Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS
(2022) In Cell death discovery 8(1).- Abstract
Systemic inflammatory response syndrome (SIRS) is a sepsis-associated inflammatory state and a self-defense mechanism against specific and nonspecific stimuli. Ketamine influences many key processes that are altered during sepsis. However, the underlying mechanisms remain incompletely understood. In this study, TNF-α-treated mice, as well as HT-29 and L929 cell models, were applied to characterize TNF-α-induced systemic and local cecal tissue inflammatory responses. Behavioral, biochemical, histological, and molecular biological approaches were applied to illustrate the related processes. Mice with TNF-α-induced SIRS showed systemic and local cecal tissue inflammatory responses, as indicated by increased levels of high mobility group... (More)
Systemic inflammatory response syndrome (SIRS) is a sepsis-associated inflammatory state and a self-defense mechanism against specific and nonspecific stimuli. Ketamine influences many key processes that are altered during sepsis. However, the underlying mechanisms remain incompletely understood. In this study, TNF-α-treated mice, as well as HT-29 and L929 cell models, were applied to characterize TNF-α-induced systemic and local cecal tissue inflammatory responses. Behavioral, biochemical, histological, and molecular biological approaches were applied to illustrate the related processes. Mice with TNF-α-induced SIRS showed systemic and local cecal tissue inflammatory responses, as indicated by increased levels of high mobility group box 1 protein (HMGB1), chemokines (C-X-C motif) ligand 10 (CXCL10), interleukin-6 (IL-6), and IL-10, as well as high mortality. Ketamine pretreatment alleviated death rates, symptoms, and the production of inflammatory cytokines induced by TNF-α in mice. Moreover, ketamine also protected the mice from TNF-α-induced cecal damage by suppressing the phosphorylation of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). In addition, our results showed that ketamine efficiently inhibited TNF-α-induced necroptosis in HT-29 and L929 cells. Furthermore, we explored the mechanism using different L929 cell lines. The results displayed that ketamine inhibited TNF-α-induced necroptosis by enhancing RIP1 ubiquitination and reducing the RIP1-RIP3 and RIP3-MLKL interactions, as well as the formation of necrosomes. Thus, our study may provide a new theoretical and experimental basis for treating diseases characterized by SIRS-associated inflammatory factor storms. Moreover, our exploration may provide potential molecular mechanisms and targets for therapeutic intervention and clinical application of ketamine.
(Less)
- author
- organization
- publishing date
- 2022-02
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell death discovery
- volume
- 8
- issue
- 1
- article number
- 72
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85125340855
- pmid:35184141
- ISSN
- 2058-7716
- DOI
- 10.1038/s41420-022-00869-x
- language
- English
- LU publication?
- yes
- additional info
- Funding Information: We would like to thank Prof. Jiahuai Han and Dr. Tingting Ai in the State Key Laboratory of Cellular Stress Biology, Xiamen University, as well as Prof. Lichao Hou in the Xiang’an Hospital of Xiamen University, for their technical help and support. We also would like to thank Haiping Zheng, Xiang You, and Jingru Huang in the Core Facility of Biomedical, Xiamen University, for their technical support on flow cytometry and laser scanning confocal microscope. This work was supported by the National Natural Science Foundation of China (81870828); General project of Fujian Natural Science Foundation (2021J01018); Fujian Health Science and Technology program (2021GGB038); Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2019KF015); Science and Technology Project of Xiamen Municipal Bureau of Science and Technology (3502Z20194046); Fundamental Research Funds for the Central Universities (20720200037); Key Scientific Research Projects of Fujian Strait Medical and Health Exchange Association (2020HYH10). Publisher Copyright: © 2022, The Author(s).
- id
- 95c9e0a7-2805-43df-af7f-654d2ad2a1b7
- date added to LUP
- 2022-04-19 08:43:14
- date last changed
- 2024-06-16 21:02:14
@article{95c9e0a7-2805-43df-af7f-654d2ad2a1b7,
abstract = {{<p>Systemic inflammatory response syndrome (SIRS) is a sepsis-associated inflammatory state and a self-defense mechanism against specific and nonspecific stimuli. Ketamine influences many key processes that are altered during sepsis. However, the underlying mechanisms remain incompletely understood. In this study, TNF-α-treated mice, as well as HT-29 and L929 cell models, were applied to characterize TNF-α-induced systemic and local cecal tissue inflammatory responses. Behavioral, biochemical, histological, and molecular biological approaches were applied to illustrate the related processes. Mice with TNF-α-induced SIRS showed systemic and local cecal tissue inflammatory responses, as indicated by increased levels of high mobility group box 1 protein (HMGB1), chemokines (C-X-C motif) ligand 10 (CXCL10), interleukin-6 (IL-6), and IL-10, as well as high mortality. Ketamine pretreatment alleviated death rates, symptoms, and the production of inflammatory cytokines induced by TNF-α in mice. Moreover, ketamine also protected the mice from TNF-α-induced cecal damage by suppressing the phosphorylation of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). In addition, our results showed that ketamine efficiently inhibited TNF-α-induced necroptosis in HT-29 and L929 cells. Furthermore, we explored the mechanism using different L929 cell lines. The results displayed that ketamine inhibited TNF-α-induced necroptosis by enhancing RIP1 ubiquitination and reducing the RIP1-RIP3 and RIP3-MLKL interactions, as well as the formation of necrosomes. Thus, our study may provide a new theoretical and experimental basis for treating diseases characterized by SIRS-associated inflammatory factor storms. Moreover, our exploration may provide potential molecular mechanisms and targets for therapeutic intervention and clinical application of ketamine.</p>}},
author = {{Deng, Bin and Yang, Daowei and Wu, Huanghui and Wang, Lu and Wu, Rui and Zhu, Hongrui and Huang, Ailing and Song, Jingyi and Cai, Tieliang and Liu, Shanshan and Wu, Jingsi and Zhou, Huiying and Li, Chunhui}},
issn = {{2058-7716}},
language = {{eng}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Cell death discovery}},
title = {{Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS}},
url = {{http://dx.doi.org/10.1038/s41420-022-00869-x}},
doi = {{10.1038/s41420-022-00869-x}},
volume = {{8}},
year = {{2022}},
}