Atractylenolide-III suppresses lipopolysaccharide-induced inflammation via downregulation of toll-like receptor 4 in mouse microglia

Ela Novianti,Goro Katsuura,Namiko Kawamura,Akihiro Asakawa,Akio Inui

doi:10.1016/j.heliyon.2021.e08269

Ela Novianti, Goro Katsuura + Show 3 more

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https://doi.org/10.1016/j.heliyon.2021.e08269

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Journal: Heliyon	Publication Date: Oct 1, 2021
Citations: 12	License type: cc-by

Affiliation: Kagoshima University, Indonesian Institute of Sciences

Abstract

Atractylenolide-III (AIII), a sesquiterpene compound isolated from the rhizome of Atractylodes macrocephala, has been reported to have anti-inflammatory effects in the peripheral organs. However, its effects on brain inflammation remain elusive. The present study investigated the effects of AIII on the response to lipopolysaccharide (LPS) in mouse microglia and clarified the underlying mechanism. In this study, treatment of MG6 cells with AIII (100 μM) significantly decreased the mRNA expression and protein levels of toll-like receptor 4 (TLR4). In addition, pretreatment of MG6 cells and primary cultured microglia cells with AIII (100 μM) significantly decreased the mRNA expression and protein levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 induced by LPS (5 ng/mL) without cytotoxicity. Subsequently, pretreatment with AIII significantly suppressed the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) after LPS stimulation in MG6 cells. These results showed that AIII downregulated TLR4 expression, leading to suppression of the p38 MAPK and JNK pathways, which in turn inhibited the production of pro-inflammatory cytokines and enzymes in LPS-stimulated microglia. Our findings, therefore, suggest the potential for AIII as a therapeutic agent for the treatment of brain inflammation, particularly in microglia-associated inflammation.

Highlights

Byakujutsu (Baizhu in Chinese), the rhizome of Atractylodes macrocephala, is used as an herbal medicine because of its broad biological functions, ranging from alleviating fatigue to anti-cancer effects
AIII pretreatment significantly inhibited the mRNA expression and protein levels of tumor necrosis factor-α (TNF-α), IL-1β, and IL6, and inflammatory enzymes including inducible nitric oxide synthase (iNOS) and COX-2 induced by LPS in MG6 cells and Primary cultured microglia cells (PMC) with no cytotoxic effects
These findings demonstrated that AIII downregulated toll-like receptor 4 (TLR4) expression, inhibited the p38 mitogen-activated protein kinases (MAPKs) and Jun NH2-terminal kinase (JNK) pathways, and subsequently suppressed the LPS-induced production of cytokines and enzymes in mouse microglia

Summary

Introduction

Byakujutsu (Baizhu in Chinese), the rhizome of Atractylodes macrocephala, is used as an herbal medicine because of its broad biological functions, ranging from alleviating fatigue to anti-cancer effects. One of the main active compounds in Byakujutsu is atractylenolide-III (AIII), chemically a sesquiterpene lactone [1]. Previous reports revealed anti-inflammatory effects of AIII in the peripheral organs. In vitro studies demonstrated inhibitory effects of AIII on the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated mouse macrophages [2, 3] and in 12-myristate 13-acetate- and calcium ionophore A2318-stimulated human mast cells [4]. The effects of AIII on brain inflammation and its underlying mechanisms remain to be elucidated. A pharmacokinetic assessment results demonstrated that AIII exerts high permeability to the blood-brain barrier [6, 7], suggesting that this compound might regulate brain inflammation

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