Structure-function analysis of interleukin-6 utilizing human/murine chimeric molecules. Involvement of two separate domains in receptor binding

• Published in: The Journal of biological chemistry Vol. 268; no. 20; pp. 15285 - 15290
• Main Authors: VAN DAM, M, MÜLLBERG, J, SCHOOLTINK, H, STOYAN, T, BRAKENHOFF, J. P. J, GRAEVE, L, HEINRICH, P. C, ROSE-JOHN, S
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 15.07.1993
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Base Sequence; Binding Sites; Biological and medical sciences; Cloning, Molecular; DNA; Escherichia coli; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Interleukin-6 - genetics; Interleukin-6 - metabolism; Lymphokines, interleukins ( function, expression); Mice; Molecular Sequence Data; Receptors, Immunologic - metabolism; Receptors, Interleukin-6; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Regulatory factors and their cellular receptors; Structure-Activity Relationship; Tumor Cells, Cultured; Human; Interleukin 6; Vertebrata; Membrane receptor; Mammalia; Mouse; Cytokine; Rodentia; Structure function relationship; Biological activity; Hybrid gene
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(18)82467-x

As an approach to understanding the interaction of interleukin-6 (IL-6) and its 80-kDa receptor (gp80), we have constructed chimeric human/murine IL-6-molecules, which were expressed in Escherichia coli and analyzed for biological activity and receptor binding. This experimental strategy was based on the observation that human IL-6 acts on human and murine cells, whereas murine IL-6 stimulates only murine cells. The regions to be exchanged were chosen according to the four antiparallel helix model of the hematopoietic cytokine family. All 14 chimeras constructed showed biological activity on murine cells. From the differential biological activities on human cells we deduced that three out of four domains of IL-6 are involved in species specificity, whereas only two domains are necessary for specific recognition by the gp80 IL-6-receptor protein.