Abstract

Propofol promotes endotoxin tolerance by upregulating microRNA-let-7e

Author(s): Ya-Ying Chang,Wei-HorngJean,Yuh-Huey Chao,Cheng-Wei Lu

Background: Endotoxin Tolerance (ET) refers to the hypo-responsiveness to repeated endotoxin stimulation. During ET, the production of Lipopolysaccharide (LPS)-triggered cytokines is reduced after pre-exposure to LPS, and macrophages polarize toward M2-phenotype. ET protects against hyperactive inflammation, but leads to immunosuppression. MicroRNA-let-7e (miR-let-7e) mitigates toll-like receptor 4 signaling, leading to ET development. Propofol, a widely used sedative agent for critical patients, upregulates miR-let-7e expression. Effects of propofol on ET remain unstudied. Methods: To induce ET, J774.1 cells were stimulated with LPS (200 ng/ml, 24 h) after pre-exposured to LPS (200 ng/ml, 24 h). Propofol (10 µg/ml, 24 h) was administered before pre-exposure to LPS. Levels of Tumor Necrosis Factor-⍺ (TNF-⍺), Interleukin-6 (IL-6), Nuclear Factor-κB (NF-κB) p65, and arginase1 (Arg1, an M2-associated enzyme) were measured with or without inhibiting miR-let-7e. Results: During ET, propofol mitigated NF-κB-triggered TNF-⍺ and IL-6, and increased Arg1 expression, suggesting the enhancing effect of propofol on ET. Furthermore, propofol upregulated miR-let-7e. Effects of propofol on cytokine levels, Arg1 expression, and NF-κB activity were counteracted by inhibiting miR-let-7e. Conclusions: propofol promoted ET by upregulating miR-let-7e. The immunosuppressive effect of propofol through enhancing ET in critical patients should be considered