Pyruvate Dehydrogenase Kinase 2 Accelerates Endotoxin Shock by Promoting Mitogen-Activated Protein Kinase Activation

被引:0
作者
Chunxia Li
Jun Dai
Chuanbin Liu
Guanjun Dong
Xin Zhang
Junfeng Zhang
Fenglian Yan
Hui Zhang
Changying Wang
Mingsheng Zhao
Zhaochen Ning
Qun Ma
Hui Shi
Zhihua Li
Huabao Xiong
机构
[1] Jining Medical University,Institute of Immunology and Molecular Medicine, Basic Medical School
[2] Jining Stomatological Hospital,Department of Pediatric Dentistry
来源
Inflammation | 2023年 / 46卷
关键词
pyruvate dehydrogenase kinase 2; toll-like receptor 4; lipopolysaccharide; endotoxic shock; mitogen-activated protein kinase.;
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中图分类号
学科分类号
摘要
Endotoxin shock remains one of the major causes of mortality worldwide. Pyruvate dehydrogenase kinase (PDK) 2 is an important regulatory enzyme involved in glucose metabolism. The purpose of this study was to determine the regulatory effect of PDK2 on LPS-induced endotoxin shock and explore the mechanisms in vivo and in vitro. Here, we showed that PDK2 contributed to Toll-like receptor (TLR)-mediated inflammation. Lipopolysaccharide (LPS) activation of TLR4 pathways resulted in PDK2 upregulation in macrophages and dendritic cells (DCs). PDK2 overexpression enhanced TLR4 signaling pathway activation, whereas downregulating PDK2 expression inhibited TLR4 signaling pathway activation. Pharmacological inhibition of PDK2 significantly decreased the mortality rate and alleviated pathological injury in the lungs and livers of LPS-challenged mice, while significantly suppressing proinflammatory cytokine production. Thus, we confirmed that PDK2 is involved in LPS-induced endotoxin shock by modulating TLR4-mitogen-activated protein kinase signaling and inducing the production of proinflammatory cytokines in macrophages and DCs. Our findings highlight the importance of PDK2 as a novel target to treat septic shock.
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页码:418 / 431
页数:13
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