key: cord-0768084-wlwxwrer authors: Kaplanski, Gilles title: Interleukin‐18: Biological properties and role in disease pathogenesis date: 2017-12-16 journal: Immunol Rev DOI: 10.1111/imr.12616 sha: 83915d38aca3b16b855c297657e8fbc5d326bd6f doc_id: 768084 cord_uid: wlwxwrer Initially described as an interferon (IFN)γ‐inducing factor, interleukin (IL)‐18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL‐17‐producing γδ T cells and macrophage activation. IL‐18, a member of the IL‐1 family, is similar to IL‐1β for being processed by caspase 1 to an 18 kDa‐biologically active mature form. IL‐18 binds to its specific receptor (IL‐18Rα, also known as IL‐1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL‐18Rβ chain. IL‐18 then uses the same signaling pathway as IL‐1 to activate NF‐kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL‐18 also binds to the circulating high affinity IL‐18 binding protein (BP), such as only unbound free IL‐18 is active. IL‐18Rα may also bind IL‐37, another member of the IL‐1 family, but in association with the negative signaling chain termed IL‐1R8, which transduces an anti‐inflammatory signal. IL‐18BP also binds IL‐37 and this acts as a sink for the anti‐inflammatory properties of IL‐37. There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain‐of‐function mutations, IL‐18 circulates in the range of tens of nanograms/mL. HS is treated with the IL‐1 Receptor antagonist (anakinra) but also specifically with IL‐18BP. Systemic juvenile idiopathic arthritis or adult‐onset Still's disease are also characterized by high serum IL‐18 concentrations and are treated by IL‐18BP. KAPLANSKI 2 | IL-18BIOLOGY IL-18 gene is located on chromosome 11 in humans and chromosome 9 in mice whose gene contains 7 exons with two distinct promoters on exon 1 and 2 including an interferon consensus sequence binding protein and a PU.1 binding sites. 5 In contrast to other cytokine genes, IL-18 gene has few RNA-destabilizing elements, resulting in an unusually stable cytokine expression. Transcription of IL-18 precursor can be induced after TLR binding of PAMPs and activation of the NF-κB pathway. IL-18 gene encodes for a 193 amino acids precursor, first synthesized as an inactive 24-kDa precursor with no signal peptide, which accumulates in cell cytoplasm. In contrast with IL-1β, the IL-18 precursor is constitutively present in blood monocytes, macrophages, dendritic cells from healthy subjects. 6, 8 Similarly to IL-1α and IL-33, Similarly to IL-1β, the IL-18 precursor is processed intracellularly by caspase 1 into its mature biologically molecule of 18 kDa. 9,10 For IL-18, the consensus is I-N-D at amino acid 50 but the N-terminus generated by caspase-1 is 14 amino acids before the consensus sequence, rather than 9 amino acids for IL-1β. Caspase 1 can be activated by various canonical inflammasomes belonging to the Nod-like receptors, AIM2-like receptors or TRIM family containing either a CARD or a PYD domain. 11 Among the best known inflammasomes are NLRP-3, NLRC4, NLRP-1 and AIM2 which sense various danger signals. Caspase 1 activation also results in a cell-death program termed pyroptosis, which induces membrane pores and mature IL-1β and IL-18 release. Mature IL-1β can also be released from the cells by lysosome exocytosis or membrane microvesicles, but it is not clear whether IL-18 used the same pathways. Caspase 1-independent mechanisms of IL-18 cleavage have also been described. Notably, Fas Ligand activation of Fas-expressing Kupffer cells or splenic macrophages from Propiobacterium acnes-infected mice, can process active IL-18 in a caspase 1-independent but caspase 8-mediated fashion. 12, 13 Alternatively, caspase 3 cleaves IL-18 precursor and mature forms in inactive fragments. 14 In addition, granzyme B from cytotoxic cells, chymase from mast cells or meprin β from intestinal and kidney epithelial cells can cleave IL-18 precursor in biologically active forms. [15] [16] [17] IL-18 can also be released in its precursor form from dying cells and processed extracellularly in an active form by neutrophil proteases such as proteinase 3. 18 IL-18 forms a signaling complex by binding to the IL-18 alpha chain (IL-18Rα), which is the ligand binding chain for mature IL-18; however, this binding is of low affinity ( Figure 1 ). 19 In cells that express the co-receptor, termed IL-18 receptor beta chain (IL-18Rβ), a high affinity complex is formed, which then signals. 20 The complex of IL-18 with the IL-18Rα and IL-18Rβ chains is similar to that formed by other members of the IL-1 family with the co-receptor, the IL-1R accessory chain IL-1RAcP (also termed IL-1R3). Although nearly all cells express the IL-1R1, not all cells express IL-1RAcP. 21 Similarly, most cells express the IL-18Rα but not all cells express the IL-18Rβ. IL-18Rβ is expressed on T-cells and dendritic cells but not commonly expressed in mesenchymal cells. Following the formation of the heterodimer, the Toll-IL-1 receptor (TIR) domains approximate and it appears that the cascade of sequential recruitment of MyD88, the four IRAKs and TRAF-6 followed by the degradation of IκB and release of NFκB are nearly identical as that for IL-1. 