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  2. Toll-like Receptor 4 Inhibitor TAK-242 Improves Fulminant Hepatitis by Regulating Accumulation of Myeloid-Derived Suppressor Cell

Toll-like Receptor 4 Inhibitor TAK-242 Improves Fulminant Hepatitis by Regulating Accumulation of Myeloid-Derived Suppressor Cell

  • Inflammation. 2021 Apr;44(2):671-681. doi: 10.1007/s10753-020-01366-y.
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 4 Huabao Xiong 5
Affiliations

Affiliations

  • 1 Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 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 Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, 272067, Shandong, China. zhanghuitjwh@hotmail.com.
  • 5 Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, 272067, Shandong, China. xionghbl@yahoo.com.
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)/D-galactosamine (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)/D-GalN (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 involved in suppressing inflammation, reducing oxidative stress, and increasing the proportion of MDSCs.

Keywords

Fulminant hepatitis; Inflammation; MDSCs; TAK-242; TLR4.

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