IDENTIFICATION OF 2 NOVEL REGIONS OF HUMAN IL-6 RESPONSIBLE FOR RECEPTOR-BINDING AND SIGNAL-TRANSDUCTION

The pleiotropic cytokine IL-6 has been predicted to be a protein with four antiparallel cr-helices. Human IL-6 acts on human and murine cell s, whereas murine IL-6 is only active on murine cells. The constructio n of a set of chimeric human/murine IL-6 proteins has recently allowed us to define a new region (residues Lys41-Glu95) within the IL-6 mole cule as being important for receptor binding and biologic activity. We subdivided and analyzed this region, which primarily corresponds to t he loop between the first and second alpha-helix of IL-6 with respect to its role in the interaction with the ligand binding subunit of the IL-6 receptor complex and with the IL-6 signal-transducing protein gp1 30. By construction and analysis of human/murine chimeric IL-6 molecul es with only 7 to 10 amino acid residues different from human IL-6 we show that two distinct parts of this region are responsible for recept or binding and signal transduction. On the basis of the recently publi shed structure of granulocyte-CSF, we present a three-dimensional mode l for the tertiary structure of IL-6, which, together with the IL-6 re ceptor interaction data, allows for the rational design of human IL-6 receptor antagonists.