Cytokine 74 (2015) 313–317

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Review Article

Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD) Efrossini Dima a,1, Ourania Koltsida a,1, Paraskevi Katsaounou b, Sofia Vakali a, Antonia Koutsoukou a, Nikolaos G. Koulouris a, Nikoletta Rovina a,⇑ a b

1st Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens and ‘‘Sotiria’’ Chest Disease Hospital, 11527 Athens, Greece Pumonary Department, Intensive Care Medicine, Evaggelismos Hospital, Medical School, University of Athens, Greece

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Article history: Received 24 November 2014 Received in revised form 13 April 2015 Accepted 15 April 2015 Available online 25 April 2015 Keywords: Interleukin (IL)-18 Inflammasome Chronic obstructive pulmonary disease

a b s t r a c t Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)c-inducing factor. Similar to IL-1b, IL-18 is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine. The platform for activating caspase-1 is known as the inflammasome, a multiple protein complex. Macrophages and dendritic cells are the primary sources for the release of active IL-18, whereas the inactive precursor remains in the intracellular compartment of mesenchymal cells. Finally, the IL-18 precursor is released from dying cells and processed extracellularly. IL-18 has crucial host defense and antitumor activities, and gene therapy to increase IL-18 levels in tissues protects experimental animals from infection and tumor growth and metastasis. Moreover, multiple studies in experimental animal models have shown that IL-18 over-expression results to emphysematous lesions in mice. The published data prompt to the hypothesis that IL-18 induces a broad spectrum of COPD-like inflammatory and remodeling responses in the murine lung and also induces a mixed type 1, type 2, and type 17 cytokine responses. The majority of studies identify IL-18 as a potential target for future COPD therapeutics to limit both the destructive and remodeling processes occurring in COPD lungs. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Chronic obstructive pulmonary disease (COPD) is nowadays the fourth leading cause of death and its prevalence is rapidly increasing [1]. Chronic inflammation and varying degrees of emphysematous alveolar destruction are the key pathological features of the disease [2]. Furthermore, airway remodeling and tissue fibrosis, mucus metaplasia, vascular remodeling, smooth muscle proliferation, and collagen deposition are also present, contributing to the establishment of airflow limitation [3]. The inflammation seen throughout the bronchial tree and lung parenchyma of patients with COPD is characterized by the infiltration of neutrophils, macrophages, and lymphocytes [4–6] and it is strongly correlated with disease severity in patients and with disease development experimentally [7]. The inflammatory cells can produce proteases, including neutrophil elastase and matrix metalloprotease (MMP)-9 and release ⇑ Corresponding author at: 152 Mesogeion Ave, 11527 Athens, Greece. Tel.: +30 210 7763650, mobile: +30 6945 830212. E-mail address: [email protected] (N. Rovina). 1 Equal contribution of the authors. 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved.

various mediators, such as cytokines (e.g., Interleukin (IL)-1b, IL6, Tumor Necrosis Factor (TNF)-a, and Interferon (IFN)-c), growth factors (e.g. Epidermal Growth Factor (EGF), Granule macrophage colony-stimulating factor (GMC-SF), and Transdermal Growth Factor (TGF-b), and chemokines (e.g., CCL2, CXCL1, CXCL8,CXCL9, CXCL10, and CXCL11) [8,9]. Furthermore, increasing data associate COPD with autoimmune response [10–13]. Recently, increasing interest has been raised in the participation of the inflammasome in COPD [13–17]. Inflammasome is a multimeric protein complex important in stimulating caspase-1 activation and subsequently the release of the mature form of the inflammatory cytokines IL-1b and IL-18. The primary role of the inflammasome and its products seems to be a part of the body’s innate immune system, in that they can be triggered to assist in defence against invading pathogens [18,19]. This is mediated through the detection of pathogen-associated (PAMPs) and danger-associated molecular patterns (DAMPs) by receptors termed pattern-recognition receptors (PRRs) expressed in alveolar macrophages, dendritic cells, and epithelial cells [20]. The PRRs include transmembrane Toll-like receptors (TLRs) cytosolic NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) [21]. Activation


