title: IL-1 Receptor Antagonist Chimeric Protein: Context-Specific and Inflammation-Restricted Activation.
abstract: 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.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; riderp@gmail.com.
authors.forename: Peleg
authors.identifier: http://orcid.org/0000-0003-3265-946X
authors.initials: P
authors.lastname: Rider
authors.affiliation: Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA 95305; The Shraga Segal Department of Microbiology, Immunology and Genetics and The Cancer Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
authors.forename: Yaron
authors.initials: Y
authors.lastname: Carmi
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics and The Cancer Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
authors.forename: Rami
authors.initials: R
authors.lastname: Yossef
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
authors.forename: Ofer
authors.initials: O
authors.lastname: Guttman
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
authors.forename: Hadar
authors.initials: H
authors.lastname: Eini
authors.affiliation: University of Colorado at Denver, Aurora, CO 80045; and.
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.affiliation: University of Colorado at Denver, Aurora, CO 80045; and Radboud University Medical Centre, Nijmegen 6500, the Netherlands.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel;
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010196:Pancreatic Elastase / Q000378:metabolism; D010446:Peptide Fragments; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D059748:Proteolysis; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D010446:Peptide Fragments; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D010196:Pancreatic Elastase