Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cordderived mesenchymal stem cells by increasing PD-L1 expression  

作　　者：Zhuo Chen Meng-Wei Yao Zhi-Lin Shen Shi-Dan Li Wei Xing Wei Guo Zhan Li Xiao-Feng Wu Luo-Quan Ao Wen-Yong Lu Qi-Zhou Lian Xiang Xu Xiang Ao 

机构地区：[1]Department of Stem Cell&Regenerative Medicine,State Key Laboratory of Trauma,Burn and Combined Injury,Daping Hospital,Army Medical University,Chongqing 400042,China [2]College of Basic Medical Sciences,Army Medical University,Chongqing 400038,China [3]Department of Orthopedics,Daping Hospital,Army Medical University,Chongqing 400042,China [4]Department of Hepatobiliary Surgery,The First Affiliated Hospital of Wenzhou Medical University,The South of Shangcai Village,Wenzhou 325005,Zhejiang Province,China [5]Department of Medicine,Li Ka Shing Faculty of Medicine,The University of Hong Kong,Hong Kong 999077,China [6]Department of Orthopedics,953 Hospital of PLA Army,Shigatse Branch of Xinqiao Hospital,Army Medical University,Shigatse 857000,Tibet Autonomous Region,China

出　　处：《World Journal of Stem Cells》2023年第8期787-806,共20页世界干细胞杂志（英文版）（电子版）

基　　金：Supported by the National Natural Science Foundation of China,No.81871568,No.32100643;COVID-19 Infection and Prevention Emergency Special Project of Chongqing Education Commission,No.KYYJ202009.

摘　　要：BACKGROUND The immunosuppressive capacity of mesenchymal stem cells(MSCs)is dependent on the“license”of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1(PD-L1),which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases.In MSCs,interferon-gamma(IFN-γ)is a key inducer of PD-L1 expression,which is synergistically enhanced by tumor necrosis factor-alpha(TNF-α);however,the underlying mechanism is unclear.AIM To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis.METHODS We assessed PD-L1 expression in human umbilical-cord-derived MSCs(hUC-MSCs)induced by IFN-γand TNF-α,alone or in combination.Additionally,we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γalone or in combination with TNF-αinduces PD-L1 expression.Moreover,we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters.Finally,we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γand TNF-αin both an in vitro mixed lymphocyte culture assay,and in vivo in mice with dextran sulfate sodium-induced acute colitis.RESULTS Our results suggest that IFN-γinduction alone upregulates PD-L1 expression in hUC-MSCs while TNF-αalone does not,and that the co-induction of IFN-γand TNF-αpromotes higher expression of PD-L1.IFN-γinduces hUCMSCs to express PD-L1,in which IFN-γactivates the JAK/STAT1 signaling pathway,up-regulates the expression of the interferon regulatory factor 1(IRF1)transcription factor,promotes the binding of IRF1 and the PD-L1 gene promoter,and finally promotes PD-L1 mRNA.Although TNF-αalone did not induce PD-L1 expression in hUCMSCs,the addition of TNF-αsignificantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation.TNF-αupregulated IFN-γreceptor e

关 键 词：Human umbilical-cord-derived mesenchymal stem cells Programmed cell death 1 ligand 1 IMMUNOMODULATION INTERFERON-GAMMA Tumor necrosis factor-alpha Ulcerative colitis 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]