21 However, there are differences between IL-1 and IL-18 signaling. With few exceptions, IL-1α or IL-1β are active on cells in the low nanogram/mL range and often in the picogram/mL range. In contrast, IL-18 activation of cells expressing the two IL-18 receptor chains requires 10 to 20 ng/mL and sometime higher levels. 22 In addition to NF-kB, the IL-18/IL-18Rα/IL-18Rβ complex has been shown to induce phosphorylation of STAT3 in an NK and hippocampal cell lines and the p38 MAP kinase pathway in neutrophils. [23] [24] [25] The tertiary structure of IL-18 is closely related to IL-37 and the intron-exon borders of the IL-18 and IL-37 genes suggest a close F I G U R E 1 IL-18 regulation by IL-18 binding protein and IL-37. IL-18 binds the ligand receptor IL-18Rα, inducing the recruitment of IL-18Rβ to form a high affinity receptor. The Toll-IL-1R Receptor (TIR) domains approximate and allow the binding of MyD88, then inducing a pro-inflammatory signal into the cells terminating in NF-κB activation. IL-18 binding protein (IL-18BP) which is present in the extracellular compartment may bind soluble mature IL-18 with a higher affinity than IL-18Rα and prevents IL-18 binding to IL-18 receptor. IL-18BP may also bind IL-37, preventing its binding to IL-18Rα. Free IL-37 binds to IL-18Rα inducing the recruitment of IL-1R8 to form a high affinity receptor, which does not bind MyD88, but induces instead an anti-inflammatory signal into the cell Signal Anti-inflammatory Signal Neutralization association. IL-37 is an inhibitor of the innate immune response. IL-37 binds to the IL-18Rα but does not recruit IL-18Rβ. 26, 27 Moreover, silencing of IL-18Rα in mice has been shown to result in a surprising paradoxical increase in inflammation, suggesting the presence of an anti-inflammatory ligand and of a co-receptor that delivers an inhibitory signal. 28, 29 In fact, IL-37 binds to an orphan receptor of the IL-1 family formerly known as SIGIRR, now designated as IL-1R8, which forms a tripartite complex with IL-18Rα and induces an antiinflammatory response ( Figure 1 ). 30 IL-18 is a unique cytokine involved in activation and differentiation of various T cell populations ( Figure 2 Macrophages can also produce IFNγ, when activated by IL-18 and IL-12. 36 Importantly, without IL-12 or IL-15, IL-18 does not induce IFNγ production, but plays an important role in the differentiation of naive T cells into Th2 cells, producing IL-13 and IL-4 Independently of IFNγ or other cytokines, IL-18 exhibits characteristics of other proinflammatory cytokines, such as increases in cell adhesion molecules, nitric oxide synthesis, and chemokine production. F I G U R E 2 Biological functions of IL-18. Activation of dendritic cells (DC) or macrophages may induce IL-18 precursor transcription, but IL-18 precursor is also constitutively present in the cells. Upon activation of NLRP3, pro-IL-18 is processed by caspase 1 and released in its 18 kDamature form. In association with IL-12 or IL-15 which increase IL-18Rβ expression on T cells, IL-18 induces IFNγ production by CD4 T cells. IFNγ in turn, activates macrophages to produce inflammatory cytokines. IL-18 can also activate macrophages directly to induce chemokine secretion and NK cells to induce IFNγ secretion or to stimulate perforin-and FasL-mediated cytotoxicity. In macrophages, the interaction of FasL with Fas induces IL-18 processing by caspase 8. Alternatively, in the absence of IL-12 or IL-15, IL-18 activates Th2 CD4 lymphocytes to produce IL-13 and IL-4 IL-18 induces ICAM-1 expression on myeloid cells, and also VCAM-1 expression on micro-endothelial cells or synovial fibroblasts in vitro and in vivo via NF-kB activation. 45, 46 Blocking IL-18 activity reduces metastasis in a mouse model of melanoma due to a reduction in IL-18induced expression of VCAM-1. 47 IL-18 also induces CXC chemokines by macrophages or synovial fibroblasts as well as angiogenic factors in rheumatoid arthritis tissues. [48] [49] [50] A unique property of IL-18 is the induction of Fas ligand (FasL), which may account for severe hepatic damages in several pathogenic conditions. 12, 51 The induction of fever, a well-studied property of IL-1β is not a property of IL-18 since injection of IL-18 into mice, rabbits or humans does not produce fever. 52 The discovery of the IL-18BP took place during the search for the is not sufficiently high enough to neutralize IL-18 and therefore, the level of free IL-18 is higher than in healthy subjects. The same observation has been made in situations such as sepsis, sJIA and macrophage activation syndrome. 55, 56 A unique property of IL-18BP is that the molecule also binds the Innate immunity and inflammasome activation, notably NLRP3, are implicated in the earlier phases of Crohn's disease. 