Interleukin-6 receptor antagonists inhibit interleukin-11 biological activity

Sun Ren-Xiao, Ciliberto Gennaro, Savino Rocco, Gu Zong-Jiang, Klein . Bernard

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)51-56
Number of pages6
JournalEuropean Cytokine Network
Volume8
Issue number1
Publication statusPublished - 1997

Keywords

  • Ciliary neurotrophic factor
  • Interleukin-11
  • Interleukin-6
  • Leukemia inhibitory factor
  • Multiple myeloma
  • Oncostatin M

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

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