The epistatic interrelationships of IL-1, IL-1 receptor antagonist, and the type IIL-1 receptor
The epistatic interrelationships of IL-1, IL-1 receptor antagonist, and the type IIL-1 receptor
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DOI：
10.4049/jimmunol.169.1.393
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发表时间：
2002-07-01
影响因子：
4.4
通讯作者：
Hirsh, D
中科院分区：
文献类型：
--
作者：
Irikura, VM;Lagraoui, M;Hirsh, D
缺乏IL-1R拮抗剂(IL-1ra)基因的小鼠表现出发育和动态平衡异常，以及对感染和炎症刺激的反应改变。IL-1信号水平的降低，无论是由于受体的缺失或IL-1ra表达的增加，都不会影响发育或内稳态，但会改变免疫反应。在这项研究中，我们使用遗传上位性来研究IL-1家族中选定的基因在这些发育和免疫过程的调节中的相互依赖性。I型IL-1R(IL-1RI)基因缺失是IL-1ra基因缺失的上位效应。因此，IL-1ra的所有功能依赖于功能性受体的存在；没有其他靶点。同样，编码分泌形式的IL-1ra的mRNA的过度表达与受体拮抗剂的缺失是上位的，使得IL-1ra的细胞内剪接变异体的作用未知。IL-1ra缺陷小鼠的异常发育可能是由于IL-1对促炎途径的慢性过度刺激，但并不明显的单一病理缺陷。这些结果支持这一模型，即IL-1ra在健康和疾病中唯一的基本功能是竞争性抑制IL-1RI。
Mice lacking the gene for the IL-1R antagonist (IL-1ra) show abnormal development and homeostasis as well as altered responses to infectious and inflammatory stimuli. A reduction in the level of IL-1 signaling, either by deletion of the receptor or increased expression of IL-1ra, does not affect development or homeostasis, but does alter immune responses. In this study we use genetic epistasis to investigate the interdependence of selected genes in the IL-1 family in the regulation of these developmental and immunological processes. Deletion of the gene encoding the type I IL-1R (IL-1RI) is epistatic to deletion of the IL-1ra gene. Therefore, all functions of IL-1ra depend upon the presence of a functional receptor; there is no other target. Similarly, overexpression of the mRNA encoding the secreted form of IL-1ra is epistatic to deletion of the receptor antagonist, leaving the role of the intracellular splice variants of IL-1ra unknown. The abnormal development of IL-1ra-deficient mice is probably due to chronic overstimulation of the proinflammatory pathway via IL-1, but a clear single pathological defect is not apparent. These results support the model that the only essential function of IL-1ra in both health and disease is competitive inhibition of the IL-1RI.