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Volume 270, Number 20, Issue of May 19, pp. 12242-12249, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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Interleukin-6 (IL-6) Antagonism by Soluble IL-6 Receptor Mutated in the Predicted gp130-binding Interface

Anna Laura Salvati , Armin Lahm , Giacomo Paonessa , Gennaro Ciliberto , Carlo Toniatti

Interleukin-6 (IL-6) triggers the formation of a high affinity receptor complex constituted by the ligand-binding subunit IL-6 receptor (IL-6R) and the signal-transducing chain gp130. Since the cytoplasmic region of IL-6R is not required for signal transduction, soluble forms of IL-6R (sIL-6R) show agonistic properties because they are still able to originate IL-6sIL-6R complexes, which in turn associate with gp130. A three-dimensional model of the human IL-6IL-6Rgp130 complex has been constructed and verified by site-directed mutagenesis of regions in shIL-6R (where ``h'' is human) anticipated to contact hgp130, with the final goal of generating receptor variants with antagonistic properties. In good agreement with our structural model, substitutions at Asn-230, His-280, and Asp-281 selectively impaired the capability of shIL-6R to associate with hgp130 both in vitro and on the cell surface, without affecting its affinity for hIL-6. Moreover, the multiple substitution mutant A228D/N230D/H280S/D281V expressed as a soluble protein partially antagonized hIL-6 bioactivity on hepatoma cells.

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