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of both PAMPs and DAMPs together leads to enhanced release of the mature forms of the inflammatory cytokines. In the inflammatory milieu of the lungs of COPD patients or of animals exposed to CS the increased levels of cytokines are linked to the activation of the NLRP3 inflammasome i.e. IL-1b and IL-18. Furthermore, there is some evidence to suggest that these cytokines are central to the inflammation seen in models of COPD [22,23]. Studies of antibodies against IL-18 and IL-1b are currently either being undertaken or planned. However, complete understanding of the implication of IL-18 in the mechanisms involved in COPD pathogenesis and its potential role as a therapeutic target remain to be further elucidated. 1.1. IL-18: inflammation and immune response IL-18 is a pro-inflammatory cytokine that was firstly described as an interferon IFN-c-inducing factor [24,25]. Although, belonging to the IL-1 family, and sharing similar characteristics to IL-1b it has unique features [26,27]. For example, similar to IL-1b, it is synthesized as an inactive precursor requiring processing by caspase-1 into an active cytokine, but unlike IL-1b, the IL-18 precursor is constitutively present in nearly all cells in healthy humans and animals. The platform for activating caspase-1 is known as the inflammasome, a multiple protein complex [28–30]. Following cleavage by active caspase-1, mature IL-18 is secreted from the monocyte/macrophage, although over 80% of the IL-18 precursor remains unprocessed inside the cell. Macrophages and dendritic cells are the primary sources for the release of active IL-18, whereas the inactive precursor remains in the intracellular compartment of mesenchymal cells [31,32]. Finally, the IL-18 precursor is released from dying cells and processed extracellularly, most likely by neutrophil proteases such as proteinase-3 [33,34]. IL-18 forms a signaling complex by a low affinity binding to the IL-18 alpha chain receptor (IL-18Ra), which is present in most cells [35]. In T-cells and dendritic cells which express the co-receptor, termed IL-18 receptor beta chain (IL-18Rb), a high affinity complex is formed, which then signals [36,37]. IL-18 is well known to play an important role in Th1/Th2 polarization due to its ability to induce IFN-c either with IL-12 or IL-15 [38–42]. IL-12 or IL-15 increases the expression of IL-18Rb, which is essential for IL-18 signal transduction. Importantly, without IL12 or IL-15, IL-18 plays a role in Th2 diseases [41,42]. The importance of IL-18 as an immunoregulatory cytokine is derived from its prominent biological property of inducing IFN-c from Natural Killer (NK) cells [43,44]. Upon shedding of membrane IL-18 into a soluble form, NK cells expressed CCR7 and produced high levels of IFN-c. However, there are several activities of IL-18 that are independent of IFN-c. For example, IL-18 inhibits proteoglycan synthesis in chondrocytes and increases vascular cell adhesion molecule-1 (VCAM-1) expression in endothelial cells independently of IFN-c [45]. Macrophage colony stimulating factor (M-CSF) induces human blood monocytes to differentiate into a subset of macrophages; these cells express a membrane-bound form of IL-18 [46]. In contrast, dendritic cells, and monocytes differentiated into M1 macrophages do not express membrane IL-18. Interleukin-18 exhibits characteristics of other pro-inflammatory cytokines. It increases cell adhesion molecules, promotes nitric oxide synthesis and chemokine production, regulates macrophage/neutrophil accumulation and function, as well as cellular apoptosis [28,31,35]. Furthermore, IL-18 promotes Th2 cytokine production from T cells (e.g., IL-4, IL-5, IL-9, and IL-13), NK cells, basophils, and mast cells, and can act as a co-factor for Th2 cell development and IgE production [38,47,48]. Gamma-delta T-cells produce IL-17 when stimulated with IL-18 plus IL-23, as these T-cells express high levels of the IL-18 receptor alpha chain.

