Inhibitory Activity of IL-1 Receptor Antagonist Depends on the Balance between Binding Capacity for IL-1 Receptor Type 1 and IL-1 Receptor Type II

Paolo Ruggiero, Paola Bossù, Giovanni Macchia, Egidio Del Grosso, Vilma Sabbatini, Riccardo Bertini, Antonella Colagrande, Cinzia Bizzarri, Giovanni Maurizi, Vito Di Cioccio, Gabriele D'Andrea, Antonio Di Giulio, Francesco Frigerio, Renata Grifantini, Guido Grandi, Aldo Tagliabue, Diana Boraschi

Research output: Contribution to journalArticlepeer-review

Abstract

A series of mutants of human IL-1 receptor antagonist (IL-1ra) has been designed by comparison of IL-1ra and IL-1β structures in order to increase receptor antagonist capacity. Upon in vitro and in vivo assay of IL-1 antagonism, the IL-1ra mutants DoB 0039 (N91→R), DoB 0040 (T109→A) and DoB 0041 (N91/T109→R/A) could inhibit IL-1β effects more efficiently than wild-type IL-1ra, with DoB 0041 being the most active. Analysis of the receptor-binding capacity of the IL-1ra mutants showed that all three mutants could inhibit binding of IL-1α or IL-1β to IL-1RI-bearing cells more efficiently than wild-type IL-1ra. Conversely, binding of IL-1β to IL-1RII-bearing cells could be inhibited by DoB 0041 much less efficiently than by wild-type IL-1ra. It is known that the two types of IL-1 receptors (IL-1RI and IL-1RII) play different roles in the regulation of IL-1 activity, with IL-1RI being solely responsible for cell triggering upon IL-1 binding, whereas IL-1RII acts as a scavenger of IL-1 and can thus be considered as a natural IL-1 inhibitor. Thus, the enhanced inhibitory capacity of DoB 0041 as compared with wild-type IL-1ra is explained in terms of better binding to the activating receptor IL-1RI and poorer interaction with the inhibitory receptor IL-1RII.

Original languageEnglish
Pages (from-to)3881-3887
Number of pages7
JournalJournal of Immunology
Volume158
Issue number8
Publication statusPublished - Apr 15 1997

ASJC Scopus subject areas

  • Immunology

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