Interleukin-6 (IL-6) antagonism by soluble IL-6 receptor α mutated in the predicted gp130-binding interface

A. L. Salvati, A. Lahm, G. Paonessa, G. Ciliberto, C. Toniatti

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Interleukin-6 (IL-6) triggers the formation of a high affinity receptor complex constituted by the ligand-binding subunit IL-6 receptor α (IL-6Rα) and the signal-transducing β chain gp130. Since the cytoplasmic region of IL-6Rα is not required for signal transduction, soluble forms of IL-6Rα (sIl-6Rα) show agonistic properties because they are still able to originate IL-6·sIL-6Rα complexes, which in turn associate with gp130. A three- dimensional model of the human IL-6·IL-6Rα·gp130 complex has been constructed and verified by site-directed mutagenesis of regions in shIL- 6Rα (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-6Rα 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.

Original languageEnglish
Pages (from-to)12242-12249
Number of pages8
JournalJournal of Biological Chemistry
Volume270
Issue number20
DOIs
Publication statusPublished - 1995

Fingerprint

Interleukin-6 Receptors
Interleukin-6
Substitution reactions
Signal transduction
Mutagenesis
Structural Models
Site-Directed Mutagenesis
Bioactivity
Hepatocellular Carcinoma
Signal Transduction
Ligands
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Interleukin-6 (IL-6) antagonism by soluble IL-6 receptor α mutated in the predicted gp130-binding interface. / Salvati, A. L.; Lahm, A.; Paonessa, G.; Ciliberto, G.; Toniatti, C.

In: Journal of Biological Chemistry, Vol. 270, No. 20, 1995, p. 12242-12249.

Research output: Contribution to journalArticle

Salvati, A. L. ; Lahm, A. ; Paonessa, G. ; Ciliberto, G. ; Toniatti, C. / Interleukin-6 (IL-6) antagonism by soluble IL-6 receptor α mutated in the predicted gp130-binding interface. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 20. pp. 12242-12249.
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