Interleukin-6 family of cytokines induced activation of different functional sites expressed by gp130 transducing protein.
Gp130 transducing protein was shown to be involved in the formation of the high affinity receptors for interleukin 6 (IL-6), interleukin-11 (IL-11), leukemia inhibitory factor, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1. In the present study we have characterized the functional properties of antibodies directed against this protein and identified a group of monoclonal antibodies able to antagonize the biological activities of all the cytokines belonging to the IL-6 cytokine family. The B-R3 pan-blocking antibody weakly interfered with the binding of the radiolabeled ligands (with the exception of OSM, whose binding was abrogated in the presence of B-R3 monoclonal antibody) but inhibited the gp130 homodimerization or its association with gp190/leukemia inhibitory factor receptor, as well as the subsequent tyrosine phosphorylation events. In addition we identified antibodies that were able to neutralize only one single cytokine of the IL-6 family. This was the case for the B-K5 antibody, which antagonized the binding of OSM to gp130 but did not interfere with the signals provided by the related cytokines triggering the proliferation of the TF1 erythroleukemia cell line or the induction of haptoglobin synthesis in the HepG2 hepatoma cell line. Similarly, we also characterized two additional antibodies B-P8 and B-P4, which inhibited the TF1 cell proliferation observed in the presence of CNTF and IL-11, respectively. B-P8 antibody only faintly interfered with the binding of the gp130-ligands and might modulate the signal transduction pathways. This study indicates that in addition to functional site(s) required by the whole family of IL-6 type cytokines to transduce the signal insight the cell, specific cognate functional sites were recruited by OSM, CNTF, or IL-11.
Chevalier
S
S
Laboratoire de Biologie Cellulaire, 4 rue Larrey, CHRU Angers, 49033 Angers Cedex, France.
Fourcin
M
M
Robledo
O
O
Wijdenes
J
J
Pouplard-Barthelaix
A
A
Gascan
H
H
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular; D002455:Cell Division / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006242:Haptoglobins / Q000096:biosynthesis; D006801:Humans; D017370:Interleukin-11 / Q000494:pharmacology; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D004915:Leukemia, Erythroblastic, Acute; D008113:Liver Neoplasms; D008222:Lymphokines / Q000494:pharmacology; D008545:Melanoma; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009447:Neuroblastoma; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine / Q000187:drug effects / Q000502:physiology*; D018123:Receptors, Interleukin / Q000502:physiology; D053702:Receptors, Interleukin-11; D019947:Receptors, Interleukin-6; D017475:Receptors, Nerve Growth Factor / Q000502:physiology; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D020934:Ciliary Neurotrophic Factor; D016207:Cytokines; D006131:Growth Inhibitors; D006242:Haptoglobins; C508428:IL11RA protein, human; C494199:IL6ST protein, human; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C508351:OSM protein, human; D010455:Peptides; D020801:Receptor, Ciliary Neurotrophic Factor; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D019947:Receptors, Interleukin-6; D017475:Receptors, Nerve Growth Factor; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; C092073:cardiotrophin 1