PMID- 38438106
OWN - NLM
STAT- Publisher
LR  - 20240317
IS  - 1532-8600 (Electronic)
IS  - 0026-0495 (Linking)
VI  - 155
DP  - 2024 Mar 2
TI  - Interleukin-6 classic and trans-signaling utilize glucose metabolism 
      reprogramming to achieve anti- or pro-inflammatory effects.
PG  - 155832
LID - S0026-0495(24)00058-1 [pii]
LID - 10.1016/j.metabol.2024.155832 [doi]
AB  - Interleukin (IL)-6 has anti- and pro-inflammatory functions, controlled by IL-6 
      classic and trans-signaling, respectively. Differences in the downstream 
      signaling mechanism between IL-6 classic and trans-signaling have not been 
      identified. Here, we report that IL-6 activates glycolysis to regulate the 
      inflammatory response. IL-6 regulates glucose metabolism by forming a complex 
      containing signal-transducing activators of transcription 3 (STAT3), hexokinase 2 
      (HK2), and voltage-dependent anion channel 1 (VDAC1). The IL-6 classic signaling 
      directs glucose flux to oxidative phosphorylation (OxPhos), while IL-6 
      trans-signaling directs glucose flux to anaerobic glycolysis. Classic IL-6 
      signaling promotes STAT3 translocation into mitochondria to interact with 
      pyruvate dehydrogenase kinase-1 (PDK1), leading to pyruvate dehydrogenase alpha 
      (PDHA) dissociation from PDK1. As a result, PDHA is dephosphorylated, and STAT3 
      is phosphorylated at Ser727. By contrast, IL-6 trans-signaling promotes the 
      interaction of sirtuin 2 (SIRT2) and lactate dehydrogenase A (LDHA), leading to 
      the dissociation of STAT3 from SIRT2. As a result, LDHA is deacetylated, and 
      STAT3 is acetylated and phosphorylated at Tyr705. IL-6 classic signaling promotes 
      the differentiation of regulatory T cells via the PDK1/STAT3/PDHA axis, whereas 
      IL-6 trans-signaling promotes the differentiation of Th17 cells via the 
      SIRT2/STAT3/LDHA axis. Conclusion: IL-6 classic signaling generates 
      anti-inflammatory functions by shifting energy metabolism to OxPhos, while IL-6 
      trans-signaling generates pro-inflammatory functions by shifting energy 
      metabolism to anaerobic glycolysis.
CI  - Copyright (c) 2024 Elsevier Inc. All rights reserved.
FAU - Xu, Shilei
AU  - Xu S
AD  - Department of General Surgery, The Third Affiliated Hospital, Sun Yat-Sen 
      University, Guangzhou, Guangdong 510530, China. Electronic address: 
      xushl5@mail.sysu.edu.cn.
FAU - Deng, Ke-Qiong
AU  - Deng KQ
AD  - Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, 
      China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430072, 
      China. Electronic address: dengkeqiong@whu.edu.cn.
FAU - Lu, Chengbo
AU  - Lu C
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China.
FAU - Fu, Xin
AU  - Fu X
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China.
FAU - Zhu, Qingmei
AU  - Zhu Q
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China. 
      Electronic address: 2022202040038@whu.edu.cn.
FAU - Wan, Shiqi
AU  - Wan S
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China. 
      Electronic address: 2022202040020@whu.edu.cn.
FAU - Zhang, Lin
AU  - Zhang L
AD  - Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, 
      China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430072, 
      China.
FAU - Huang, Yu
AU  - Huang Y
AD  - Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, 
      China. Electronic address: huangyuu@whu.edu.cn.
FAU - Nie, Longyu
AU  - Nie L
AD  - Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, 
      China. Electronic address: nielongyu@whu.edu.cn.
FAU - Cai, Huanhuan
AU  - Cai H
AD  - Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, 
      China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430072, 
      China. Electronic address: caihuanhuan@whu.edu.cn.
FAU - Wang, Qiming
AU  - Wang Q
AD  - College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 
      410128, Human Province, China.
FAU - Zeng, Hao
AU  - Zeng H
AD  - The State Key Laboratory Breeding Base of Basic Science of Stomatology 
      (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & 
      Hospital of Stomatology, Wuhan University, China. Electronic address: 
      hao.zeng@whu.edu.cn.
FAU - Zhang, Yufeng
AU  - Zhang Y
AD  - The State Key Laboratory Breeding Base of Basic Science of Stomatology 
      (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & 
      Hospital of Stomatology, Wuhan University, China. Electronic address: 
      zyf@whu.edu.cn.
FAU - Wang, Fubing
AU  - Wang F
AD  - Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of 
      Medical Sciences, Wuhan 430072, China.
FAU - Ren, Hong
AU  - Ren H
AD  - Shanghai Children's Medical Center, Affiliated Hospital to Shanghai Jiao Tong 
      University School of Medicine, China. Electronic address: renhong@scmc.com.cn.
FAU - Chen, Yu
AU  - Chen Y
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China. 
      Electronic address: chenyu@whu.edu.cn.
FAU - Yan, Huan
AU  - Yan H
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China. 
      Electronic address: huanyan@whu.edu.cn.
FAU - Xu, Ke
AU  - Xu K
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China. 
      Electronic address: xuke03@whu.edu.cn.
FAU - Zhou, Li
AU  - Zhou L
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China. 
      Electronic address: zhouli_jerry@whu.edu.cn.
FAU - Lu, Mengji
AU  - Lu M
AD  - Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 
      Essen 45122, Germany. Electronic address: mengji.lu@uni-due.de.
FAU - Zhu, Ying
AU  - Zhu Y
AD  - State Key Laboratory of Virology, Modern Virology Research Center, College of 
      Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China. 
      Electronic address: yingzhu@whu.edu.cn.
FAU - Liu, Shi
AU  - Liu S
AD  - Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, 
      China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430072, 
      China; State Key Laboratory of Virology, Modern Virology Research Center, College 
      of Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science 
      Center for Immunology and Metabolism, Wuhan University, Wuhan 430072, China; 
      College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 
      410128, Human Province, China. Electronic address: liushi_liushi@whu.edu.cn.
FAU - Lu, Zhibing
AU  - Lu Z
AD  - Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430072, 
      China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430072, 
      China. Electronic address: luzhibing222@163.com.
LA  - eng
PT  - Journal Article
DEP - 20240302
PL  - United States
TA  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
SB  - IM
OTO - NOTNLM
OT  - Glucose metabolism
OT  - Inflammatory functions
OT  - Interleukin-6
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2024/03/05 00:45
MHDA- 2024/03/05 00:45
CRDT- 2024/03/04 19:16
PHST- 2023/12/15 00:00 [received]
PHST- 2024/02/26 00:00 [revised]
PHST- 2024/02/29 00:00 [accepted]
PHST- 2024/03/05 00:45 [pubmed]
PHST- 2024/03/05 00:45 [medline]
PHST- 2024/03/04 19:16 [entrez]
AID - S0026-0495(24)00058-1 [pii]
AID - 10.1016/j.metabol.2024.155832 [doi]
PST - aheadofprint
SO  - Metabolism. 2024 Mar 2;155:155832. doi: 10.1016/j.metabol.2024.155832.