Cardiac steroid ouabain transcriptionally increases human leukocyte antigen DR expression on monocytes

Sepsis is a life-threatening disease characterized by acute multiple organ dysfunction and immunosuppression that is also called as immunoparalysis. Increasing evidence suggests that immunoparalysis largely contributes to the high mortality of sepsis, but the effective remedies are lacking. As an important antigen presentation molecule, human leukocyte antigen DR (HLA-DR) is remarkably down-regulated in sepsis-induced immunoparalysis, therefore, re-stimulation of HLA-DR expression is expected to be useful in reversing immunoparalysis. We previously described that ouabain, as a Na⁺, K⁺-ATPase ligand, is able to counteract immunoparalysis by regulating TH1 cytokines expression. Here, we expanded the finding that ouabain not only prevents LPS-induced down-regulation of HLA-DR on monocytes, but also transcriptionally activates HLA-DR α/β expression mediated by CIITA4, IRF1, c-Src, and Stat1 phosphorylation. Since ouabain can improve sepsis-induced immunoparalysis by multiple mechanisms, we propose that ouabain may be a promising agent in septic therapy that deserves further investigation.