State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
Department of Anesthesiology and Critical Care, Changhai Hospital, Naval Medical University, Shanghai, China.
Steroids. 2021 Nov;175:108915. doi: 10.1016/j.steroids.2021.108915. Epub 2021 Sep 9.
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.
脓毒症是一种以急性多器官功能障碍和免疫抑制为特征的危及生命的疾病，也称为免疫麻痹。越来越多的证据表明，免疫麻痹在很大程度上导致了脓毒症的高死亡率，但缺乏有效的治疗方法。作为一种重要的抗原呈递分子，人类白细胞抗原 DR（HLA-DR）在脓毒症引起的免疫麻痹中显著下调，因此，重新刺激 HLA-DR 表达有望用于逆转免疫麻痹。我们之前描述过，哇巴因作为一种 Na+，K+-ATP 酶配体，能够通过调节 TH1 细胞因子的表达来对抗免疫麻痹。在这里，我们扩展了发现，哇巴因不仅可以防止 LPS 诱导的单核细胞 HLA-DR 的下调，还可以通过 CIITA4、IRF1、c-Src 和 Stat1 磷酸化转录激活 HLA-DRα/β的表达。由于哇巴因可以通过多种机制改善脓毒症引起的免疫麻痹，我们提出哇巴因可能是脓毒症治疗中有前途的药物，值得进一步研究。