61 The dysbiotic microbiota is transferrable to wildtype mice in which it suppresses NLRP6 activation, dampens IL-18 production, decreases antimicrobial peptide production, and increases the severity of DSS colitis. 83, 84 Interestingly, this phenotype can be reversed by IL-18 injection. 82, 83 The digestive tract is a complex organ since it tolerates millions of commensal bacteria yet the intestine rapidly recognizes pathogenic microorganisms and eliminates them. This is due to the different bar- Repair express the IL-18R. 87 In case of chronic inflammation with anatomical barrier rupture and dysbiosis on the contrary, IL-18 is detrimental. NLRP3 and other inflammasomes may be activated in mononuclear cells from the lamina propria inducing large concentrations of pathogenic IL-18, leukocyte recruitment and severe inflammation. 88, 89 In this setting, IL-1α constitutively present in intestinal epithelial cells is released by injured cells and has an important pro-inflammatory role, whereas IL-1β secreted by mononuclear cells from the lamina propria has been shown to play a rather protective healing role. 90 Anti-TNFα and anti-IL-12/23 are efficient treatments in inflammatory bowel diseases, likely via the decrease in IFNγ. 91, 92 Since TNFα can induce IL-18, it is possible that part of the action of anti-TNFα may in fact be due to IL-18 inhibition. The metabolic syndrome is characterized by central obesity, acquired insulin resistance, high blood triglycerides, low HDL, blood hypertension and increases the risk of type 2 diabetes (5-7 fold), and that of cardiovascular disease by twofold. 93, 94 Obesity, type 2 diabetes and atherogenesis are characterized by low-grade underlying inflammation. NLRP3, caspase 1 and IL-1β play an important role in type 2 diabetes pathogenesis since IL-1β mediates obesity-induced inflammation, increases insulin resistance and destroys β-cells. 95 Thus high IL-18 levels in obese patients, metabolic syndrome or type 2 diabetes is not unexpected. [96] [97] [98] In addition, a polymorphism of IL-18 gene associated with increased serum IL-18 levels has been linked to insulin resistance and metabolic syndrome. 99 The visceral rather than subcutaneous adipose tissue from obese individuals produces more IL-18 than lean controls, and serum IL-18 concentrations decreased after bariatric surgery. [100] [101] [102] Despite these data suggesting a link between high IL-18 concentrations and metabolic syndrome or type 2 diabetes, studies in mice reveal paradoxical observations. IL-18 or IL-18Rα-deficient mice, far from being protected from metabolic syndrome, appeared to become obese and develop insulin-resistance after 6 months of normal chow diet, due to both hyperphagia and decrease energy consumption. 103, 104 Intravenous, intracerebral or intraperitoneal injection of exogenous IL-18 corrected hyperphagia, increased catabolism (possibly via IL-18induced IFNγ production) and decreased insulin-resistance. 100 NLRP3 inflammasome and IL-1β play important roles in early atherogenesis. 110 Cholesterol crystals which accumulate in atherosclerotic lesions activate NLRP3 and induce caspase1 activation, leading to IL-1β and IL-18 secretion. In addition, irradiated atherogenic-prone LDLR-deficient mice were protected from atherosclerosis, when reconstituted with NLRP3 or ASC-deficient bone marrow. 110 Whereas IL-18 is a well-known inducer of the Th1-type immune response, as discussed earlier, several studies have shown that in absence of IL-12, IL-18 acts to induce Th2 functions. IL-18 is involved in the pathogenesis of allergic asthma, which is characterized by a Th2-type airway inflammation with eosinophils, IgE production, airway hyperresponsiveness, mucus metaplasia and cytokines such as Chronic obstructive pulmonary diseases (COPD) include lung emphysema and chronic bronchitis, both characterized by chronic inflammation, alveolar destruction, airway remodeling and fibrosis. 141 The main causes of COPD are cigarette smoking (primary or second-hand) and air pollution. Cigarette smoke contain more than 4500 chemical products, oxidants and free-radicals that activate the innate immune system and induce lung inflammation. 142 IL-18 has been shown to be highly expressed in alveolar macrophages, CD8 T lymphocytes as well as bronchiolar and alveolar epithelial cells from patient lungs, whereas circulating 18Rα-expressing T cells were higher in COPD patients. [143] [144] [145] Serum IL-18 concentrations are increased in COPD and smokers when compared to non-smokers healthy controls, correlated positively with disease severity and negatively with the forced expiratory volume tests. 144 In mice, chronic exposure to cigarette smoke induces emphysema, small-airway remodeling and even pulmonary hypertension thus mimicking COPD. After 2-week smoke exposure in this model, IL-18 was increased in lung biopsies and the broncho-alveolar lavage fluid, especially in alveolar macrophages, associated with increased levels of caspases 1 and 11. In IL-18Rα KO mice, alveolar cell apoptosis, protease and chemokine production significantly decreased, reducing both inflammation and lung emphysema. 