Baicalein ameliorates TNBS-induced colitis by suppressing TLR4/MyD88 signaling cascade and NLRP3 inflammasome activation in mice

Xiaoping Luo,Zhengtao Wang,Zhilun Yu,Wei Dou,Aning Sun,Chao Deng,Gaiyan Ren,Sridhar Mani,Jingjing Zhang

doi:10.1038/s41598-017-12562-6

Abstract

Baicalein (5,6,7-trihydroxyflavone), a predominant bioactive component isolated from the root of Scutellaria baicalensis Georgi, has established potent anti-inflammatory activity via multi-targeted mechanisms. However, little is known about the effect of baicalein on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which shares pathology related to human Crohn’s disease (CD). The present study demonstrated that baicalein alleviated the severity of TNBS-induced colitis in mice by decreasing the activity of myeloperoxidase (MPO) and the expression of pro-inflammatory mediators. The decline in the activation of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) correlated with a decrease in the expression of mucosal toll-like receptor 4 (TLR4) and its adaptor myeloid differentiation factor 88 (MyD88). In vitro, baicalein down-regulated the TLR4/MyD88 signaling cascades (NF-κB and MAPKs) in lipopolysaccharide (LPS)-stimulated macrophages. At the upstream level, baicalein bound to the hydrophobic region of the myeloid differentiation protein-2 (MD-2) pocket and inhibited the formation of the LPS-induced MD-2/TLR4 complex. Furthermore, baicalein reduced NOD-like receptor 3 (NLRP3) inflammasome activation and downstream interleukin-1β expression in a dose-dependent manner. Our study provided evidence for the first time that baicalein attenuated TNBS-induced colitis, at least in part, via inhibition of TLR4/MyD88 signaling cascade as well as inactivation of NLRP3 inflammasome.

Highlights

Baicalein (5,6,7-trihydroxyflavone) is a principle bioactive flavonoid isolated from the roots of Scutellaria baicalensis Georgi, a traditional herbal medicine used to treat various types of inflammatory diseases[5]
We demonstrated that baicalein exerted significant anti-inflammatory activity in trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice possibly via abrogating toll-like recptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway and its downstream signaling molecules, NF-κB and mitogen-activated protein kinases (MAPKs)
We have demonstrated that baicalein could ameliorate the disease symptoms of TNBS-induced colitis, including body weight loss, diarrhea, colon shortening and histological injury

Summary

Introduction

Baicalein (5,6,7-trihydroxyflavone) is a principle bioactive flavonoid isolated from the roots of Scutellaria baicalensis Georgi, a traditional herbal medicine used to treat various types of inflammatory diseases[5]. Our group have previously reported the potent anti-inflammatory activity of baicalein on dextran sodium sulfate (DSS)-induced colitis in mice, a well-established experimental model with features resembling human UC, via targeting to caudal-type homeobox 2 (CDX2/pregnane X receptor (PXR) pathway[6]. In this regard, other mechanisms implicated in the actions of baicalein on DSS-induced colitis include reduced peroxisome proliferator-activated receptor-γ (PPARγ) signaling[7]. We demonstrated that baicalein exerted significant anti-inflammatory activity in TNBS-induced colitis in mice possibly via abrogating TLR4/myeloid differentiation factor 88 (MyD88) signaling pathway and its downstream signaling molecules, NF-κB and mitogen-activated protein kinases (MAPKs). The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) pyrin domain containing 3 (NLRP3) inflammasome, which was required for the secretion of interleukin 1β (IL-1β), was abrogated by baicalein

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