Functional inhibition of hematopoietic and neurotrophic cytokines by blocking the interleukin 6 signal transducer gp130.
Functional pleiotropy and redundancy are characteristic features of cytokines. To understand the signaling mechanisms of such cytokines, we have proposed a two-chain interleukin (IL) 6 receptor model: IL-6 triggers the association of a ligand-binding chain (IL-6 receptor) and a nonbinding signal transducer (gp130) to form a high-affinity receptor complex, resulting in transmission of the signal by the cytoplasmic portion of gp130. This model would explain the functional redundancy of cytokines if we were to assume that gp130 interacts with several different receptor chains. Here we present data indicating that gp130 functions as a common signal transducer for IL-6, oncostatin M, leukemia inhibitory factor, and ciliary neurotrophic factor. We show that anti-gp130 monoclonal antibodies completely block the biological responses induced by all of these factors. Since leukemia inhibitory factor functions as a cholinergic differentiation factor in nerve cells, as does ciliary neurotrophic factor, these results suggest that gp130 may also play a role in the nervous system.
Taga
T
T
Institute for Molecular and Cellular Biology, Osaka University, Japan.
Narazaki
M
M
Yasukawa
K
K
Saito
T
T
Miki
D
D
Hamaguchi
M
M
Davis
S
S
Shoyab
M
M
Yancopoulos
G D
GD
Kishimoto
T
T
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001402:B-Lymphocytes; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D020934:Ciliary Neurotrophic Factor; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000494:pharmacology*; D003593:Cytoplasm / Q000502:physiology; D004921:Erythropoietin / Q000494:pharmacology*; D005340:Fibrinogen / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000187:drug effects / Q000502:physiology*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D053683:Oncostatin M; D004921:Erythropoietin; D050822:Cytokine Receptor gp130; D005340:Fibrinogen