Jensen L E, Muzio M, Mantovani A, Whitehead A S
Department of Pharmacology, Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
J Immunol. 2000 May 15;164(10):5277-86. doi: 10.4049/jimmunol.164.10.5277.
The proinflammatory cytokine IL-1 induces the biosynthesis of a number of immunologically important proteins during infection, tissue damage, and/or stress, in part through the activation of the transcription factor NF-kappaB. Signal transduction is initiated at the cell membrane by complex formation between extracellular IL-1 and the transmembrane IL-1R type I (IL-1RI) and IL-1R accessory protein (IL-1RAcP). The intracellular signaling cascade involves recruitment of two IL-1R-associated kinases, IRAK1 and IRAK2, and the adapter protein MyD88, events which are dependent on the intracellular domain of membrane-bound IL-1RAcP (mIL-1RAcP). In mouse liver, IL-1RAcP is expressed as a soluble protein (sIL-1RAcP), the function of which is unknown. We have cloned the human sIL-1RAcP and established by sequence analysis that the human sIL-1RAcP mRNA arises from alternative splicing of the IL-1RAcP gene (shown here to encompass 12 exons spanning more than 56 kb). Furthermore, we demonstrate that human HepG2 hepatoma cells express both mIL-1RAcP and sIL-1RAcP and that signal transduction in these cells is mediated through IRAK1, IRAK2, and MyD88. We show that phorbol esters induce a change in the pre-mRNA splice pattern such that sIL-1RAcP mRNA becomes the dominant form. Overexpression of a membrane-anchored fusion protein of sIL-1RAcP and MHC in HepG2 cells inhibits IL-1-mediated NF-kappaB activation, whereas coexpression of IL-1RI with membrane-anchored sIL-1RAcP restores the capacity of the cells to respond to IL-1. This suggests that sIL-1RAcP may act as an inhibitor of IL-1 by directly interacting with IL-1RI to abolish its capacity to transduce signal.
促炎细胞因子白细胞介素-1（IL-1）在感染、组织损伤和/或应激期间，部分通过激活转录因子核因子κB（NF-κB）诱导多种具有免疫重要性的蛋白质的生物合成。信号转导通过细胞外IL-1与跨膜I型IL-1受体（IL-1RI）和IL-1受体辅助蛋白（IL-1RAcP）之间形成复合物在细胞膜上启动。细胞内信号级联反应涉及募集两种IL-1受体相关激酶，即IRAK1和IRAK2，以及衔接蛋白髓样分化因子88（MyD88），这些事件依赖于膜结合IL-1RAcP（mIL-1RAcP）的细胞内结构域。在小鼠肝脏中，IL-1RAcP以可溶性蛋白（sIL-1RAcP）的形式表达，其功能尚不清楚。我们克隆了人sIL-1RAcP，并通过序列分析确定人sIL-1RAcP mRNA源自IL-1RAcP基因的可变剪接（此处显示该基因包含12个外显子，跨度超过56 kb）。此外，我们证明人肝癌细胞系HepG2同时表达mIL-1RAcP和sIL-1RAcP，并且这些细胞中的信号转导是通过IRAK1、IRAK2和MyD88介导的。我们发现佛波酯可诱导前体mRNA剪接模式发生改变从而使sIL-1RAcP mRNA成为主要形式。在HepG2细胞中过表达sIL-1RAcP与主要组织相容性复合体（MHC）的膜锚定融合蛋白可抑制IL-1介导的NF-κB激活，而IL-1RI与膜锚定sIL-1RAcP的共表达可恢复细胞对IL-1的反应能力。这表明sIL-1RAcP可能通过直接与IL-1RI相互作用以消除其转导信号的能力而作为IL-1的抑制剂发挥作用。
