Oleoylethanolamide exerts anti-inflammatory effects on LPS-induced THP-1 cells by enhancing PPARα signaling and inhibiting the NF-κB and ERK1/2/AP-1/STAT3 pathways.

Lichao Yang,Dan Zhang Dan Zhang,Ying Li,Han Guo,Sangang Wu,Lu Peng,Lu Yan,Hao Zhou,Xianglan Meng,Qiang Xie,Xin Jin

doi:10.1038/srep34611

Abstract

The present study aimed to examine the anti-inflammatory actions of oleoylethanolamide (OEA) in lipopolysaccharide (LPS)-induced THP-1 cells. The cells were stimulated with LPS (1 μg/ml) in the presence or absence of OEA (10, 20 and 40 μM). The pro-inflammatory cytokines were evaluated by qRT-PCR and ELISA. The THP-1 cells were transiently transfected with PPARα small-interfering RNA, and TLR4 activity was determined with a blocking test using anti-TLR4 antibody. Additionally, a special inhibitor was used to analyse the intracellular signaling pathway. OEA exerted a potent anti-inflammatory effect by reducing the production of pro-inflammatory cytokines and TLR4 expression, and by enhancing PPARα expression. The modulatory effects of OEA on LPS-induced inflammation depended on PPARα and TLR4. Importantly, OEA inhibited LPS-induced NF-κB activation, IκBα degradation, expression of AP-1, and the phosphorylation of ERK1/2 and STAT3. In summary, our results demonstrated that OEA exerts anti-inflammatory effects by enhancing PPARα signaling, inhibiting the TLR4-mediated NF-κB signaling pathway, and interfering with the ERK1/2-dependent signaling cascade (TLR4/ERK1/2/AP-1/STAT3), which suggests that OEA may be a therapeutic agent for inflammatory diseases.

Highlights

Inflammation is closely related to the development of vascular diseases, such as restenosis, hypertension, and atherosclerosis
Treatment of the cells with combined ERK1/2 antagonist and OEA synergistically reversed the effects elicited by LPS compared with treatment using the ERK1/2 antagonist or OEA alone. These findings reveal that the inhibitory effects of OEA on LPS-induced inflammatory responses in THP-1 cells are mediated through the ERK1/2/ AP-1/STAT3 signaling pathway
We illustrated that the modulatory effects of OEA on LPS-induced inflammation depended on both PPARαand Toll-like receptor 4 (TLR4)

Summary

Introduction

Inflammation is closely related to the development of vascular diseases, such as restenosis, hypertension, and atherosclerosis. When monocytes/macrophages are stimulated with LPS, TLR4 expression is markedly increased, which triggers pro-inflammatory cytokine production[4]. These pro-inflammatory cytokines play important roles in inflammatory diseases. The PPARαactivator fenofibrate inhibits inflammatory responses through the TLR4-dependent signaling pathway and decreases serum levels of pro-inflammatory mediators in atherosclerotic patients[11]. Fenofibrate, a synthetic PPARαagonist with a range of anti-inflammatory properties, decreases serum levels of pro-inflammatory cytokines in atherosclerotic patients[19,20] and exerts anti-inflammatory properties by antagonizing LPS-induced inflammatory responses in vascular smooth muscle cells[21]. OEA is an endogenous ligand of PPARαthat which mediates anti-inflammatory effects via the inhibition of inflammatory signaling pathways, little is known about the inhibitory effects of OEA on LPS-induced inflammatory responses or the underlying mechanisms involved. The aim of this study was to examine the anti-inflammatory actions and mechanisms of OEA in LPS-induced THP-1 cells

Objectives

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Results

Conclusion