144 NLRP3 is expressed in lung epithelial cells as well as in monocytes and macrophages and NLRP3 activation is protective in various models of lung infection, however, excessive NLRP3 stimulation has been demonstrated to be detrimental and may cause acute lung injury. 150 The most severe form of acute lung injury is represented by acute respiratory distress syndrome (ARDS) with a 40%-mortality. 151 and M2 proteins are known to activate NLRP3 inflammasome in a protective way, since NLRP3-and caspase-1-deficient mice demonstrate more severe lung lesions as well as increased lethality. 154, 155 In this setting, although controversial, IL-18 but not IL-12, has been shown to be protective in the early defenses against influenza by inducing NK cell cytotoxicity and INFγ production. [156] [157] [158] On the contrary, avian influenzae H5N1 and H7N9 contain a PB1-F2 protein which maintain both inhibits IFNα production and activates NLRP3 in a strong and prolonged way. 159 This prolonged NLRP3 activation leads to excess IL-18 production and induces a very detrimental IFNγ-biased cytokine storm which appears to characterize ARDS pathogenesis. [160] [161] [162] Interestingly, this pathogenesis appears common to coronavirusinduced severe acute respiratory syndrome (SARS), another severe form of ARDS and possibly to the 1918 influenza virus. 163 Sepsis is characterized by both excessive inflammation and immune suppression. 168 Interestingly, NLRP3-deficient mice are not protected against sepsis, despite the fact that NLRP3 controls caspase 1 activation and both IL-1β and IL-18 secretion, suggesting that caspase 11, rather than caspase 1 may play an essential role in the protection of caspase 1/11-deficient mice toward sepsis. 178 Caspase 11 is mainly involved in a non-canonical inflammasome in mice. Caspase 11 oligomerizes with CARD to sensor intra-cytoplasmic LPS, usually due to high serum concentrations of LPS, and induces pyroptosis-mediated cell death. This mechanism dominates over that of canonical inflammasomes, which activate caspase1, such as NLRP3. 179 Excess of pyroptotic cell death may induce both strong IL-18 and DAMPS release inducing an "ecosanoid storm," shock and death. 11 Hemophagocytic syndromes or hemophaphagocytic lymphohistiocytosis (HLH) are characterized by the association of clinical and biological symptoms such as fever, hepatomegaly, splenomegaly, cytopenia, hyperferritininemia, hypertriglyceridemia, intravascular coagulation and could result in multivisceral deficiency. 180 The presence of hemophagocytosis in the bone marrow is not required for the diagnosis, but its presence in this clinical picture is highly suggestive of the disease. Noteworthy is the fact that hemophagocytosis may also be frequently observed in the bone marrow of sepsis patients. 181 HLH can be divided in two presentations. 188, 189 In humans as well as in all these animal models, excess circulating inflammatory cytokines with a rather Th1 profile, designed as a "cytokine storm," is the primary event. 184, 187, 190 Among them, IFNγ seems to play the important pathogenic role, since inhibition of IFNγ appears protective in most murine models. 184, 187, 191 It is not completely clear, however, since some models depend also on TNFα or other cytokines. 189, 192, 193 The role of IL-18 in HLH is likely due to its capacity to induce IFNγ and pro-inflammatory cytokines. Several reports have found elevated IL-18 concentrations in the serum of patients with both primary and secondary HLH as well as in animal models and IL-18 correlated with the biological criteria and evolution of the disease. 56, 184, 187, 191, 194, 195 Usually, the concentrations of IL-18 range from 0.6 to 3 ng/mL in HLH patients. There is the exception in two conditions, in which IL-18 concentrations are higher than 5 ng/mL, namely XLP type 2 due to XIAP mutations and sJIA/AOSD. 195, 196 In both situations, IL-18 concentrations do not return to normal levels even after recovery of the HLH. Such elevated concentrations are unusual for an inflammatory cytokine and question its significance, especially since in the majority of these studies, the distinction between total IL-18 and free IL-18 was not made. In a previous study of Secondary HLH complicating lymphoma, infections and AOSD, we observed an increase in free IL-18, IL-18BP concentrations being similar to those in control patients without HLH, perhaps suggesting a relative resistance of IL-18BP synthesis to IFNγ which was elevated in these patients. 56 trations. 198 Noteworthy is the fact that in this animal model, no anticytokine strategy has been shown to increase survival probably due to the fact that concentrations of IFNγ and TNFα are found, respectively, 10-fold and 5-fold higher than in the LCMV-infected perforin-deficient model. 