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

Cellular & Molecular Immunology volume 14, pages 783–791 (2017)Cite this article

Abstract

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.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81371823 to SZ and No. 31500697 to JS), by the 973 Project (No. 2015CB554300 to SZ) and by the Shanghai Pujiang Program (No. 15PJ1407300 to JS). We wish to thank Biogot Technology for kindly providing us with the pCMV-Myc-Ub plasmid. We thank Dr. Daqiang Li (Fudan University) for technical advice.

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  1. Jingjing Yan and Yuling Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China

    Jingjing Yan, Yuling Zhang, Shimeng Cheng, Bin Kang, Jinbiao Peng, Xiaodan Zhang, Meichun Yuan, Wenqi Chu, Wen Zhang, Jiayin Shen & Shuye Zhang

  2. School of Life Sciences, Hebei Normal University, Shi-Jiazhuang, Hebei

    Yuling Zhang

  3. Key Laboratory of Medical Molecular Virology of Ministries of Education/Health, Institute of Medical Microbiology, Shanghai Medical College of Fudan University, Shanghai, China

    Shuye Zhang

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  1. Jingjing Yan
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Correspondence to Jiayin Shen or Shuye Zhang.

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Yan, J., Zhang, Y., Cheng, S. et al. Common genetic heterogeneity of human interleukin-37 leads to functional variance. Cell Mol Immunol 14, 783–791 (2017). https://doi.org/10.1038/cmi.2016.48

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