title: The interleukin (IL)-1 cytokine family--Balance between agonists and antagonists in inflammatory diseases.
abstract: The interleukin (IL)-1 family of cytokines comprises 11 members, including 7 pro-inflammatory agonists (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) and 4 defined or putative antagonists (IL-1R antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38) exerting anti-inflammatory activities. Except for IL-1Ra, IL-1 cytokines do not possess a leader sequence and are secreted via an unconventional pathway. In addition, IL-1β and IL-18 are produced as biologically inert pro-peptides that require cleavage by caspase-1 in their N-terminal region to generate active proteins. N-terminal processing is also required for full activity of IL-36 cytokines. The IL-1 receptor (IL-1R) family comprises 10 members and includes cytokine-specific receptors, co-receptors and inhibitory receptors. The signaling IL-1Rs share a common structure with three extracellular immunoglobulin (Ig) domains and an intracellular Toll-like/IL-1R (TIR) domain. IL-1 cytokines bind to their specific receptor, which leads to the recruitment of a co-receptor and intracellular signaling. IL-1 cytokines induce potent inflammatory responses and their activity is tightly controlled at the level of production, protein processing and maturation, receptor binding and post-receptor signaling by naturally occurring inhibitors. Some of these inhibitors are IL-1 family antagonists, while others are IL-1R family members acting as membrane-bound or soluble decoy receptors. An imbalance between agonist and antagonist levels can lead to exaggerated inflammatory responses. Several genetic modifications or mutations associated with dysregulated IL-1 activity and autoinflammatory disorders were identified in mouse models and in patients. These findings paved the road to the successful use of IL-1 inhibitors in diseases that were previously considered as untreatable.
authors.affiliation: Division of Rheumatology, Departments of Internal Medicine Specialties and of Pathology-Immunology, University of Geneva School of Medicine, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Palomo
authors.affiliation: Division of Rheumatology, Departments of Internal Medicine Specialties and of Pathology-Immunology, University of Geneva School of Medicine, Switzerland.
authors.forename: Damien
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Division of Rheumatology, Departments of Internal Medicine Specialties and of Pathology-Immunology, University of Geneva School of Medicine, Switzerland.
authors.forename: Praxedis
authors.initials: P
authors.lastname: Martin
authors.affiliation: Division of Rheumatology, Departments of Internal Medicine Specialties and of Pathology-Immunology, University of Geneva School of Medicine, Switzerland.
authors.forename: Gaby
authors.initials: G
authors.lastname: Palmer
authors.affiliation: Division of Rheumatology, Departments of Internal Medicine Specialties and of Pathology-Immunology, University of Geneva School of Medicine, Switzerland. Electronic address: cem.gabay@hcuge.ch.
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007375:Interleukin-1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D000067596:Interleukin-33 / Q000819:agonists / Q000276:immunology; D007378:Interleukins / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007375:Interleukin-1; D020382:Interleukin-18; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; D017472:Receptors, Interleukin-1; D020170:Caspase 1
keywords: Autoinflammatory disorders; Cytokine antagonists; Inflammasome; Interleukin-1