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 E(h) 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)-1β levels. Results showed a 1.7-fold increase in secreted pro-IL-1β levels in U937 monocytes exposed to oxidized E(h) Cys/CySS (−46 mV), compared to controls exposed to a physiological E(h) of −80 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-1β compared to control mice fed an isonitrogenous SAA-adequate diet (P<0.01). Analysis of E(h) Cys/CySS and IL-1β in human plasma revealed a significant positive association between oxidized E(h) Cys/CySS and IL-1β 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-1β levels, and suggest that strategies to preserve E(h) Cys/CySS may represent a means to control IL-1β in inflammatory disease states.