Neddermann P, Graziani R, Ciliberto G, Paonessa G
Istituto di Ricerche di Biologia Molecolare "P. Angeletti" (IRBM), Department of Genetics, 00040 Pomezia (Roma), Italy.
J Biol Chem. 1996 Nov 29;271(48):30986-91. doi: 10.1074/jbc.271.48.30986.
The interleukin-6 (IL-6) family of cytokines activates signaling through the formation of either gp130 homodimers, as for IL-6, or gp130-leukemia inhibitory factor receptor (LIFR) heterodimers as for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor, oncostatinM, and cardiotrophin-1. Recent in vitro studies with IL-6 and CNTF have demonstrated that higher order hexameric receptor complexes are assembled in which signaling chain dimerization is accompanied by the dimerization of both the cytokine molecule and its specific receptor alpha subunits (IL-6Ralpha or CNTFRalpha, respectively). IL-11 is a member of the IL-6 family and known to require gp130 but not LIFR for signaling. In this study we investigate the functional and biochemical composition of the IL-11 receptor complex. The human IL-11 receptor alpha-chain was cloned from a human bone marrow cDNA library. IL-11Ralpha was shown to confer IL-11 responsiveness to human hepatoma cells either by cDNA transfection or by adding a soluble form of the receptor (sIL11Ralpha) expressed in the baculovirus system to the culture medium. In vitro immunoprecipitation experiments showed that sIL11Ralpha specifically binds IL-11 and that binding is enhanced by gp130. Similarly to IL-6 and CNTF, gp130 is able to induce dimerization of the IL-11.IL-11Ralpha subcomplex, the result of which is the formation of a pentameric receptor complex. However, in contrast to the other two cytokines, IL-11 was unable to induce either gp130 homodimerization or gp130/LIFR heterodimerization. These results strongly suggest that an as yet unidentified receptor beta-chain is involved in IL-11 signaling.
白细胞介素-6（IL-6）细胞因子家族通过形成gp130同二聚体（如IL-6）或gp130-白血病抑制因子受体（LIFR）异二聚体（如睫状神经营养因子（CNTF）、白血病抑制因子、制瘤素M和心肌营养素-1）来激活信号传导。最近对IL-6和CNTF的体外研究表明，会组装更高阶的六聚体受体复合物，其中信号链二聚化伴随着细胞因子分子及其特异性受体α亚基（分别为IL-6Rα或CNTFRα）的二聚化。IL-11是IL-6家族的成员，已知其信号传导需要gp130而不需要LIFR。在本研究中，我们调查了IL-11受体复合物的功能和生化组成。人IL-11受体α链是从人骨髓cDNA文库中克隆出来的。通过cDNA转染或将杆状病毒系统中表达的受体可溶性形式（sIL11Rα）添加到培养基中，IL-11Rα被证明可赋予人肝癌细胞对IL-11的反应性。体外免疫沉淀实验表明，sIL11Rα特异性结合IL-11，并且gp130可增强这种结合。与IL-6和CNTF类似，gp130能够诱导IL-11.IL-11Rα亚复合物的二聚化，其结果是形成五聚体受体复合物。然而，与其他两种细胞因子不同，IL-11无法诱导gp130同二聚化或gp130/LIFR异二聚化。这些结果强烈表明，一种尚未确定的受体β链参与了IL-11信号传导。
