Common genetic heterogeneity of human interleukin-37 leads to functional variance.
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.
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Jingjing
J
Yan
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|School of Life Sciences, Hebei Normal University, Shi-Jiazhuang, Hebei.
Yuling
Y
Zhang
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Shimeng
S
Cheng
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Bin
B
Kang
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Jinbiao
J
Peng
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Xiaodan
X
Zhang
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Meichun
M
Yuan
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Wenqi
W
Chu
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Wen
W
Zhang
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Jiayin
J
Shen
Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.|Key Laboratory of Medical Molecular Virology of Ministries of Education/Health, Institute of Medical Microbiology, Shanghai Medical College of Fudan University, Shanghai, China.
Shuye
S
Zhang
D000595:Amino Acid Sequence; D002460:Cell Line; D018740:Genetic Heterogeneity; D006579:Heterozygote; D006801:Humans; D007375:Interleukin-1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D010641:Phenotype; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D054875:Ubiquitination; D015854:Up-Regulation
C508587:IL37 protein, human; D007375:Interleukin-1; D015850:Interleukin-6; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex
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