Toll-like Receptor 4 Inhibitor TAK-242 Improves Fulminant Hepatitis by Regulating Accumulation of Myeloid-Derived Suppre
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ORIGINAL ARTICLE
Toll-like Receptor 4 Inhibitor TAK-242 Improves Fulminant Hepatitis by Regulating Accumulation of Myeloid-Derived Suppressor Cell Haiyan Wang,1 Xuehui Li,1 Guanjun Dong,2 Fenglian Yan,2 Junfeng Zhang,2 Hui Shi,2 Zhaochen Ning,2 Min Gao,3 Dalei Cheng,1 Qun Ma,2 Changying Wang,2 Mingsheng Zhao,2 Jun Dai,2 Chunxia Li,2 Zhihua Li,2 Hui Zhang,2,4 and Huabao Xiong 2,4 Received 16 June 2020; accepted 13 October 2020
Abstract— Fulminant hepatitis (FH) is an acute clinical disease with a poor prognosis
and high mortality rate. The purpose of this study was to determine the protective effect of the Toll-like receptor 4 (TLR4) inhibitor TAK-242 on lipopolysaccharide (LPS)/Dgalactosamine (D-GalN)-induced explosive hepatitis and explore in vivo and in vitro mechanisms. Mice were pretreated with TAK-242 for 3 h prior to LPS (10 μg/kg)/DGalN (250 mg/kg) administration. Compared to the LPS/D-GalN group, the TAK-242 pretreatment group showed significantly prolonged survival, reduced serum alanine aminotransferase and aspartate aminotransferase levels, relieved oxidative stress, and reduced inflammatory interleukin (IL)-6, IL-12, and tumor necrosis factor-α levels. In addition, TAK-242 increased the accumulation of myeloid-derived suppressor cells (MDSCs). Next, mice were treated with an anti-Gr-1 antibody to deplete MDSCs, and adoptive transfer experiments were performed. We found that TAK-242 protected against FH by regulating MDSCs. In the in vitro studies, TAK-242 regulated the accumulation of MDSCs and promoted the release of immunosuppressive inflammatory cytokines. In addition, TAK-242 inhibited protein expression of nuclear factor-κB and mitogen-activated protein kinases. In summary, TAK-242 had a hepatoprotective effect against LPS/D-GalN-induced explosive hepatitis in mice. Its protective effect may be
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-020-01366-y) contains supplementary material, which is available to authorized users. 1
Cheeloo College of Medicine, Shandong University, Jinan, China Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, 272067, Shandong, China 3 Clinical Laboratory, Jining First People’s Hospital, Shandong Province, Jining, 272011, China 4 To whom correspondence should be addressed at Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, 272067, Shandong, China. E-mails: [email protected]; [email protected] 2
0360-3997/20/0000-0001/0 # 2020 Springer Science+Business Media, LLC, part of Springer Nature
Wang, Li, Dong, Yan, Zhang, Shi, Ning, Gao, Cheng, Ma, Wang, Zhao, Dai, Li, Li, Zhang, and Xiong involved in suppressing inflammation, reducing oxidative stress, and increasing the proportion of MDSCs. KEY WORDS: TAK-242; TLR4; MDSCs; Fulminant hepatitis; Inflammation.
INTRODUCTION
Fulminant hepatitis (FH), also known as acute liver failure, is a serious disease with rapid destruction of liver cells and severely damaged liver function [1, 2]. FH is an
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