Cytokine 122 (2019) 154215 Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/cytokine IL-1 family cytokines in cardiovascular disease T ⁎ Susanne Pfeilera, Holger Winkelsb, Malte Kelma, Norbert Gerdesa,c, a Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany b Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, United States c Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany ARTICLE INFO ABSTRACT Keywords: The interleukin (IL)-1 family is a group of cytokines crucially involved in regulating immune responses to in- Interleukin fectious challenges and sterile insults. The family consists of the eponymous pair IL-1α and IL-1β, IL-18, IL-33, IL-1 IL-37, IL-38, and several isoforms of IL-36. In addition, two endogenous inhibitors of functional receptor binding, IL-18 IL-1R antagonist (IL-1Ra) and IL-36Ra complete the family. To gain biological activity IL-1β and IL-18 require Caspase 1 processing by the protease caspase-1 which is associated with the multi-protein complex inflammasome. Inflammasome Numerous clinical association studies and experimental approaches have implicated members of the IL-1 family, Cardiovascular disease their receptors, or component of the processing machinery in underlying processes of cardiovascular diseases (CVDs). Here we summarize the current state of knowledge regarding the pro-inflammatory and disease-mod- ulating role of the IL-1 family in atherosclerosis, myocardial infarction, aneurysm, stroke, and other CVDs. We discuss clinical evidence, experimental approaches and lastly lend a perspective on currently developing ther- apeutic strategies involving the IL-1 family in CVD. 1. The history of IL-1 family members responses, the major contributors to non-communicable diseases [7]. The cytokines IL-1α and IL-1β represent close homologues of IL-1 Among the broad range of cell signaling-inducing cytokines the gene family-coded proteins. Neither contains a secretion sequence, interleukin 1 family represents a group of molecules principally tar- however, both share a similar structures and are initial present as geting leukocytes. In the 1940 s discovery of cytokines began with the 30 kDa precursor forms [18]. They are converted to their bioactive search of endogenous mediators of fever, yet until today the overall 17.5 kDa forms by enzymatic cleavage [19]. In contrast to IL-1β, IL-1α goal was and remains to clarify the axis of infection, fever, and in- shows biologically activity as intact, full-length form [20]. IL-1α and IL- flammation. Indeed, Menkin and Bennett discovered fever-inducing 1β bind to the same receptor and share similar functional character- factors in the supernatant of rabbit neutrophils unrelated to endotoxin istics as potent pro-inflammatory cytokines. involvement [1,2]. For the next two decades the characterization of the The IL-1 receptor type 1 (IL-1R1) is expressed by several cell types, endogenous fever protein termed “Leukocytic Pyrogen” continued [3]. including immune cells and non-hematopoietic cells (e.g. smooth The examination of the unfractionated supernatant revealed involve- muscle cells). The binding of the two distinct ligands IL-1α and IL-1β ment of the so called “Lymphocyte Activating Factor” in excessive induces pro-inflammatory effects [19,21]. proliferation of lymphocytes in response to antigen [4]. The char- In contrast, the IL-1 receptor antagonist (IL-1Ra) acts as endogenous acterization of the small, non-structural proteins was the challenging inhibitor blocking the binding of IL-1α and IL-1β to IL-1R1. IL-1Ra task for next decade. The reported successful purification of human contains a signal peptide at the N-terminus for the effective secretion. Leukocyte Pyrogen in 1977 demonstrated its similarity with the Lym- Rare mutations associated with absence of IL-1Ra lead to uncontrolled phocyte Activating Factor [5]. activity of IL-1 and severe systemic inflammation [22,23]. Subtle To unify the nomenclature of the broad range of terms used, the changes in the carefully regulated IL-1/IL-1Ra system result in a broad name interleukin (IL) was defined by a committee of the International range of chronic inflammatory conditions (e.g., type 2 diabetes mel- Union of Immunological Societies (IUIS) for these 17–20 kDa evolu- litus, psoriasis, rheumatoid arthritis, inflammatory bowel disease) tionarily ancient cytokines expressed by leukocytes [6]. With its cur- [24,25]. rently 11 members, the IL-1 family (Table 1) is the largest family of Engagement of the ligand (IL-1α or -β) with the heterodimeric re- interleukins and closely linked to innate inflammatory and immune ceptor consisting of IL-1R1 and IL-1R-accessory protein (IL-1RAcP) ⁎ Corresponding author at: Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Moorenstr. 