184, 186, 199 However even in the perforin KO-LCMV model, anti-IL-18 treatment did not significantly influence animal survival. 184 Despite disappointing animal data, the role of IL-18 in HLH is valide. In 2014, two independent groups reported on two pediatric patients with severe refractory HLH and digestive tract lesions without mutations affecting cytotoxicity, but bearing gain-of-function mutations of the NLRC4 inflammasome. 66, 200 Ex vivo experiments showed that these mutations induced very high concentrations of IL-18 (10 ng/mL), whereas IL-1β was modestly affected. 204 An unusually frequent complication of sJIA is macrophage activation syndrome (MAS), a form of secondary HLH, which occurs in 15% of the patients, whereas hemophagocytosis ("occult MAS") may be present in the bone marrow of almost 50% of the patients with active sJIA, suggesting a special pathogenic link between these 2 diseases. 205 Initial gene expression profile study discovered an IL-1 signature in sJIA, and other studies have found upregulation of a cluster of genes involved in innate immunity and IL-1R/TLR signaling. 206, 207 Nevertheless, treatments with anakinra (IL-1 Receptor antagonist) or canakinumab (anti-IL-1β monoclonal antibody) are effective in nearly 50% of the patients. Another group of patients, however, with a greater number of involved joints and lower neutrophil count may not or incompletely respond to anakinra, developing persistent synovitis. 208 It is also possible to distinguish two different subgroups of sJIA patients depending on their serum cytokine profile, the group with more severe arthritis having higher concentrations of IL-6. 209 Indeed IL-6 is markedly elevated in sJIA patients and correlates with the severity of joint involvement. 210 Inhibition of IL-6 using the IL-6 receptor blocking antibody tocilizumab may be an effective treatment in sJIA patients not responding to IL-1β blockade. 211 IL-18 has been found highly elevated in the serum of active sJIA in numerous studies. 212 220 The authors considered IFNγ-mediated inhibition of Th17 as a possible explanation of this protective effect. It should be noted that IL-17 has been found elevated in sJIA patients, due to increased IL-17 positive γδ cells expressing IL-18Rα whose proliferation is dependent on IL-1β and IL-18. 42 Another explanation may be the long-term recognized negative effect of IFNγ on IL-1β production. 214 In addition, the links of MAS with primary HLH leads to the search for a common pathogenic pathway. NK cell cytotoxicity was reported to be abnormal in patients with active sJIA with or without MAS, consisting in decreased circulating NK numbers, perforin expression and cytotoxicity. [223] [224] [225] As a member of the IL-1 family, IL-18 appears to share characteristics of IL-1β with caspase-1 processing of the inactive precursor to an active cytokine. But the IL-18 precursor also shares characteristics with the precursor IL-1α, as both are constitutively present in healthy mesenchymal tissues and are released following necrotic cell death. IL-18 acts differently than IL-1β notably due its effects on lymphocyte ac- Purification of a factor which provides a costimulatory signal for gamma interferon production Cloning of a new cytokine that induces IFN-gamma production by T cells IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family Interleukin-18 Interleukin-18 regulates both Th1 and Th2 responses Interleukin-18 and IL-18 binding protein Interleukin-18, more than a Th1 cytokine Overview of interleukin-18: more than an interferon-gamma inducing factor Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme Caspase-1 processes IFNgamma-inducing factor and regulates LPS-induced IFN-gamma production Pyroptotic cell death defends against intracellular pathogens Caspase-1-independent, Fas/ Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice Cutting edge: FAS (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells Granzyme B is a novel interleukin-18 converting enzyme Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment Prointerleukin-18 is activated by meprin beta in vitro and in vivo in intestinal inflammation Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells Purification and characterization of the human interleukin-18 receptor Cutting edge: Generation of IL-18 receptor-deficient mice: Evidence for IL-1 receptorrelated protein as an essential IL-18 binding receptor Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist Differences in signaling pathways by IL-1beta and IL-18 IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 and by the extracellular regulated kinases p44erk-1 and p42erk-21 Interleukin 18 activates MAPKs and STAT3 but not NF-κB in hippocampal HT-22 cells Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation A complex of the IL-1 homologue IL-1F7b and IL-18-binding protein reduces IL-18 activity IL-37 is a fundamental inhibitor of innate immunity