IL-10 gene down-expression in circulating mononuclear cells duringafter 36h infusion of drotrecogin-α activated: a pilot study

Introduction: To investigate the gene expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in circulating mononuclear cells harvested from septic shock patients on drotrecogin-α activated (DAA) in order to determine whether this treatment has any effect on the inflammation phase. Methods: We have conducted a prospective cohort study in two intensive care departments. Blood samples were collected at inclusion (T1) and 36h later (T2) to measure plasma cytokines and the changes in intracellular TNF-α, IL-10 and IFN-γ mRNA expressions using RT-qPCR. Thirty two septic shock patients were included: 16 with DAA at 24 μg/kg/h/96h (DAA+) and 16 control (DAA−) eligible but contraindicated for DAA because of low platelet count. Results: The basal characteristics were similar in both groups: mortality (50%), plasma cytokine concentrations, and baseline IFN-γ, TNF-α and IL-10 mRNA expressions (DAA+ vs. DAA−). At T2, there was a significant IFN-γ gene down-regulation in DAA+ but not in DAA− patients (-0.34 [-0.62;+1.54] vs. +1.41 [+0.35;+5.87], p=0.008). In survivors, DAA administration was associated with a down-expression of both IFN-γ (-0.65 [-0.93;0.48] vs. +0.7 [-0.04;+1.26], p=0.01) and IL-10 (-0.78 [-0.92;-0.6] vs. -0.18 [-0.68;+0.46], p=0.038). In the non-survivors, DAA infusion was associated with IL-10 over-expression when compared with survivors (+0.54 [-0.35;+11.52] vs. -0.78 [-0.92;-0.6], p<0.001). Conclusion: In this study, lack of IL-10 gene down-expression despite a 36-h infusion of DAA is an ominous sign in septic shock patients suggesting that DAA is not able to reverse outcome. Our results suggesthow that DAA can significantly decreases the expression of antiinflammatory cytokines expression in septic shock patients. and IL-10 or IFN-γ gene downexpression could represent be markers of DAA response.