Emodin Attenuates Lipopolysaccharide-Induced Acute Liver Injury via Inhibiting the TLR4 Signaling Pathway in vitro and in vivo

Yan Ding,Pan Liu,Lei Zhao,Zhi-Lin Chen,Xuan Zhou,You-Qin Wang,Lei Luo,Shao-Jun Zhang,Xin Cai

doi:10.3389/fphar.2018.00962

Abstract

Aims: Emodin is an anthraquinone with potential anti-inflammatory properties. However, the possible molecular mechanisms and protective effects of emodin are not clear. The objective of this study was to investigate the possible molecular mechanisms and protective effects of emodin on lipopolysaccharide (LPS)-induced acute liver injury (ALI) via the Toll-like receptor 4 (TLR4) signaling pathway in the Raw264.7 cell line and in Balb/c mice.Methods: This study established an inflammatory cellular model and induced an ALI animal model. TLR4 was overexpressed by lentivirus and downregulated by small interfering RNA (siRNA) technology. The mRNA and protein levels of TLR4 and downstream molecules were detected in cells and liver tissue. The tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 levels in supernatant and serum were determined by ELISA. The distribution and expression of mannose receptor C type 1 (CD206) and arginase 1 (ARG1) in the liver were tested by immunofluorescence. Mouse liver function and histopathological observations were assessed.Results: Administration of emodin reduced the protein and/or mRNA levels of TLR4 and its downstream molecules following LPS challenge in Raw264.7 cells and in an animal model. Additionally, emodin suppressed the expression of TNF-α and IL-6 in cell culture supernatant and serum. The inhibitory effect of emodin was also confirmed in RAW264.7 cells, in which TLR4 was overexpressed or knocked down. Additionally, ARG1 and CD206 were elevated in the emodin groups. Emodin also decreased serum ALT and AST levels and alleviated the liver histopathological damage induced by LPS.Conclusion: Emodin showed excellent hepatoprotective effects against LPS-induced ALI, possibly by inhibiting TLR4 signaling pathways.

Highlights

Hepatic disorder is a major disease endangering human health
The inhibitory effect of emodin was confirmed in RAW264.7 cells, in which Toll-like receptor 4 (TLR4) was overexpressed or knocked down
The results of this study clearly indicated that emodin could significantly inhibit the expression levels of the myeloid differentiation factor88 (MyD88) and TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathways on the TLR4 pathway and reduce the expression levels of TNFα and IL-6

Summary

Introduction

Lipopolysaccharide (LPS)-induced liver injury belongs to a class of liver inflammatory response syndromes. This type of injury exhibits a high incidence, high fatality rate, high cost, and increasing morbidity (Liu et al, 2017). Macrophages, a type of immunological cell, have an important role in both innate and adaptive immune systems (Sun et al, 2016; Zhu et al, 2016). LPS, a large molecule consisting of a polysaccharide and a lipid, is the main constituent of the outer membrane of intracellular Gramnegative bacteria and can activate liver macrophages, which advances the secretion of inflammatory cytokines. No specific treatment interventions are currently available for LPS-induced acute liver injury (ALI). Safe and efficacious treatment strategies against an LPS-induced ALI model are urgently needed (Chen et al, 2017)

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Discussion

Conclusion