AP-1-Targeting Anti-Inflammatory Activity of the Methanolic Extract of Persicaria chinensis.

Muhammad Jahangir Hossen,Jae Youl Cho,Sang Yeol Lee,Woo Seok Yang,Young-Jin Son,Jae Gwang Park,Keejung Yoon,Woo-Jae Chung,Chongsuk Ryou,Deok Jeong,Jong-Hoon Kim,Eunji Kim,Kwang-Soo Baek,Han Gyung Kim,Seung Cheol Kim

doi:10.1155/2015/608126

Abstract

In traditional Chinese medicine, Persicaria chinensis L. has been prescribed to cure numerous inflammatory disorders. We previously analyzed the bioactivity of the methanol extract of this plant (Pc-ME) against LPS-induced NO and PGE2 in RAW264.7 macrophages and found that it prevented HCl/EtOH-induced gastric ulcers in mice. The purpose of the current study was to explore the molecular mechanism by which Pc-ME inhibits activator protein- (AP-) 1 activation pathway and mediates its hepatoprotective activity. To investigate the putative therapeutic properties of Pc-ME against AP-1-mediated inflammation and hepatotoxicity, lipopolysaccharide- (LPS-) stimulated RAW264.7 and U937 cells, a monocyte-like human cell line, and an LPS/D-galactosamine- (D-GalN-) induced acute hepatitis mouse model were employed. The expression of LPS-induced proinflammatory cytokines including interleukin- (IL-) 1β, IL-6, and tumor necrosis factor-α (TNF-α) was significantly diminished by Pc-ME. Moreover, Pc-ME reduced AP-1 activation and mitogen-activated protein kinase (MAPK) phosphorylation in both LPS-stimulated RAW264.7 cells and differentiated U937 cells. Additionally, we highlighted the hepatoprotective and curative effects of Pc-ME pretreated orally in a mouse model of LPS/D-GalN-intoxicated acute liver injury by demonstrating the significant reduction in elevated serum AST and ALT levels and histological damage. Therefore, these results strongly suggest that Pc-ME could function as an antihepatitis remedy suppressing MAPK/AP-1-mediated inflammatory events.

Highlights

Inflammation and innate immune response are considered beneficial for host survival [1] and are part of the complex biological response of living organisms to harmful stimuli, such as infection, cellular damage, and tissue injury [2]
We performed a transfection experiment with the activator protein- (AP-)1Luc construct and HEK293 cells and used luciferase assays to examine whether Pc-ME suppressed the functional activation of AP-1
We found that AP-1-mediated luciferase activity was increased by PMA treatment or cotransfection with adaptor molecules TRIF and MyD88, whereas Pc-ME treatment significantly (P < 0.01) and dose-dependently (100, 200, and 300 μg/mL) inhibited

Summary

Introduction

Inflammation and innate immune response are considered beneficial for host survival [1] and are part of the complex biological response of living organisms to harmful stimuli, such as infection, cellular damage, and tissue injury [2]. Numerous cellular and biochemical alterations including downregulation of anti-inflammatory proteins and upregulation of proinflammatory gene products occur during inflammatory conditions to facilitate immune cell recruitment and to boost body’s defensive mechanism [3, 4]. During LPS-induced inflammation, LPS binds to toll-like receptor 4 (TLR4) and stimulates the recruitment of both cytoplasmic MyD88 and TRIF adaptor proteins, which activate mitogen-activated protein kinase (MAPK) signaling [9]. Continual activation of the MAPK signaling pathway has been shown to increase the activation of activator protein- (AP-) 1, a heterodimeric transcription factor, composed of c-Fos, cJun, ATF, and JDP families [10]. Activated AP-1 eventually upregulates the transcription of inflammatory genes containing the 12-O-tetradecanoylphorbol-13-acetate (TPA) DNA response element (TRE, 5󸀠-TGAG/CTCA-3󸀠) [11]. Targeting MAPK/AP-1 pathways is an attractive anti-inflammatory therapeutic approach

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