Inhibition of TLR-4/MD-2 signaling by RP105/MD-1
Inhibition of TLR-4/MD-2 signaling by RP105/MD-1
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DOI：
10.1179/096805105x67300
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发表时间：
2005-12-01
期刊：
影响因子：
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通讯作者：
Karp, CL
中科院分区：
文献类型：
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作者：
Divanovic, S;Trompette, A;Karp, CL
Toll样受体（TLR）信号通过微生物和宿主分子特征的激活对于诱导免疫应答是至关重要的。这样的信号必然会受到严格的控制。我们最近发现了一种新的TLR-4-RP 105内源性抑制剂。RP 105最初被鉴定为B细胞特异性分子，在响应RP 105 mAb和LPS的B细胞增殖中起作用，RP 105是TLR-4同源物。此外，与TLR-4（其表面表达和信号传导依赖于分泌蛋白MD-2的共表达）一样，RP 105的表面表达依赖于MD 2同源物MD-1的共表达。然而，与TLR不同，RP 105缺乏信号传导结构域，具有TLR抑制剂的表观结构。此外，RP 105不是B细胞特异性的;其表达直接反映了树突状细胞和巨噬细胞上TLR-4的表达。这些考虑表明RP 105作为TLR-4信号传导的生理抑制剂的作用。事实上，我们最近发现：（i）RP 105是HEK 293细胞中TLR-4信号传导的特异性抑制剂;（ii）RP 105/MD-1直接与TLR-4/MD-2相互作用，抑制该信号传导复合物结合LPS的能力;（iii）RP 105调节树突状细胞和巨噬细胞中TLR-4信号传导;和（iv）RP 105调节对LPS的体内应答。
Activation of Toll-like receptor (TLR) signaling by microbial and host molecular signatures is critical to the induction of immune responses. Such signaling is, perforce, kept under tight control. We recently discovered a novel endogenous inhibitor of TLR-4-RP105. Initially identified as a B-cell-specific molecule with a role in B-cell proliferation in response to RP105 mAb and LPS, RP105 is a TLR-4 homologue. Further, like TLR-4 whose surface expression and signaling depends upon co-expression of the secreted protein MD-2, surface expression of RP105 is dependent upon co-expression of the MD2 homologue, MD-1. Unlike the TLRs, however, RP105 lacks a signaling domain, having the apparent structure of a TLR inhibitor. Further, RP105 is not B-cell-specific; its expression directly mirrors that of TLR-4 on dendritic cells and macrophages. These considerations suggested a role for RP105 as a physiological inhibitor of TLR-4 signaling. Indeed, we have recently found that: (i) RP105 is a specific inhibitor of TLR-4 signaling in HEK293 cells; ( ii) RP105/MD-1 interacts directly with TLR-4/MD-2, inhibiting the ability of this signaling complex to bind LPS; (iii) RP105 regulates TLR-4 signaling in dendritic cells and macrophages; and (iv) RP105 regulates in vivo responses to LPS.