Luteolin-Mediated Inhibition of Hepatic Stellate Cell Activation via Suppression of the STAT3 Pathway.

Claire Cummins,Gabriel Graham,Xiaofu Wang,Ravi Radhakrishnan,Hong-Yan Tie,Omar Nunez Lopez,Jia Zhou

doi:10.3390/ijms19061567

Abstract

Hepatic stellate cell (HSC) activation is responsible for hepatic fibrogenesis and is associated with an overexpression of transcription 3 (STAT3). Luteolin, a common dietary flavonoid with potent anti-inflammatory properties, has previously demonstrated antifibrogenic properties in HSCs but the mechanism has not been fully elucidated. Activated human and rat hepatic stellate cell lines LX-2 and HSC-T6 were used to study the effects of luteolin on HSCs. Cellular proteins were determined by western blot and immunofluorescence. Cell proliferation was assessed with Alamar Blue assay. Luteolin significantly decreased LX-2 and HSC-T6 cell viability in a time-and-dose-dependent manner, as well as decreased HSC end-products α-smooth muscle actin (α-SMA), collagen I, and fibronectin. Luteolin decreased levels of total and phosphorylated STAT3, suppressed STAT3 nuclear translocation and transcriptional activity, and attenuated expression of STAT3-regulated proteins c-myc and cyclin D1. STAT3 specific inhibitors stattic and SH-4-54 demonstrated similar effects on HSC viability and α-SMA production. In LX-2 and HSC-T6 cells, luteolin demonstrates a potent ability to inhibit hepatic fibrogenesis via suppression of the STAT3 pathway. These results further elucidate the mechanism of luteolin as well as the effect of the STAT3 pathway on HSC activation.

Highlights

Hepatic fibrosis is a wound-healing response that is the result of hepatic stellate cell (HSC)activation and subsequent excess extracellular matrix (ECM) deposition
signal transducer and activator of transcription 3 (STAT3) pathway after luteolin administration, we looked at total and
To examine the role of the STAT3 pathway after luteolin administration, we looked at total and levels To in examine a dose-dependent manner

Summary

Introduction

Hepatic fibrosis is a wound-healing response that is the result of hepatic stellate cell (HSC)activation and subsequent excess extracellular matrix (ECM) deposition. The ECM is a hydrated gel with several components, including up to 30% collagens, as well as elastins, fibronectins, laminins, and proteoglycans [1]. HSC activation leads to cell proliferation and over-expression of α-smooth muscle actin (α-SMA), collagens I and III, and over-expression of multiple cytokines [3,4,5,6,7]. HSCs are activated by a variety of stimuli, including transforming growth factor ß1 (TGF-ß), nuclear factor kappa light-chain enhancer of activated B cells (NF-κB), lipopolysaccharide (LPS), and tissue hypoxia [8]. The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is responsible for regulation of cell growth and survival. Activation of STAT3 in HSCs can help promote HSC survival, Int. J.

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Conclusion