Common genetic heterogeneity of human interleukin-37 leads to functional variance

查看全文 作　　者：Jingjing [1]Yan;Yuling [1,2]Zhang;Shimeng [1]Cheng;Bin [1]Kang;Jinbiao [1]Peng;Xiaodan [1]Zhang;Meichun [1]Yuan;Wenqi [1]Chu;Wen [1]Zhang;Jiayin [1]Shen;Shuye [1,3]Zhang

机构地区：[1]Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences,Fudan University,Shanghai,China;[2]School of Life Sciences,Hebei Normal University,Shi-Jiazhuang,Hebei;[3]Key Laboratory of Medical Molecular Virology of Ministries of Education/Health,Institute of Medical Microbiology,Shanghai Medical College of Fudan University,Shanghai,China

出　　处：《Cellular & Molecular Immunology》索引2017年第14卷第9期,共9页

基　　金：supported by grants from the National Natural Science Foundation of China(No.81371823 to SZ and No.31500697 to JS);the 973 Project(No.2015CB554300 to SZ);the Shanghai Pujiang Program(No.15PJ1407300 to JS). 摘　　要：Interleukin-37(IL-37)is an inhibitory member of the IL-1 family of cytokines.We previously found that balanced selection maintains common variations of the human IL37 gene.However,the functional consequences of this selection have yet to be validated.Here,using cells expressing exogenous IL-37 variants,including IL-37 Ref and IL-37 Var1 and Var2,we found that the three variants of IL-37 exhibited different immunoregulatory potencies in response to immune stimulation.The protein level of IL-37 Var2 was found to be significantly less than that of IL-37 Ref or Var1,despite the comparable mRNA levels of all three variants.Further study showed that IL-37 Var2 was rapidly degraded by a proteasome-dependent mechanism mediated by enhanced polyubiquitination,leading to a transient upregulation of IL-37 Var2 after immune stimulation.Finally,when ectopically expressed in cells,human IL-37 Var2 exerted less inhibition on proinflammatory cytokine production than did other IL-37 variants.Conversely,purified extracellular IL-37 variant proteins demonstrated comparable inhibitory abilities in vitro.In conclusion,our study reveals that common genetic variants of IL37 lead to different immune-inhibitory potencies,primarily as a result of differences in IL-37 protein stability,suggesting the possible involvement of these variants in various human diseases. 关键词：CYTOKINE gene variation INFLAMMATION protein stability

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Common genetic heterogeneity of human interleukin-37 leads to functional variance

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