Thus, IL-18 induces T-cells to produce IL-17 and promote autoimmune responses to specific antigens [49–51]. 2. Implication of IL-18 in the pathogenesis of COPD 2.1. Animal studies COPD can be modeled in mice following chronic exposure of animals to cigarette smoke inducing emphysema, small-airway remodeling and pulmonary hypertension [52]. Multiple studies in experimental animal models have demonstrated the role of IL-18 in COPD pathophysiology. Several studies have shown that IL-18 over-expression results to emphysematous lesions in mice. Hoshino et al. [53] developed two different lines of transgenic (Tg) mice that overproduced mouse mature IL-18, using the human surfactant protein C promoter to drive expression of mature mouse IL-18 cDNA. Constitutive over production of IL-18 protein resulted in severe emphysema accompanied by inflammatory cell accumulation mostly by CD8+ T cells, macrophages, neutrophils and eosinophils. IL-18 induced severe emphysematous changes, increased lung volume, dilatation of the right ventricle and mild pulmonary hypertension in Tg mice. Although, IL-18 over-expression in the lung increased the production of IFN-c, IL-13 and IL-5, disruption of the IL-13 gene but not IFN-c, prevented IL-18 induced-emphysema. Specifically, IFN-c / Tg+ mice presented with more severe emphysema and pulmonary inflammation than the IFNc+/+Tg+ mice or wild type (WT) littermates. In contrast, emphysematous changes were largely absent in the lungs of IL-13 / Tg+ compared with IL-13+/+Tg+ mice or littermates. Kang et al. [54] demonstrated that IL-18 induced inflammation in the mature murine lung is associated with the accumulation of CD4+, CD8+, CD19+ and NK1.1+ cells and is characterized by emphysema, mucus metaplasia, airway fibrosis, vascular remodeling and right ventricle cardiac hypertrophy. Moreover, IL-18 induces type 1, type 2, and type 17 cytokines with IFN-c–inhibiting macrophage, lymphocyte, and eosinophil accumulation while stimulating alveolar destruction and genes associated with cell cytotoxicity and IL-13 and IL-17A inducing mucus metaplasia, airway fibrosis, and vascular remodeling. Finally, they highlighted the interactions between these responses with IL-18 inducing IL-13 via an IL-17A–dependent mechanism and the type 1 and type17/type 2 responses counter-regulating each other. Analysis of lung mRNA expression profiles of a murine model of COPD in IL-18-transgenic mice [55] revealed that the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested that Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. IL-13 gene deletion did not significantly reduce the protein level of Chi3l1 in the lungs of IL-18 transgenic mice, suggesting that IL-18 drives the expression of Chi3l1 independently of the IL-13 pathway [56]. COPD is a disease characterized by the presence of co-morbidities which increase the burden of the disease and contribute to mortality. Takenaka et al. [57] evaluated the progression of comorbidity in IL-18 transgenic COPD mouse model. They observed significant weight loss in female Tg mice, at 16 weeks and beyond compared to control wild-type (WT) mice. The weight loss was suppressed in IL-13-deficient (knockout; KO) Tg mice. Muscle weight and bone mineral density were significantly decreased in aged Tg mice relative to control WT and IL-13 KO Tg mice. The aged Tg mice also showed impaired glucose tolerance. IL-18 and IL-13 may play important roles in the pathogenesis of co-morbidity in COPD patients.

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Multiple studies in cigarette smoke (CS)-induced COPD animal models demonstrated the role of IL-18 in COPD pathogenesis. In this regard, CS-induced neutrophilia in mice was associated with increased caspase-1 activity and downstream markers of inflammasome activation and expression of IL-18 and IL-1b cytokines. To investigate the role of IL-18 signaling in the pathogenesis of CS-induced emphysema, Kang et al. [23] compared the effects of CS between wild type mice and mice with null mutations of IL-18Ra (IL-18Ra / ). Notably, IL-18Ra / mice were protected against CS-induced inflammation and emphysema. Moreover, cigarette smoke induced epithelial apoptosis, activated effector caspases [3,8] and [12] and stimulated proteases (MMP-12, cathepsin-S, and cathepsin-B) and chemokines (MCP-1, MCP-3, and MIP-1) via IL-18Ra-dependent pathways. Studies investigating the interactions between CS and the presence of bacterial stimuli have shown that cigarette has immunosuppressive properties with the ability to inhibit macrophage function [58]. Moreover, exposure to cigarette smoke and RNA viruses leads to alveolar cell apoptosis involving type I epithelial, type II epithelial, and endothelial cells, and enhanced alveolar inflammation (with influx of neutrophils and macrophages), via activation of the RLH adaptor mitochondrial antiviral signaling protein (MAVS), the cytokines IL-12, IL-18, and IFN-c, and the phosphorylation of the RNA- dependent protein kinase (PKR) [59,60]. In this context, later on, the same authors [59] defined the effects of CS on pathogen-associated molecular pattern-induced (PAMP-induced) pulmonary inflammation and remodeling in mice. CS was found to enhance parenchymal and airway inflammation and apoptosis induced by the viral PAMP poly(I:C). CS and poly(I:C) also induced accelerated emphysema and airway fibrosis. The effects of a combination of CS and poly(I:C) were associated with early induction of type I IFN and IL-18, later induction of IL12/IL-23 p40 and IFN-c, and the activation of double-stranded RNA-dependent protein kinase (PKR) and eukaryotic initiation factor-2alpha (eIF2alpha). Further analysis using mice lacking specific proteins indicated a role for TLR3-dependent and independent pathways as well as a pathway or pathways that are dependent on MAVS, IL-18Ralpha, IFN-c, and PKR. Importantly, CS enhanced the effects of influenza but not other agonists of innate immunity in a similar fashion. These studies demonstrate that CS selectively augments the airway and alveolar inflammatory and remodeling responses induced in the murine lung by viral PAMPs and viruses. The NLRP3 inflammasome can be activated in a number of ways; one of which is through ATP acting on the P2X7 purinergic receptor. Recently it has been shown that levels of an activator of the NLRP3 inflammasome, ATP, are increased in pre-clinical smoke-exposure models [61–64]. Increases in ATP levels have been reported in in vitro/in vivo models of COPD [65,66] and in clinical samples [67,68]. This increase in ATP levels has been suggested to play a role in the chemotaxis and activation of inflammatory cells, such as neutrophils, through P2Y and P2X7 receptors [62–64]. Eltom et al. [61] demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL1b/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were nonfunctional attenuated caspase 1 activation, IL-1b release and airway neutrophilia. In an attempt to further explore the role of the P2X7 receptor in COPD inflammation Eltom et al. [64] exposed mice to CS twice a day to induce COPD-like inflammation. They demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation (increased caspase 1 activity and release of IL-1b/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1b release and airway neutrophilia.