Responses of IL-18-and IL-18 receptordeficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor Increased cytokine production in interleukin-18 receptor alpha-deficient cells is associated with dysregulation of suppressors of cytokine signaling IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted antiinflammatory program upon innate signal transduction Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8 Interleukin 37 expression protects mice from colitis Interleukin-18 and interleukin-1 beta: Two cytokine substrates for ICE (caspase-1) IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones M-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation IL-18 is a potent coinducer of IL-13 in NK and T cells: A new potential role for IL-18 in modulating the immune response IL-18 induction of IgE: Dependence on CD4 + T cells, IL-4 and STAT6 IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils Caspase-1 has both proinflammatory and regulatory properties in Helicobacter infections, which are differentially mediated by its substrates IL-1β and IL-18 Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity Proinflammatory cytokine environments can drive interleukin-17 overexpression by γ/δ T cells in systemic juvenile idiopathic arthritis Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18 DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection Interleukin-18/interferongamma-inducing factor, a novel cytokine, up-regulates ICAM-1 (CD54) expression in KG-1 cells A novel role for interleukin-18 in adhesion molecule induction through NF kappa B and phosphatidylinositol (PI)3-kinase-dependent signal transduction pathways IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1 Interleukin-18 (IFNgamma-inducing factor) induces IL-8 and IL-1beta via TNFalpha production from non-CD14 + human blood mononuclear cells Interleukin-18 induces rheumatoid arthritis synovial fibroblast CXC chemokine production through NFkappaB activation Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways Pathophysiological roles of interleukin-18 in inflammatory liver diseases Effect of interleukin-18 on mouse core body temperature Interleukin-18 binding protein: A novel modulator of the Th1 cytokine response Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18 A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18 Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome Mechanisms of inhibition of collagen-induced arthritis by murine IL-18 binding protein Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells The promoter of IL-18 binding protein: Activation by an IFN-gamma -induced complex of IFN regulatory factor 1 and CCAAT/enhancer binding protein beta Plasma levels of interleukin-18 and interleukin-18 binding protein are elevated in patients with chronic liver disease The goldilocks conundrum: NLR inflammasome modulation of gastrointestinal inflammation during inflammatory bowel disease Interleukin-18 and its binding protein in patients with inflammatory bowel disease during remission and exacerbation Local and systemic interleukin-18 and interleukin-18-binding protein in children with inflammatory bowel disease Bioactive IL-18 expression is up-regulated in Crohn's disease IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: Expression and localization in intestinal mucosal cells An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: Blocking interleukin 18 attenuates intestinal damage Epithelial IL-18 equilibrium controls barrier function in colitis Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome Common variants in the NLRP3 region contribute to Crohn's disease susceptibility Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese population Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases NLRP6: A multifaceted innate immune sensor Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion New insights into the dichotomous role of innate cytokines in gut homeostasis and inflammation Opposing functions of classic and novel IL-1 family members in gut health and disease Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine Interleukin-18 in intestinal inflammation: Friend and foe? Interleukin-18: The bouncer at the mucosal bar Non-redundant properties of IL-1α and IL-1β during acute colon inflammation in mice First-line therapy in adult Crohn's disease: Who should receive anti-TNF agents? Anti-IL-12/23 in Crohn's disease: Bench and bedside The metabolic syndrome Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement Role of IL-1beta in type 2 diabetes Elevated interleukin-18 levels are associated with the metabolic syndrome independent of obesity and insulin resistance Interleukin-18, the metabolic syndrome, and subclinical atherosclerosis: Results from the Dallas Heart Study Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans IL-18 gene polymorphism and metabolic syndrome Interleukin-18 in plasma and adipose tissue: Effects of obesity, insulin resistance, and weight loss