Cargando…

IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING

Endometrial carcinoma (EC) is a commonly diagnosed gynecological malignancy. Interleukin-6 (IL6) plays a critical role in modulating the progression of several types of tumors, including EC. However, the specific mechanism of IL6 in regulating EC progression has not been clearly elucidated. In this...

Descripción completa

Detalles Bibliográficos
Autores principales: Zeng, Xue, Li, Xiaosong, Zhang, Yundong, Cao, Chaoxia, Zhou, Qin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184159/
https://www.ncbi.nlm.nih.gov/pubmed/35692503
http://dx.doi.org/10.1155/2022/3815853
_version_ 1784724448852574208
author Zeng, Xue
Li, Xiaosong
Zhang, Yundong
Cao, Chaoxia
Zhou, Qin
author_facet Zeng, Xue
Li, Xiaosong
Zhang, Yundong
Cao, Chaoxia
Zhou, Qin
author_sort Zeng, Xue
collection PubMed
description Endometrial carcinoma (EC) is a commonly diagnosed gynecological malignancy. Interleukin-6 (IL6) plays a critical role in modulating the progression of several types of tumors, including EC. However, the specific mechanism of IL6 in regulating EC progression has not been clearly elucidated. In this study, we performed a series of functional experiments to explore the potential mechanisms involved in IL6 function in the progression of EC. Here, we found that IL6 increased reactive oxygen species (ROS) generation by enhancing the NADPH oxidase (NOX) level and induced mtDNA leakage in EC cells, which further caused the activation of the downstream cGAS-STING signaling and increased production of extracellular vesicle (EV) production from EC cells. Besides, the activation of cGAS-STING signaling enhanced the expression of type I IFN and its downstream molecule PD-L1 through the TBK1-IRF3 pathway. Importantly, a high level mtDNA and PD-L1 were present in EVs derived from IL6-induced EC cells; these vesicles were shown to be able to induce T cell apoptosis. Finally, anti-PD-L1 treatment in mice showed that blockade of PD-L1 significantly reversed tumor immune escape mediated by IL6-induced EVs. Together, we provide evidence that IL6 induced mtDNA leakage to regulate the immune escape of EC cells. Our findings may provide a novel clue for the development of therapeutic targets for EC.
format Online
Article
Text
id pubmed-9184159
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Hindawi
record_format MEDLINE/PubMed
spelling pubmed-91841592022-06-10 IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING Zeng, Xue Li, Xiaosong Zhang, Yundong Cao, Chaoxia Zhou, Qin J Immunol Res Research Article Endometrial carcinoma (EC) is a commonly diagnosed gynecological malignancy. Interleukin-6 (IL6) plays a critical role in modulating the progression of several types of tumors, including EC. However, the specific mechanism of IL6 in regulating EC progression has not been clearly elucidated. In this study, we performed a series of functional experiments to explore the potential mechanisms involved in IL6 function in the progression of EC. Here, we found that IL6 increased reactive oxygen species (ROS) generation by enhancing the NADPH oxidase (NOX) level and induced mtDNA leakage in EC cells, which further caused the activation of the downstream cGAS-STING signaling and increased production of extracellular vesicle (EV) production from EC cells. Besides, the activation of cGAS-STING signaling enhanced the expression of type I IFN and its downstream molecule PD-L1 through the TBK1-IRF3 pathway. Importantly, a high level mtDNA and PD-L1 were present in EVs derived from IL6-induced EC cells; these vesicles were shown to be able to induce T cell apoptosis. Finally, anti-PD-L1 treatment in mice showed that blockade of PD-L1 significantly reversed tumor immune escape mediated by IL6-induced EVs. Together, we provide evidence that IL6 induced mtDNA leakage to regulate the immune escape of EC cells. Our findings may provide a novel clue for the development of therapeutic targets for EC. Hindawi 2022-06-02 /pmc/articles/PMC9184159/ /pubmed/35692503 http://dx.doi.org/10.1155/2022/3815853 Text en Copyright © 2022 Xue Zeng et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Zeng, Xue
Li, Xiaosong
Zhang, Yundong
Cao, Chaoxia
Zhou, Qin
IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING
title IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING
title_full IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING
title_fullStr IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING
title_full_unstemmed IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING
title_short IL6 Induces mtDNA Leakage to Affect the Immune Escape of Endometrial Carcinoma via cGAS-STING
title_sort il6 induces mtdna leakage to affect the immune escape of endometrial carcinoma via cgas-sting
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9184159/
https://www.ncbi.nlm.nih.gov/pubmed/35692503
http://dx.doi.org/10.1155/2022/3815853
work_keys_str_mv AT zengxue il6inducesmtdnaleakagetoaffecttheimmuneescapeofendometrialcarcinomaviacgassting
AT lixiaosong il6inducesmtdnaleakagetoaffecttheimmuneescapeofendometrialcarcinomaviacgassting
AT zhangyundong il6inducesmtdnaleakagetoaffecttheimmuneescapeofendometrialcarcinomaviacgassting
AT caochaoxia il6inducesmtdnaleakagetoaffecttheimmuneescapeofendometrialcarcinomaviacgassting
AT zhouqin il6inducesmtdnaleakagetoaffecttheimmuneescapeofendometrialcarcinomaviacgassting