Sun R X, Gennaro C, Rocco S, Gu Z J, Klein B
Unit for Cellular Therapy, Hopital St. Eloi, Montpellier, France.
Eur Cytokine Netw. 1997 Mar;8(1):51-6.
The IL-6 receptor system comprises two functionally different chains: a binding chain (IL-6R) and a signal-transducing chain (gp130). The IL-6/IL-6R complexes associate with gp130, induce its dimerization and signal transduction. When IL-6 is complexed to IL-6R, two distinct sites of IL-6 are able to bind gp130. Other cytokines-oncostatin M (OM), leukemia inhibitory factor (LIF) or ciliary neurotrophic factor (CNTF) also use the gp130 transducer and induce its heterodimerization with LIF receptor (LIFR). A series of IL-6 mutants have been generated which function as IL-6 receptor antagonists (IL-6RA). These IL-6RA carried substitutions that increased their affinity with IL-6R and abolished 1 or the 2 sites of interaction with gp130. All the IL-6RA inhibited wild-type IL-6. The IL-6RA with one mutated binding site to gp130 inhibited IL-11 activity. They did not affect those of CNTF, LIF and OM, even when used at a very high concentration at which virtually all membrane IL-6R were bound to IL-6RA. IL-6RA with two mutated gp130 binding sites did not affect IL-11, CNTF, LIF or OM activities. The results indicate that the interaction of one gp130 chain with IL-6R/IL-6R complexes inhibited further the dimerization of gp130 induced by IL-11/IL-11R but not its heterodimerization with LIFR. Thus these IL-6RA can also function as IL-11 antagonists.
白细胞介素-6受体系统由两条功能不同的链组成：一条结合链（白细胞介素-6受体）和一条信号转导链（糖蛋白130）。白细胞介素-6/白细胞介素-6受体复合物与糖蛋白130结合，诱导其二聚化并进行信号转导。当白细胞介素-6与白细胞介素-6受体形成复合物时，白细胞介素-6的两个不同位点能够结合糖蛋白130。其他细胞因子——抑瘤素M（OM）、白血病抑制因子（LIF）或睫状神经营养因子（CNTF）也利用糖蛋白130作为信号转导分子，并诱导其与白血病抑制因子受体（LIFR）形成异源二聚体。已经产生了一系列作为白细胞介素-6受体拮抗剂（IL-6RA）发挥作用的白细胞介素-6突变体。这些白细胞介素-6RA发生了取代，增加了它们与白细胞介素-6受体的亲和力，并消除了与糖蛋白130相互作用的1个或2个位点。所有的白细胞介素-6RA都抑制野生型白细胞介素-6。与糖蛋白130有一个突变结合位点的白细胞介素-6RA抑制白细胞介素-11的活性。它们不影响CNTF、LIF和OM的活性，即使在使用非常高的浓度时，几乎所有膜结合的白细胞介素-6受体都与白细胞介素-6RA结合。有两个突变的糖蛋白130结合位点的白细胞介素-6RA不影响白细胞介素-11、CNTF、LIF或OM的活性。结果表明，一条糖蛋白130链与白细胞介素-6受体/白细胞介素-受体复合物的相互作用进一步抑制了由白细胞介素-11/白细胞介素-11受体诱导的糖蛋白130的二聚化，但不抑制其与白血病抑制因子受体的异源二聚化。因此，这些白细胞介素-6RA也可以作为白细胞介素-11拮抗剂发挥作用。
