M. Ehlers et al., IDENTIFICATION OF 2 NOVEL REGIONS OF HUMAN IL-6 RESPONSIBLE FOR RECEPTOR-BINDING AND SIGNAL-TRANSDUCTION, The Journal of immunology, 153(4), 1994, pp. 1744-1753
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.