Schuster Björn, Kovaleva Marina, Sun Yi, Regenhard Petra, Matthews Vance, Grötzinger Joachim, Rose-John Stefan, Kallen Karl-Josef
Biochemisches Institut, Christian Albrechts Universität zu Kiel, Olshausenstr. 40, D-24098 Kiel, Germany.
J Biol Chem. 2003 Mar 14;278(11):9528-35. doi: 10.1074/jbc.m210044200.
Human ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine that exerts a neuroprotective effect in multiple sclerosis and amyotrophic lateral sclerosis. Clinical application of human CNTF, however, was prevented by high toxicity at higher dosages. Human CNTF elicits cellular responses by induction of a receptor complex consisting of the CNTF alpha-receptor (CNTFR), which is not involved in signal transduction, and the beta-receptors gp130 and leukemia inhibitory factor receptor (LIFR). Previous studies with rat CNTF demonstrated that rat CNTF is unable to interact with the human interleukin-6 alpha-receptor, whereas at high concentrations, it can directly induce a signaling heterodimer of human gp130 and human LIFR in the absence of the CNTF receptor. Here, we demonstrate that human CNTF cannot directly induce a heterodimer of human gp130 and LIFR. However, human CNTF can use both the membrane-bound and the soluble human IL-6R as a substitute for its cognate alpha-receptor and thus widen the target spectrum of human CNTF. Engineering a CNTFR-specific human CNTF variant may therefore be a prerequisite to improving the safety profile of CNTF.
人睫状神经营养因子（CNTF）是一种神经营养细胞因子，在多发性硬化症和肌萎缩侧索硬化症中发挥神经保护作用。然而，人CNTF在较高剂量时具有高毒性，这阻碍了其临床应用。人CNTF通过诱导由CNTFα受体（CNTFR）组成的受体复合物引发细胞反应，CNTFR不参与信号转导，而β受体gp130和白血病抑制因子受体（LIFR）参与信号转导。先前对大鼠CNTF的研究表明，大鼠CNTF无法与人白细胞介素-6α受体相互作用，而在高浓度时，它可以在没有CNTF受体的情况下直接诱导人gp130和人LIFR形成信号异二聚体。在这里，我们证明人CNTF不能直接诱导人gp130和LIFR形成异二聚体。然而，人CNTF可以使用膜结合型和可溶性人IL-6R作为其同源α受体的替代品，从而拓宽人CNTF的靶标谱。因此，构建一种CNTFR特异性的人CNTF变体可能是改善CNTF安全性的先决条件。
