Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis  

作　　者：Mengqi Zhu Sainan Min Xiangdi Mao Yuan Zhou Yan Zhang Wei Li Li Li Liling Wu Xin Cong Guangyan Yu 

机构地区：[1]Department of Oral and Maxillofacial Surgery,Peking University School and Hospital of Stomatology&National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices,Beijing,China [2]Department of Physiology and Pathophysiology,Peking University School of Basic Medical Sciences,Key Laboratory of Molecular Cardiovascular Sciences,Ministry of Education,and Beijing Key Laboratory of Cardiovascular Receptors Research,Beijing,China [3]Department of Biomedical Informatics,Peking University School of Basic Medical Sciences,Key Laboratory of Molecular Cardiovascular Sciences,Ministry of Education,Beijing,China

出　　处：《International Journal of Oral Science》2022年第3期321-333,共13页国际口腔科学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81974151,31972908,81991500,and 81991502)。

摘　　要：Immunoglobulin G4-related sialadenitis(IgG4-RS)is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood.The aim of this study was to explore the role and mechanism of interleukin-13(IL-13)in the cellular senescence during the progress of IgG4-RS.We found that the expression of IL-13 and IL-13 receptorα1(IL-13Rα1)as well as the number of senescent cells were significantly higher in the submandibular glands(SMGs)of IgG4-RS patients.IL-13 directly induced senescence as shown by the elevated activity of senescence-associatedβ-galactosidase(SA-β-gal),the decreased cell proliferation,and the upregulation of senescence markers(p53 and p16)and senescence-associated secretory phenotype(SASP)factors(IL-1βand IL-6)in SMG-C6 cells.Mechanistically,IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6(p-STAT6)and mitochondrial-reactive oxygen species(mt ROS),while decreased the mitochondrial membrane potential,ATP level,and the expression and activity of superoxide dismutase 2(SOD2).Notably,the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger Mito TEMPO.Moreover,IL-13 increased the interaction between p-STAT6 and c AMP-response element binding protein(CREB)-binding protein(CBP)and decreased the transcriptional activity of CREB on SOD2.Taken together,our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.

关 键 词：Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis IgG 

分 类 号：R329.25[医药卫生—人体解剖和组织胚胎学]