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Proc Natl Acad Sci U S A. 2010 May 25;107(21):9789-94. doi: 10.1073/pnas.1000779107. Epub 2010 May 5.

Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1beta secretion.

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1
Cell Biology Unit, National Cancer Research Institute, 16132 Genoa, Italy.

Abstract

In healthy monocytes, Toll-like receptor (TLR) engagement induces production of reactive oxygen species (ROS), followed by an antioxidant response involved in IL-1beta processing and secretion. Markers of the antioxidant response include intracellular thioredoxin and extracellular release of reduced cysteine. Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory diseases in which Nod-like receptor family pyrin domain-containing 3 (NLRP3) gene mutations lead to increased IL-1beta secretion. We show in a large cohort of patients that IL-1beta secretion by CAPS monocytes is much faster than that by healthy monocytes. This accelerated kinetics is caused by alterations in the basal redox state, as well as in the redox response to TLR triggering displayed by CAPS monocytes. Indeed, unstimulated CAPS monocytes are under a mild oxidative stress, with elevated levels of both ROS and antioxidants. The redox response to LPS is quickened, with early generation of the reducing conditions favoring IL-1beta processing and secretion, and then rapidly exhausted. Therefore, secretion of IL-1beta is accelerated, but reaches a plateau much earlier than in healthy controls. Pharmacologic inhibition of the redox response hinders IL-1beta release, confirming the functional link between redox impairment and altered kinetics of secretion. Monocytes from patients with juvenile idiopathic arthritis display normal kinetics of redox response and IL-1beta secretion, excluding a role of chronic inflammation in the alterations observed in CAPS. We conclude that preexisting redox alterations distinct from CAPS monocytes anticipate the pathogen-associated molecular pattern molecule-induced generation of the reducing environment favorable to inflammasome activation and IL-1beta secretion.

PMID:
20445104
PMCID:
PMC2906851
DOI:
10.1073/pnas.1000779107
[Indexed for MEDLINE]
Free PMC Article
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