M. Ehlers et al., COMBINING 2 MUTATIONS OF HUMAN INTERLEUKIN-6 THAT AFFECT GP130 ACTIVATION RESULTS IN A POTENT INTERLEUKIN-6 RECEPTOR ANTAGONIST ON HUMAN MYELOMA CELLS, The Journal of biological chemistry, 270(14), 1995, pp. 8158-8163
The pleiotropic cytokine interleukin-6 (IL-6) interacts with the speci
fic ligand binding subunit (IL-6R alpha) of the IL-6 receptor, and thi
s complex associates with the signal-transducing subunit gp130 (IL-6R
beta). 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 region
(residues 43-55) within the human IL-6 protein, which is important for
the interaction with gp130. Subdividing this region shows that mainly
residues 50-55 of the human IL-6 are necessary for this interaction.
Recently, another human IL-6 double mutant (Q159E and T162P) showed re
duced affinity to gp130 but residual activity on the human myeloma cel
l line XG-1. Into this IL-6 mutant we introduced the murine residues 4
3-49 or 50-55 together with two point mutations, F170L and S176A, whic
h had been reported to increase the affinity of IL-6 to the IL-6R alph
a. The resulting IL-6 molecule, which contained the murine residues 50
-55, was inactive on human myeloma cells and in addition completely in
hibited wild type IL-6 activity on these cells. Such an antagonist may
be used as a specific inhibitor of IL-6 activity in vivo.