IL-1 receptor antagonist chimeric protein: Context-specific and inflammation-restricted activation

Peleg Rider, Yaron Carmi, Rami Yossef, Ofer Guttman, Hadar Eini, Tania Azam, Charles A. Dinarello, Eli C. Lewis

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Both IL-1α and IL-1β are highly inflammatory cytokines mediating a wide spectrum of diseases. A recombinant form of the naturally occurring IL-1R antagonist (IL-1Ra), which blocks IL-1R1, is broadly used to treat autoimmune and autoinflammatory diseases; however, blocking IL-1 increases the risk of infection. In this study, we describe the development of a novel form of recombinant IL-1Ra, termed chimeric IL-1Ra. This molecule is a fusion of the N-terminal peptide of IL-1β and IL-1Ra, resulting in inactive IL-1Ra. Because the IL-1β N-terminal peptide contains several protease sites clustered around the caspase-1 site, local proteases at sites of inflammation can cleave chimeric IL-1Ra and turn IL-1Ra active. We demonstrate that chimeric IL-1Ra reduces IL-1-mediated inflammation in vitro and in vivo. This unique approach limits IL-1 receptor blockade to sites of inflammation, while sparing a multitude of desired IL-1-related activities, including host defense against infections and IL-1-mediated repair.

Original languageEnglish
Pages (from-to)1705-1712
Number of pages8
JournalJournal of Immunology
Issue number4
StatePublished - 15 Aug 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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