Ciliary neurotrophic factor (CNTF) activates cells the non-signaling α-receptor CNTF receptor (CNTFR) and the two signaling β-receptors glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). The CNTF derivate, Axokine, was protective against obesity and insulin resistance, but clinical development was halted by the emergence of CNTF antibodies. The chimeric cytokine IC7 used the framework of interleukin (IL-)6 with the LIFR-binding site from CNTF to activate cells IL-6R:gp130:LIFR complexes. Similar to CNTF/Axokine, IC7 protected mice from obesity and insulin resistance. Here, we developed CNTF-independent chimeras that specifically target the IL-6R:gp130:LIFR complex. In GIL-6 and GIO-6, we transferred the LIFR binding site from LIF or OSM to IL-6, respectively. While GIO-6 signals gp130:IL-6R:LIFR and gp130:IL-6R:OSMR complexes, GIL-6 selectively activates the IL-6R:gp130:LIFR receptor complex. By re-evaluation of IC7 and CNTF, we discovered the Oncostatin M receptor (OSMR) as an alternative non-canonical high-affinity receptor leading to IL-6R:OSMR:gp130 and CNTFR:OSMR:gp130 receptor complexes, respectively. The discovery of OSMR as an alternative high-affinity receptor for IC7 and CNTF designates GIL-6 as the first truly selective IL-6R:gp130:LIFR cytokine, whereas GIO-6 is a CNTF-free alternative for IC7.

中文翻译：

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工程化白细胞介素 6 衍生细胞因子招募人工受体复合物并通过 OSMR 揭示 CNTF 信号传导

睫状神经营养因子 (CNTF) 激活细胞非信号传导 α 受体 CNTF 受体 (CNTFR) 和两个信号传导 β 受体糖蛋白 130 (gp130) 和白血病抑制因子受体 (LIFR)。 CNTF 衍生物 Axokine 可预防肥胖和胰岛素抵抗，但临床开发因 CNTF 抗体的出现而停止。嵌合细胞因子 IC7 使用白介素 (IL-)6 框架和 CNTF 的 LIFR 结合位点来激活细胞 IL-6R:gp130:LIFR 复合物。与 CNTF/Axokine 类似，IC7 可以保护小鼠免受肥胖和胰岛素抵抗。在这里，我们开发了不依赖于 CNTF 的嵌合体，专门针对 IL-6R:gp130:LIFR 复合物。在GIL-6和GIO-6中，我们分别将LIFR结合位点从LIF或OSM转移到IL-6。 GIO-6 向 gp130:IL-6R:LIFR 和 gp130:IL-6R:OSMR 复合物发出信号，而 GIL-6 选择性激活 IL-6R:gp130:LIFR 受体复合物。通过重新评估 IC7 和 CNTF，我们发现制瘤素 M 受体 (OSMR) 作为另一种非经典高亲和力受体，分别产生 IL-6R:OSMR:gp130 和 CNTFR:OSMR:gp130 受体复合物。 OSMR 作为 IC7 和 CNTF 的替代高亲和力受体的发现表明 GIL-6 是第一个真正选择性的 IL-6R:gp130:LIFR 细胞因子，而 GIO-6 是 IC7 的无 CNTF 替代品。