Furthermore, they demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase-1 activation in lungs from a more chronic exposure to CS and from patients with COPD. Second hand smoke (SHS) also results in a significant increase of pro-inflammatory cytokine IL-18 and chemokine (C–C motif) ligand 5 in the bronchoalveolar lavage fluid (BALF) and a significant decrease of vascular endothelial growth factor (VEGF) in the lung tissue of Sprague–Dawley rats [69]. SHS exposure resulted in progressive alveolar airspace enlargement, cell death, pulmonary vessel loss, vessel muscularization, collagen deposition, and right ventricular hypertrophy. Alveolar macrophages displayed a foamy phenotype and a decreased expression of the natural inhibitor of IL-18, namely, IL-18 binding protein (IL-18BP). IL-18 down-regulated expression of VEGF receptor-1 and VEGFR receptor-2 and induced apoptosis in pulmonary microvascular endothelial cells in vitro, suggesting that IL-18-mediated endothelial cell death may contribute to vascular destruction and disappearance in SHS-induced COPD. This study suggests that IL-18 and IL-18BP might be potential therapeutic targets. Finally, Matsuura et al. [70] demonstrated a novel regulatory role of breast regression protein-39 (BRP-39) in CS-induced inflammation and emphysematous destruction. They exposed 10-weekold wild-type and BRP-39 null mutant mice (BRP-39( / )) to room air (RA) and CS for up to 10 months. The expression of BRP-39 was significantly induced in macrophages, airway epithelial cells, and alveolar Type II cells in the lungs of CS-exposed mice compared with RA-exposed mice, at least in part via an IL-18 signaling-dependent pathway. The null mutation of BRP-39 significantly reduced CS-induced bronchoalveolar lavage and tissue inflammation. However, CS-induced epithelial cell apoptosis and alveolar destruction were further enhanced in the absence of BRP-39. The above experiments prompt to the hypothesis that IL-18 induces a broad spectrum of COPD-like inflammatory and remodeling responses in the murine lung and also induces a mixed type 1, type 2, and type 17 cytokine responses. Each one of these makes a distinct contribution to the pathogenesis of these varied pathologies. 2.2. Human studies The role of IL-18 in COPD pathogenesis has been studied in a lesser extent in COPD patients compared to the animal studies. Kang et al. [59] first examined the expression of IL-18 and cathepsins in lung tissues from current smokers, former smokers and never-smokers. In contrast to the never smokers, where modest levels of immune-reactive IL-18 were seen in airway epithelial cells, and there was no expression in the macrophages in the current smokers, increased levels of IL-18 were found in the alveolar macrophages. Additionally, in current smokers cathepsin-S and cathepsin-B were both significantly up-regulated in alveolar macrophages. Elevated levels of IL-18 were also detectable in the circulation of patients with COPD, suggesting a possible novel biomarker for COPD. Imaoka et al. [71] showed that IL-18 protein is strongly expressed in 80% of alveolar macrophages and some infiltrating mononuclear cells, both in the bronchiolar and alveolar epithelium in the lung of patients with very severe COPD (GOLD stage IV). Quantitative analysis showed that IL-18 expression was significantly greater in alveolar macrophages of COPD patients compared to non smokers or ‘‘healthy’’ smokers. In COPD patients there was a significant negative correlation between serum IL-18 levels and FEV1% pred, which was not observed in non-smokers or smokers. Finally, immunohistochemical analysis of lung tissues showed that IL-18-producing CD8+ T cells were increased in the lungs of patients with very severe COPD. In agreement with the previous studies, the authors showed that IL-18 levels were significantly


