Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex
Novel Insights into Interleukin 6 (IL-6) Cis- and Trans-signaling Pathways by Differentially Manipulating the Assembly of the IL-6 Signaling Complex
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DOI：
10.1074/jbc.m115.682138
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发表时间：
2015-11-06
影响因子：
4.8
通讯作者：
Ferlin, Walter
中科院分区：
文献类型：
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作者：
Lacroix, Marine;Rousseau, Francois;Ferlin, Walter
背景：IL-6信号复合体由IL-6顺式和反式信号转导所必需的六聚体结构组成。结果：MAb 25F10靶向IL-6R的IIb位点，干扰六聚体组装，选择性地阻断反式信号转导。结论：小鼠体内的顺式和反式信号转导机制不同，介导了IL-6R复合体的组装。意义：靶向IL-6R的IIb位点为抑制IL-6活性提供了一种独特的作用方式。IL-6信号复合体被描述为一个六角体，由两个IL-6受体(IL-6R)结合而成。gp130，其中gp130是信号转导分子，分别通过膜结合形式和可溶性形式的IL-6R诱导顺式和反式信号转导。25F10是一种抗鼠IL-6R的单抗，可与膜结合的IL-6R和可溶性IL-6R结合，具有特异性抑制反式介导的信号转导事件的独特性质。在这项研究中，表位图谱显示25F10在IL-6R的IIb位相互作用，但允许IL-6与IL-6R结合并募集gp130，形成三聚体复合体。25F10与IL-6R的结合阻止了反式介导信号转导的六聚体复合体的形成，提示IL-6信号的顺式和反式模式采用不同的受体复合体组装机制。为了在人类系统中研究这种现象，我们开发了一种单抗NI-1201，它针对人IL-6R序列中的25F10为小鼠识别的表位。然而，有趣的是，NI-1201并不选择性地抑制人IL-6的转导信号，尽管这两种单抗在IL-6加重的条件下与I位点导向的单抗相比都产生了有益的结果。这些发现揭示了IL-6信号的复杂性。首先，在小鼠体内，通过受体复合体组装的独特机制触发顺式和反式介导的IL-6信号。其次，在小鼠和人类中，导致顺式和反式信号生物学的受体复合体的形成是不同的，在制定临床抑制IL-6的策略时，这一点应该被考虑在内。
Background: The IL-6 signaling complex consists of a hexameric structure essential for IL-6 cis- and trans-signaling.Results: mAb 25F10 targets site IIb of IL-6R and disrupts hexamer assembly to selectively block trans-signaling.Conclusion: Cis- and trans-signaling in mice utilize distinct mechanisms to mediate assembly of the IL-6R complex.Significance: Therapeutic targeting of site IIb of IL-6R provides a unique mode of action for IL-6 inhibition.The IL-6 signaling complex is described as a hexamer, formed by the association of two IL-6.IL-6 receptor (IL-6R).gp130 trimers, with gp130 being the signal transducer inducing cis- and trans-mediated signaling via a membrane-bound or soluble form of the IL-6R, respectively. 25F10 is an anti-mouse IL-6R mAb that binds to both membrane-bound IL-6R and soluble IL-6R with the unique property of specifically inhibiting trans-mediated signaling events. In this study, epitope mapping revealed that 25F10 interacts at site IIb of IL-6R but allows the binding of IL-6 to the IL-6R and the recruitment of gp130, forming a trimer complex. Binding of 25F10 to IL-6R prevented the formation of the hexameric complex obligate for trans-mediated signaling, suggesting that the cis- and trans-modes of IL-6 signaling adopt different mechanisms for receptor complex assembly. To study this phenomenon also in the human system, we developed NI-1201, a mAb that targets, in the human IL-6R sequence, the epitope recognized by 25F10 for mice. Interestingly, NI-1201, however, did not selectively inhibit human IL-6 trans-signaling, although both mAbs produced beneficial outcomes in conditions of exacerbated IL-6 as compared with a site I-directed mAb. These findings shed light on the complexity of IL-6 signaling. First, triggering cis-versus trans-mediated IL-6 signaling occurs via distinctive mechanisms for receptor complex assembly in mice. Second, the formation of the receptor complex leading to cis- and trans-signaling biology in mice and humans is different, and this should be taken into account when developing strategies to inhibit IL-6 clinically.