Paclitaxel alleviated liver injury of septic mice by alleviating inflammatory response via microRNA-27a/TAB3/NF-κB signaling pathway

Abstract

Excessive inflammatory response and apoptosis play an important role in the sepsis-induced liver injury. Paclitaxel, a diterpene alkaloid of Taxus brevifolia, is widely used as an anti-tumor drug and shows protective effects on acute lung and kidney injury. However, whether it has a protective effect against sepsis-induced liver injury has not been reported. The objective of this study was to investigate the protective effects of paclitaxel in septic liver injury in mice and associated molecular mechanisms. Our results showed that paclitaxel treatment improved LPS-induced liver injury, as evidenced by the reduced aminotransferase activity, histological scores and apoptosis in the liver tissues. This was accompanied by the alleviating of inflammation and oxidative stress, such as decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-6) interleukin-1β (IL-1β) and malondialdehyde (MDA) and increased levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) in serum and liver tissues. Subsequent microarray and qRT-PCR analysis further showed that miR-27a was significantly decreased in mice with sepsis, which was recovered by paclitaxel pretreatment. Antagomir-miR-27a suppressed the therapeutic effects of paclitaxel in mice liver injury model via promoting inflammatory response. Of note, TAB3, which participated in the activation of the NF-κB signaling pathway, was identified as a direct target of miR-27 by luciferase reporter gene assays. Then, we revealed a reverse relationship between miR-27a expression levels and TAB3 mRNA levels in liver tissues from septic mice. Furthermore, paclitaxel treatment significantly decreased the expression of NF-κB p65, but increased inhibitor of nuclear factor-κB-α (IκBα) protein levels in septic mice, suggesting the inactivation of NF-κB signaling pathway. Notably, the inhibitory effects of paclitaxel on NF-κB signaling pathway were reversed by antagomir-miR-27a. Our data indicated that paclitaxel significantly attenuated septic induced liver injury through reducing inflammatory response via miR-27a/TAB3/NF-κB signaling pathway.

Keywords: Inflammatory response; MicroRNA-27a; NF-κB signaling pathway; Paclitaxel; Sepsis.