Irikura Vera M, Lagraoui Mouna, Hirsh David
Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Immunol. 2002 Jul 1;169(1):393-8. doi: 10.4049/jimmunol.169.1.393.
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.
缺乏白细胞介素-1受体拮抗剂（IL-1ra）基因的小鼠表现出异常发育和内环境稳态，以及对感染性和炎症性刺激的反应改变。通过缺失受体或增加IL-1ra的表达来降低IL-1信号水平，并不影响发育或内环境稳态，但会改变免疫反应。在本研究中，我们使用基因上位性来研究IL-1家族中选定基因在调节这些发育和免疫过程中的相互依赖性。编码I型IL-1受体（IL-1RI）的基因缺失对IL-1ra基因的缺失具有上位性。因此，IL-1ra的所有功能都依赖于功能性受体的存在；不存在其他靶点。同样，编码分泌形式IL-1ra的mRNA的过表达对受体拮抗剂的缺失具有上位性，IL-1ra细胞内剪接变体的作用尚不清楚。IL-1ra缺陷小鼠的异常发育可能是由于通过IL-1对促炎途径的慢性过度刺激，但明显的单一病理缺陷并不明显。这些结果支持了这样一种模型，即IL-1ra在健康和疾病中的唯一基本功能是对IL-1RI的竞争性抑制。