5, 40225 Düsseldorf, Germany. E-mail address: [email protected] (N. Gerdes). https://doi.org/10.1016/j.cyto.2017.11.009 Received 3 August 2017; Received in revised form 13 November 2017; Accepted 15 November 2017 Available online 01 December 2017 1043-4666/ © 2017 Elsevier Ltd. All rights reserved. S. Pfeiler et al. Cytokine 122 (2019) 154215 Table 1 IL-1 family cytokines. Name Function Gene (human/mouse) Ref. Synonym ID name location IL-1α Pro-inflammatory, Th17 cell 3552/16175 [8] IL-1F1, hematopoietin-1 response, tissue repair IL1A/Il1a 2q14.1/2 F1; 2 62.9 cM IL-1β Pro-inflammatory, Th17 cell 3553/16176 [9] IL-1F2, leukocytic pyrogen, leukocytic endogenous response, tissue repair IL1B/Il1b mediator, mononuclear cell factor, lymphocyte 2q14.1/2 F1; 2 activating factor 62.97 cM IL-1Ra Antagonist for IL-1α, IL-1β 3557/16181 [10,11] Interleukin-1 receptor antagonist, IL-1F3 IL1RN/Il1rn 2q14.1/2 A3; 2 16.36 cM IL-18 Pro-inflammatory, Th1 3606/16173 [12] IL-1F4, IFNγ-gamma inducing factor (IGIF) polarization, IL-22 signaling IL18/Il18 11q23.1/9 A5.3; 9 27.75 cM IL-33 Pro-inflammatory, Th2 90865/77125 [13] IL-1F11 polarization IL33/Il33 9p24.1/19; 19 C1 IL-36Ra Antagonist for IL-36α, IL-36β, IL- 26525/54450 [14] Interleukin 36 receptor antagonist, IL-1F5, FIL1(δ) 36γ (NFkB induced IL-1 family IL36RN/Il1f5 members) 2q14.1/2 A3; 2 16.31 cM IL-36α Pro-inflammatory 27179/54448 [15] IL-1F6, FIL1(ε) IL36A/Il1f6 2q14.1/2 A3; 2 16.26 cM IL-36β Pro-inflammatory 27177/69677 [15] IL-1F8, FIL1(η) IL36B/Il1f8 2q14.1/2 A3; 2 16.21 cM IL-36γ Pro-inflammatory 56300/215257 [16] IL1-F9 IL36G/Il1f9 2q14.1/2 A3; 2 16.24 cM IL-37 Anti-inflammatory 27178/n/a [15] IL-1F7, FIL1(ζ) IL1F7/n/a 2q14.1/n/a IL-38 Anti-inflammatory 84639/215274 [17] IL-1F10, FIL1(θ) ILF10/Il1f10 2q14.1/2 A3; 2 16.32 cM induces signal transduction leading to the synthesis of acute phase and require neutrophil proteinases (elastase, Proteinase-3 (PR3), and Ca- pro-inflammatory proteins (Fig. 1) [26]. The highly-sensitive IL-1/IL- thepsin G) for their processing [31,32]. While the other members of the 1R1/IL-1RAcP signaling complex is considered a major pathway to IL-1 family have relatively short pro-peptides (< 40 amino acid re- activate the inflammatory response during infection, tissue damage, or sidues), the pro-peptides of IL-1α, IL-1β, and IL-33 comprise ≈ 110 stress by only 10 activated receptors/cell or less [27]. amino acid residues at their N-terminus [30]. IL-1R2 (known as CD121b) provides negative regulation of the IL-1 pathway. This receptor lacks intracellular signaling capacity and acts as 2. General role of IL-1 family members a decoy receptor competitively binding IL-1α and IL-1β thus inhibiting signal transduction through the IL-1R1 complex [28]. The receptor- 2.1. IL-1α based signal transduction initiation is further negatively controlled by the antagonists IL-1Ra and IL-36Ra, which represent an additional re- IL-1α is constitutively expressed in the cytoplasm and nuclei of a pressive chain to balance the inflammation response [28]. range of non-hematopoietic cells in various tissues (e.g. lung, liver, and IL-1 family members are generally expressed as precursors that re- kidney) [33], but is also upregulated in immune cells [34]. Besides its quire specific proteolytic cleavage for the enhanced signal transduction. classical function as cytokine via local contact-dependent cell surface The preform of IL-1α is activated via calpain, a Ca-dependent cystein- receptor ligation, full-length pro-IL-1α can also directly regulate gene protease, whereas IL-1β and IL-18 precursors require proteolytic pro- expression via an N-terminal amino acid sequence within its nuclear cessing by the inflammasome, a complex of intracellular molecules localization site [35]. The proteolytic cleavage of pro-IL-1α is driven by containing the enzyme caspase-1 (see below) [29,30]. IL-33 and IL-36 the membrane-associated calcium-dependent cysteine-protease calpain 2 S. Pfeiler et al. Cytokine 122 (2019) 154215 Fig. 1. The receptor complexes of IL-1 family member. The binding to their receptors and the generation of complexes with co-receptors, can activate signaling while antagonists like IL-1Ra and IL-36Ra (red) inhibit the inflammatory responses driven by IL-1 cytokines. and through inflammasome activation [36]. While IL-1α is not com- 2.3. IL-18 monly found in the circulation or body fluids, its presence strongly increases in inflammatory disease [37]. IL-18 was initially described as IFNγ-inducing factor isolated from endotoxin-treated mice [12]. Similar to IL-1β, IL-18 is synthesized as inactive precursor from and requires processing by caspase-1. The 2.2.