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 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.
Sun
R X
RX
Unit for Cellular Therapy, Hopital St. Eloi, Montpellier, France.
Gennaro
C
C
Rocco
S
S
Gu
Z J
ZJ
Klein
B
B
D015703:Antigens, CD / Q000032:analysis* / Q000378:metabolism; D050822:Cytokine Receptor gp130; D017370:Interleukin-11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D018123:Receptors, Interleukin / Q000032:analysis* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019947:Receptors, Interleukin-6; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D017370:Interleukin-11; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130