The proatherogenic cytokine interleukin-18 is secreted by human adipocytes Effect of massive weight loss induced by bariatric surgery on serum levels of interleukin-18 and monocyte-chemoattractant-protein-1 in morbid obesity Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice Interleukin-18 resistance in patients with obesity and type 2 diabetes mellitus The role of interleukin-18 in the metabolic syndrome IL-1 family members in the pathogenesis and treatment of metabolic disease: Focus on adipose tissue inflammation and insulin resistance A study to investigate the efficacy and safety of an anti-interleukin-18 monoclonal antibody in the treatment of type 2 diabetes mellitus NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: Implications for atherogenesis Expression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice Interleukin-18: A potent pro-inflammatory cytokine in atherosclerosis Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina nterleukin-18 and the risk of coronary heart disease in European men: The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Plasma interleukin (IL)-18 concentrations is elevated in patients with previous myocardial infarction and related to severity of coronary atherosclerosis independently of C-reactive protein and IL-6 Interleukin-18 levels are not associated with subclinical carotid atherosclerosis in a community population. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS) Interleukin 18 in acute myocardial infarction Prospective study of IL-18 and risk of MI and stroke in men and women aged 60-79 years: A nested case-control study Interleukin-18 in patients with congestive heart failure: Induction of atrial natriuretic peptide gene expression Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure Increased cardiac IL-18 mRNA, pro-IL-18 and plasma IL-18 after myocardial infarction in the mouse; a potential role in cardiac dysfunction Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction Interleukin-18 is a pro-hypertrophic cytokine that acts through a phosphatidylinositol 3-kinase-phosphoinositide-dependent kinase-1-Akt-GATA4 signaling pathway in cardiomyocytes Daily administration of interleukin-18 causes myocardial dysfunction in healthy mice Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta Interleukin-18 mediates interleukin-1-induced cardiac dysfunction The effect of daily administration of IL-18 on cardiac structure and function IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice A functional polymorphism in IL-18 is associated with severity of bronchial asthma Interleukin 18 receptor 1 gene polymorphisms are associated with asthma IL-18 might reflect disease activity in mild and moderate asthma exacerbation Interleukin-18 and interleukin-18 receptor-α expression in allergic asthma Interleukin-18 expression, CD8(+) T cells, and eosinophils in lungs of nonsmokers with fatal asthma Interleukin-18 enhances antigen-induced eosinophil recruitment into the mouse airways IL-18 induces airway hyperresponsiveness and pulmonary inflammation via CD4 + T cell and IL-13 The nature of small-airway obstruction in chronic obstructive pulmonary disease Effects of cigarette smoke on the immune system IL-18 is induced and IL-18 receptor alpha plays a critical role in the pathogenesis of cigarette smoke-induced pulmonary emphysema and inflammation Interleukin-18 production and pulmonary function in COPD Increased expression of interleukin-18 and its receptor in peripheral blood of patients with chronic obstructive pulmonary disease Cigarette smoke selectively enhances viral PAMP-and virus-induced pulmonary innate immune and remodeling responses in mice Role of IL-18 in secondhand smoke-induced emphysema Pulmonary inflammation and emphysema: Role of the cytokines IL-18 and IL-13 IL-18 induces emphysema and airway and vascular remodeling via IFN-γ, IL-17A, and IL-13 Inflammasomes in the lung Acute lung injury: A clinical and molecular review Inflammasome-regulated cytokines are critical mediators of acute lung injury Interleukin-18 levels reflect the long-term prognosis of acute lung injury and acute respiratory distress syndrome The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1 Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus IL-18, but not IL-12, is required for optimal cytokine production by influenza virusspecific CD8 + T cells Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease Re-emergence of fatal human influenza A subtype H5N1 disease Clinical, virological and immunological features from patients infected with re-emergent avian-origin human H7N9 influenza disease of varying severity in Guangdong province The serum profile of hypercytokinemia factors identified in H7N9-infected patients can predict fatal outcomes An interferon-gamma-related cytokine storm in SARS patients Influenza: Fatal immunity and the 1918 virus Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection The immunopathology of sepsis and