Accessory protein-like is essential for IL-18-mediated signaling
Accessory protein-like is essential for IL-18-mediated signaling
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DOI：
10.4049/jimmunol.174.9.5351
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发表时间：
2005-05-01
影响因子：
4.4
通讯作者：
Yeh, WC
中科院分区：
文献类型：
--
作者：
Cheung, H;Chen, NJ;Yeh, WC
IL-18是先天免疫和适应性免疫的重要细胞因子。IL-18的信号传导需要IL-18R α， IL-18R α与配体特异性结合，并包含与IL-1R和tlr同源的序列。众所周知，IL-1R信号转导需要辅助细胞表面蛋白AcP。其他辅助蛋白也参与调节TLR信号，但有些具有抑制作用。一种acp样分子（AcPL）在体外被鉴定出能够与IL-18Ra合作；然而，AcPL的生理功能尚不清楚。在这项研究中，我们证明了IL-18信号在acpl缺陷小鼠和细胞中被废除。突变小鼠的脾细胞对il -18诱导的增殖和ifn - γ的产生没有反应。特别是，缺乏AcPL的Th1细胞在IL-18的作用下不能产生ifn - γ。acpl缺陷的中性粒细胞对il -18诱导的活化和细胞因子的产生也没有反应。此外，体内IL-18刺激诱导的nk介导的细胞毒性需要AcPL。然而，AcPL对于我们所研究的IL-1R和各种TLR信号的激活或抑制是必不可少的。这些结果表明，AcPL是IL-18信号传递所必需的关键和特异性细胞表面受体。
IL-18 is an essential cytokine for both innate and adaptive immunity. Signaling by IL-18 requires IL-18R alpha, which binds specifically to the ligand and contains sequence homology to IL-1R and TLRs. It is well established that IL-1R signaling requires an accessory cell surface protein, AcP. Other accessory proteins also exist with roles in regulating TLR signaling, but some have inhibitory functions. An AcP-like molecule (AcPL) has been identified with the ability to cooperate with IL-18Ra in vitro; however, the physiological function of AcPL remains unknown. In this study, we demonstrate that IL-18 signals are abolished in AcPL-deficient mice and cells. Splenocytes from mutant mice fail to respond to IL-18-induced proliferation and IFN-gamma production. In particular, Th1 cells lacking AcPL fail to produce IFN-gamma in response to IL-18. AcPL-deficient neutrophils also fail to respond to IL-18-induced activation and cytokine production. Furthermore, AcPL is required for NK-mediated cytotoxicity induced by in vivo IL-18 stimulation. However, AcPL is dispensable for the activation or inhibition of IL-1R and the various TLR signals that we have examined. These results suggest that AcPL is a critical and specific cell surface receptor that is required for IL-18 signaling.