MicroRNA-141 ameliorates alcoholic hepatitis-induced intestinal injury and intestinal endotoxemia partially via a TLR4-dependent mechanism

摘要

Alcoholic hepatitis (AH) is a fatal inflammatory syndrome with no effective treatments. Intestinal injury and intestinal endotoxemia (IETM) contribute greatly in the development of AH. MicroRNAs (miRNAs/miRs) have been reported to affect intestinal injury. The present study aims to investigate the role of miR-141 in intestinal injury and IETM of AH. An AH model was successfully established in mice and they were the injected with a series of miR-141 mimic, miR-141 inhibitor or toll like receptor 4 monoclonal antibody (TLR4mAb; an inhibitor of the Toll-like receptor TLR pathway). After that, the intestinal tissues and intestinal epithelial cells were isolated from differently treated AH mice. The expression of miR-141 and TLR pathway-associated genes and the levels of inflammatory factors were determined. Furthermore, a target prediction program and a luciferase reporter assay were employed to examine whether miR-141 targets TLR4. Finally, MTT and transwell assays were carried out to detect cell viability and cell permeability. Intestinal tissues from AH mice treated with miR-141 mimic or TLR4mAb exhibited lower levels of inflammatory factors and reduced expression of the TLR pathway-associated genes, suggesting a decreased inflammatory response as well as inactivation of the TLR pathway by miR-141. The luciferase reporter assay suggested that miR-141 negatively regulated TLR4. Intestinal epithelial cells treated with miR-141 mimic or TLR4mAb demonstrated enhanced viability and reduced permeability. Opposite results were observed in AH mice treated with a miR-141 inhibitor. Collectively, the results of the present study demonstrated that miR-141 could ameliorate intestinal injury and repress the progression of IETM through targeting TLR4 and inhibiting the TLR pathway.