potential therapeutic targets Differential regulation of systemic IL-18 and IL-12 release during postoperative sepsis: High serum IL-18 as an early predictive indicator of lethal outcome Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia Simultaneoustargeting of IL-1 and IL-18 is required for protection against inflammatory and septic shock IL-18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock Hemin inhibits NLRP3 inflammasome activation in sepsis-induced acute lung injury, involving heme oxygenase-1 Inflammatory status in sepsis alters efficacy of interleukin-18 binding protein therapy IL-18 levels and the outcome of innate immune response to lipopolysaccharide: Importance of a positive feedback loop with caspase-1 in IL-18 expression Role of caspase 1 in murine antibacterial host defenses and lethal endotoxemia Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke Non-canonical inflammasome activation targets caspase-11 Inflammatory caspases are innate immune receptors for intracellular LPS Familial and acquired hemophagocytic lymphohistiocytosis Multifactorial risk analysis of bone marrow histiocytic hyperplasia with hemophagocytosis in critically ill medical patients-a postmortem clinicopathologic analysis Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules Macrophage activation syndrome in the era of biologic therapy An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8 + T cells and interferon gamma are essential for the disorder Graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice Perforin and granzymes have distinct roles in defensive immunity and immunopathology Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: Implication for the pathogenesis of macrophage activation syndrome Mouse cytomegalovirus infection in BALB/c mice resembles virus-associated secondary hemophagocytic lymphohistiocytosis and shows a pathogenesis distinct from primary hemophagocytic lymphohistiocytosis Hypercytokinemia in familial hemophagocytic lymphohistiocytosis Use of a mouse model to identify a blood biomarker for IFNγ activity in pediatric secondary hemophagocytic lymphohistiocytosis Interferon-γ mediates anemia but is dispensable for fulminant tolllike receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency Failure of interferon gamma to induce the anti-inflammatory interleukin 18 binding protein in familial hemophagocytosis Protection from inflammatory organ damage in a murine model of hemophagocytic lymphohistiocytosis using treatment with IL-18 binding protein Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation A disease-associated mutant of NLRC4 shows enhanced interaction with SUG1 leading to constitutive FADD-dependent caspase-8 activation and cell death Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications Systemic juvenile idiopathic arthritis Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease Highly elevated serum levels of interleukin-18 in systemic juvenile idiopathic arthritis but not in other juvenile idiopathic arthritis subtypes or in Kawasaki disease: Comment on the article by Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: Tipping the balance between interleukin-18 and interferon-γ Clinical manifestations of Adult-onset Still's disease presenting with erosive arthritis: Association with low levels of ferritin and Interleukin-18 Elevated serum levels of free interleukin-18 in adult-onset Still's disease Upregulation of circulating mi-croRNA-134 in adult-onset Still's disease and its use as potential biomarker Specific gene expression profiles in systemic juvenile idiopathic arthritis The limited role of interferon-γ in systemic juvenile idiopathic arthritis cannot be explained by cellular hyporesponsiveness Systemic juvenile idiopathic arthritislike syndrome in mice following stimulation of the immune system with Freund's complete adjuvant: Regulation by interferon-γ IL-1 induces IL-1. III. Specific inhibition of IL-1 production by IFN-gamma Compensated inflammation in systemic juvenile idiopathic arthritis: Role of alternatively activated macrophages Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome Natural killer cell cytolytic function in Korean patients with adult-onset Still's disease Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis Inhibition of natural killer cell cytotoxicity by interleukin-6: Implications for the pathogenesis of macrophage activation syndrome Inflammatory gene expression profile and defective interferon-γ and granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis A novel role for interleukin-18 in human natural killer cell death: High serum levels and low natural killer cell numbers in patients with systemic autoimmune diseases Increased apoptosis of peripheral blood lymphocytes and its association with interleukin-18 in patients with active untreated adult-onset Still's disease Interleukin-18: Biological properties and role in disease pathogenesis The author declares no conflict of interest.