Interleukin-6 receptor antagonists inhibit interleukin-11 biological activity

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 t...

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Bibliographic Details
Published inEuropean cytokine network (Montrouge) Vol. 8; no. 1; p. 51
Main Authors Sun, R X, Gennaro, C, Rocco, S, Gu, Z J, Klein, B
Format Journal Article
LanguageEnglish
Published France 01.03.1997
Subjects
Antigens, CD - analysis
Antigens, CD - metabolism
Cytokine Receptor gp130
Interleukin-11 - antagonists & inhibitors
Interleukin-11 - metabolism
Membrane Glycoproteins - metabolism
Receptors, Interleukin - analysis
Receptors, Interleukin - antagonists & inhibitors
Receptors, Interleukin - metabolism
Receptors, Interleukin-6
Signal Transduction
Tumor Cells, Cultured
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Summary: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.
ISSN:1148-5493