Ets2 suppresses inflammatory cytokines through MAPK/NF-κB signaling and directly binds to the IL-6 promoter in macrophages.

Xianwei Ma,Mingjin Yang,Xiya Yu,Yan Zhang,Wei Jiang,Na Li,Peng Gao,Zhengyu Jiang,Guifang Wang

doi:10.18632/aging.102480

Abstract

Proper activation of Toll-like receptor (TLR)-mediated signaling and production of proinflammatory cytokines are critical for the initiation of innate immunity, while the specific mechanism maintaining inflammatory homeostasis remains mostly unknown. Here, we show that Ets2 is upregulated following LPS and VSV stimulation. Ets2 knockdown or knockout leads to increased IL-6, TNF-α, and IFN-β production in macrophages. Consistently, Ets2-deficient mice show exacerbated inflammatory cytokine production and are more susceptible to CLP-induced sepsis. Mechanistically, Ets2 inhibits the LPS- and VSV-induced activation of ERK1/2, JNK, p38, and p65. Ets2 also binds to the promoter of IL-6 to inhibit transcription. Collectively, the results of the present study show the negative regulatory role of Ets2 in LPS- and VSV-induced inflammation through the suppression of MAPK/NF-κB signaling, direct binding to the IL-6 promoter and inhibition of transcription.

Highlights

Toll-like receptors recognize pathogen components and activate immune cells to produce inflammatory cytokines [1]
We demonstrate that V-ets erythroblastosis virus E26 oncogene homolog 2 (Ets2) negatively regulates LPS and vesicular stomatitis virus (VSV)induced proinflammatory cytokine production in macrophages
To investigate whether Ets2 could be regulated by the activation of TLR4 and TLR7 signaling, we used mouse primary peritoneal macrophages treated with LPS or VSV to evaluate Ets2 expression

Summary

Introduction

Toll-like receptors recognize pathogen components and activate immune cells to produce inflammatory cytokines [1]. TLR4 and TLR7 both recruit protein MyD88 to activate downstream signal cascades, which cumulate in MAPK and NF-κB pathway activation and induce the production of inflammatory cytokines [2,3,4,5]. Proper production of inflammatory cytokines following TLR4 or TLR7 activation is required to initiate innate immunity in defense against pathogens. Uncontrolled activation and production of inflammatory cytokines may induce tissue damage and lethal endotoxin shock or www.aging-us.com sepsis. Excessive proinflammatory cytokine production may be induced by endogenous TLR4 ligands and contribute to chronic inflammation, autoimmune diseases, and cancers [6, 7]. It is essential to understand the mechanism by which the TLR-activated production of proinflammatory cytokines is regulated

Methods

Results

Conclusion