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higher in sputum supernatants of COPD patients compared to healthy smokers or non-smokers [72]. There was an inverse correlation between IL-18 levels, FEV1 (% pred) and FEV1/FVC ratio in COPD patients, suggesting that IL-18 could be used as a new biomarker for disease activity and progression. These observations were also supported by the findings from the ECLIPSE study of induced sputum gene profile in COPD patients [73]. IL-18R showed increased expression in airway macrophages compared to controls, supporting the case for targeting this signaling axis in the treatment of COPD. However, Di Stefano et al. [17] using immunohistochemistry in the bronchial mucosa and ELISA in the BAL of patients with stable COPD of varying severity and control healthy smokers and non-smokers demonstrated that IL-18 levels were similar across all groups. Another study that examined the role of CD8+ T cells in COPD pathogenesis correlated their phenotype and in vitro function with disease severity [41]. Expression of IL-18R and CD69 by lung CD8+ T cells correlated with disease severity whether expressed as GOLD stage or as FEV1% predicted. The investigators demonstrated a functional link of IL-18R expression on lung CD8+ T cells, as shown by the significant induction of IFN-c and TNF-a expression (but not Th2 or Th17 cytokines) after stimulation with IL-18 plus IL-12 and in the absence of TCR activation. In the study of Wang et al. [74] it was reported that the proportions of IL-18R-(expressing T lymphocytes and CD8+ T lymphocytes) in peripheral blood were significantly higher in stable COPD patients than in non smokers and current smokers, suggesting that IL-18/IL18R system is active in peripheral blood of COPD patients. A common feature of COPD is the increased susceptibility to respiratory infections. Pulmonary colonization with various bacteria such as Haemophilus influenza, Streptococcus pneumonia and Moraxella catarrhalis is found in up to 30% of COPD patients with stable disease and in more than 50% of patients during exacerbations. Recent data demonstrate the upregulation of the NLRP3 inflammasome during Nontypeable H. Influenza infection (NTHi). In the study of Rotta et al. [75] it was shown that NTHi stimulates caspase-1 expression and leads to a strong release of IL-1 family cytokines IL-1b and IL-18. 3. Conclusions Taken together, the above studies provide strong support for the involvement of IL-18 in the pathogenesis of COPD. IL-18 may represent a novel master cytokine regulator that can drive all of the key pathologies found in stable COPD. The majority of studies identify IL-18 as a potential target for future COPD therapeutics to limit both the destructive and remodeling processes occurring in COPD lungs. In this respect, it is noteworthy that neutralizing antibodies to IL-18 have efficacy in preclinical models of inflammation and tissue injury in other organ systems. However, IL-18 has crucial host defense and antitumor activities, and gene therapy to increase IL-18 levels in tissues protects experimental animals from infection and tumor growth and metastasis. Given that patients with COPD can have infective disease exacerbations and are at increased risk from developing lung cancer, it would be important to determine the safety as well as the efficacy of novel therapeutics targeting IL-18 in the lungs of patients with COPD. References [1] Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176:532–55. [2] Stockley RA, Mannino D, Barnes PJ. Burden and pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009;6:524–6.

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Implication of Interleukin (IL)-18 in the pathogenesis of chronic obstructive pulmonary disease (COPD).

Interleukin (IL)-18 is a pro-inflammatory cytokine that was firstly described as an interferon (IFN)-γ-inducing factor. Similar to IL-1β, IL-18 is syn...
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