The pleiotropic cytokine IL-6 has been predicted to be a protein with four antiparallel alpha-helices. Human IL-6 acts on human and murine cells, whereas murine IL-6 is only active on murine cells. The construction 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 molecule as being important for receptor binding and biologic activity. We subdivided and analyzed this region, which primarily corresponds to the 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 gp130. By construction and analysis of human/murine chimeric IL-6 molecules 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 receptor binding and signal transduction. On the basis of the recently published structure of granulocyte-CSF, we present a three-dimensional model for the tertiary structure of IL-6, which, together with the IL-6 receptor interaction data, allows for the rational design of human IL-6 receptor antagonists.