Cysteine Redox Potential Determines Pro-Inflammatory IL-1β Levels

Background: Cysteine (Cys) and its disulfide, cystine (CySS) represent the major extracellular thiol/disulfide redox control system. The redox potential (E-h) of Cys/CySS is centered at approximately -80 mV in the plasma of healthy adults, and oxidation of Eh Cys/CySS is implicated in inflammation associated with various diseases. Methodology/Principal Findings: The purpose of the present study was to determine whether oxidized E-h Cys/CySS is a determinant of interleukin (IL)-1 beta levels. Results showed a 1.7-fold increase in secreted pro-IL-1 beta levels in U937 monocytes exposed to oxidized E-h Cys/CySS (246 mV), compared to controls exposed to a physiological E-h of 280 mV (P,<0.01). In LPS-challenged mice, preservation of plasma E-h Cys/CySS from oxidation by dietary sulfur amino acid (SAA) supplementation, was associated with a 1.6-fold decrease in plasma IL-1 beta compared to control mice fed an isonitrogenous SAA-adequate diet (P<0.01). Analysis of Eh Cys/CySS and IL-1 beta in human plasma revealed a significant positive association between oxidized Eh Cys/CySS and IL-1 beta after controlling for age, gender, and BMI (P<0.001). Conclusions/Significance: These data show that oxidized extracellular E-h Cys/CySS is a determinant of IL-1 beta levels, and suggest that strategies to preserve E-h Cys/CySS may represent a means to control IL-1 beta in inflammatory disease states.