Down-regulation of MicroRNA-31 in CD4(+) T Cells Contributes to Immunosuppression in Human Sepsis by Promoting T(H)2 Skewing

Heide, Verena van der; Moehnle, Patrick; Rink, Jessica; Briegel, Josef und Kreth, Simone (2016): Down-regulation of MicroRNA-31 in CD4(+) T Cells Contributes to Immunosuppression in Human Sepsis by Promoting T(H)2 Skewing. In: Anesthesiology, Bd. 124, Nr. 4: S. 908-922

Abstract

Background: Immunosuppression has been recognized as a major cause of sepsis-related mortality. Currently, there is much interest in identifying central hubs controlling septic immunoparalysis. In this context, in this study, the authors investigate the role of microRNA-31 (miR-31) as a regulator of T cell functions. Methods: Primary human T cells were separated from healthy volunteers (n = 16) and from sepsis patients by magnetic beads (n = 23). Expression of mRNA/microRNA (miRNA) was determined by real-time polymerase chain reaction. Gene silencing was performed by small interfering RNA transfection, and miRNA-binding sites were validated by reporter gene assays. Effects of miR-31 or anti-miR-31 transfection were analyzed by real-time polymerase chain reaction, Western blotting, and flow cytometry. Results: Overexpression of miR-31 in stimulated CD4(+) T cells promoted a proinflammatory phenotype with increased levels of interferon- (1.63 0.43;P = 0.001;means +/- SD) and reduced expression of interleukin (IL)-2 (0.66 +/- 0.19;P = 0.005) and IL-4 (0.80 +/- 0.2;P = 0.0001). In contrast, transfection of anti-miR-31 directed cells toward a T(H)2 phenotype. Effects on IL-2 and IL-4 were mediated by targeting of nuclear factor-kappa B-inducing kinase and factor-inhibiting hypoxia-inducible factor-1. Interferon-, however, was influenced via control of signaling lymphocytic activation molecule (SLAM)-associated protein, an essential adaptor molecule of immunomodulatory SLAM receptor signaling, which was identified as a novel target gene of miR-31. In sepsis patients, an epigenetically driven down-regulation of miR-31 was found (0.44 +/- 0.25;P = 0.0001), associated with increased nuclear factor-kappa B-inducing kinase, factor-inhibiting hypoxia-inducible factor-1, SLAM-associated protein expression, and a cytokine shift toward T(H)2. Conclusions: In this study, the authors provide novel evidence of miR-31 as an emerging key posttranscriptional regulator of sepsis-associated immunosuppression. The study results contribute to a further understanding of septic immunoparalysis and provide new perspectives on miRNA-based diagnostic approaches.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0003-3022
• Allianz-/Nationallizenz: Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
• Sprache: Englisch