Epitope peptides from interleukin-6 receptor which inhibit the growth of human myeloma cells.
A panel of monoclonal antibodies against the soluble IL-6 receptor was used to search for linear epitopes by a Pepscan analysis. Two such epitopes were found and the corresponding peptides were synthesized chemically. The peptides were active to inhibit the IL-6 dependent growth of human multiple myeloma cell line and the effect of IL-6 on growth of murine hybridoma cells. The epitope-defined, antagonist peptides reduced the transduction of the IL-6 signal which activates binding of Stat transcription factors to specific enhancers, but did not affect IL-6 binding. These effects were not seen with several other peptides from the IL-6 receptor sequence. A computer three-dimensional model of the IL-6 receptor complex was built and indicates that the antagonist peptides define one of the two possible sites of interaction between the domain-II of the IL-6 receptor molecule and that of the gp130 molecule within the hexameric receptor assembly.
Halimi
H
H
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Eisenstein
M
M
Oh
J W
JW
Revel
M
M
Chebath
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003198:Computer Simulation; D050822:Cytokine Receptor gp130; D000939:Epitopes / Q000737:chemistry / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000473:pathology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019947:Receptors, Interleukin-6; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D000939:Epitopes; D006131:Growth Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130