthionine-(S,R)-sulfoximine; DNCB, 1-chloro-2,4-dinitrobenzene; DPI, diphenylene iodonium; MDP, muramyl dipeptide; DTNB, 5,5'-dithiobis-(2-nitrobenzoic acid); H₂DCF-DA, 2',7'-dichlorofluorescein diacetate; MCB, monochlorobimane.