Common genetic heterogeneity of human interleukin-37 leads to functional variance
Common genetic heterogeneity of human interleukin-37 leads to functional variance
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人类白细胞介素 37 的常见遗传异质性导致功能变异
DOI：
10.1038/cmi.2016.48
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发表时间：
2017-09-01
影响因子：
24.1
通讯作者：
Zhang, Shuye
中科院分区：
文献类型：
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作者：
Yan, Jingjing;Zhang, Yuling;Zhang, Shuye
白细胞介素-37（IL-37）是细胞因子IL-1家族的抑制性成员。我们以前发现，平衡选择保持了人类IL 37基因的常见变异。然而，这一选择的功能后果尚未得到验证。在这里，使用表达外源性IL-37变体的细胞，包括IL-37 Ref和IL-37 Var 1和Var 2，我们发现IL-37的三种变体在响应免疫刺激时表现出不同的免疫调节效力。发现IL-37 Var 2的蛋白水平显著低于IL-37 Ref或Var 1的蛋白水平，尽管所有三种变体的mRNA水平相当。进一步的研究表明，IL-37 Var 2通过增强的多聚泛素化介导的蛋白酶体依赖性机制快速降解，导致免疫刺激后IL-37 Var 2的瞬时上调。最后，当在细胞中异位表达时，人IL-37 Var 2对促炎细胞因子产生的抑制作用比其他IL-37变体小。相反，纯化的细胞外IL-37变体蛋白在体外表现出相当的抑制能力。总之，我们的研究表明，IL-37的常见遗传变异导致不同的免疫抑制效力，主要是由于IL-37蛋白稳定性的差异，这表明这些变异可能参与各种人类疾病。
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.