Levels Of Proteasome Subunit Expression Provide Information About Host’s Immune System Status

Abstract

Mortality due to bacterial septic shock is a major healthcare issue and incidence is increasing worldwide. The objective of the present study was to evaluate expression levels of proteasome subunits as circulatory markers, in plasma and blood RNA obtained from severe septic patients and control volunteers, in order to differentiate patients in a pro-inflammatory phase from those in a subsequent tolerant phase. As an in vitro model, blood CD14+ monocytes were treated with lipopolysaccharide (LPS) to investigate the mechanism of inflammation/tolerance. We evaluated plasma biomarkers from control and septic patients using ELISA or bead assays, and blood RNA samples by using real time qPCR. We identified that plasma levels of CRP, VCAM1, ICAM1, resistin, bilirubin and creatinine, were robustly upregulated in septic shock patients, as compared to controls. Whole blood total RNA analysis revealed that expression of immunoproteasome LMP subunits, cytokines such as IL-8 were downregulated, while autophagy gene atg7 and resistin were upregulated in severely septic patients, as compared to controls, suggesting that these severe septic patients were in a state of tolerance (unresponsive to LPS). However, treatment of tolerant CD14+ monocytes with IFNy, followed by LPS, reversed the tolerance response by upregulating gene expression of proteasome subunits and the other biomarkers determined in this study. Overall, our data define a novel group of clinical biomarkers that can differentiate septic shock patients that are in an inflammatory phase or a tolerant phase, which can be strongly correlated with high or low expression of proteasome subunits. These findings will be vital in designing effective novel therapeutic approaches for sepsis, and other diseases based on inflammation.