Cullinan E B, Kwee L, Nunes P, Shuster D J, Ju G, McIntyre K W, Chizzonite R A, Labow M A
Chrysalis, Princeton, NJ 08540, USA.
J Immunol. 1998 Nov 15;161(10):5614-20.
The recently described IL-1R accessory protein (IL-1R AcP) interacts with IL-1beta and the IL-1 type-IR (IL-1RI), but an essential requirement for IL-1R AcP in IL-1 signaling in vitro has not been established and its role in vivo has not been examined. In this study, IL-1R AcP-deficient mice and fibroblasts were produced and characterized. All IL-1 agonists bound to IL-1R AcP-deficient cells through the type I IL-1R, but failed to activate gene expression through either the nuclear factor-kappaB or AP-1-dependent signaling pathways. Absence of IL-1R AcP differentially affected the affinity for IL-1 ligands. IL-1R AcP-deficient fibroblasts bound murine IL-1alpha and human IL-1R antagonist protein (IL-1Ra) with only moderately reduced affinity when compared with wild-type cells, whereas murine IL-1beta affinity was reduced by 70-fold. IL-1 also failed to produce a biologic response in vivo in IL-1R AcP-deficient mice. These data demonstrate that a type I IL-1R/IL-1R AcP complex is required for signaling by all IL-1 agonists and for high affinity binding by IL-1beta. Finally, IL-1R AcP is an essential signal transducing component of the functional IL-1R and should represent a novel target for blocking IL-1 function in human disease.
最近报道的白细胞介素-1受体辅助蛋白（IL-1R AcP）可与白细胞介素-1β（IL-1β）及I型白细胞介素-1受体（IL-1RI）相互作用，但体外实验中尚未证实IL-1R AcP在IL-1信号传导中是必需的，其在体内的作用也未得到研究。在本研究中，我们制备并鉴定了IL-1R AcP缺陷型小鼠和成纤维细胞。所有IL-1激动剂均通过I型IL-1R与IL-1R AcP缺陷型细胞结合，但无法通过核因子-κB或AP-1依赖的信号通路激活基因表达。IL-1R AcP的缺失对IL-1配体的亲和力有不同影响。与野生型细胞相比，IL-1R AcP缺陷型成纤维细胞结合小鼠IL-1α和人白细胞介素-1受体拮抗剂蛋白（IL-1Ra）时亲和力仅适度降低，而小鼠IL-1β的亲和力降低了70倍。IL-1在IL-1R AcP缺陷型小鼠体内也未能产生生物学反应。这些数据表明，I型IL-1R/IL-1R AcP复合物是所有IL-1激动剂信号传导及IL-1β高亲和力结合所必需的。最后，IL-1R AcP是功能性IL-1R的必需信号转导成分，应是阻断人类疾病中IL-1功能的新靶点。
