NF-κB-DICER-miRs Axis Regulates TNF-α Expression in Responses to Endotoxin Stress

Unbalanced tumor necrosis factor (TNF)-alpha production is associated with pathogenesis of a variety of human diseases. However, the molecular pathways maintaining TNF-alpha homeostasis remain elusive. Here, we report that NF-kappa B/p65-DICER-miRs axis negatively regulates TNF-alpha production. We demonstrated that NF-kappa B bound to DICER promoter and transcriptionally regulated DICER expression. In addition, the NF-kappa B/DICER signaling suppresses TNF-alpha expression by generating mature forms of miR-125b and miR-130a which negatively regulate TNF-alpha mRNA. Furthermore, we showed that the hepatocyte-specific depletion of Dicer in mice resulted in TNF-alpha overproduction and sensitized the mice to endotoxin, which could be corrected by administration of miR-125b mimics. These data suggest that NF-kappa B/p65-DICER-miRs axis involved in maintaining of TNF-alpha homeostasis, and injection of miR-125b as a potential therapeutic method for septic shock.