Inhibiting the NLRP3 inflammasome with MCC950 ameliorates retinal neovascularization and leakage by reversing the IL-1ß/IL-18 activation pattern in an oxygen-induced ischemic retinopathy mouse model.

Activation of the nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome plays an important role in ocular neovascularization. In our study, we found that the expression and activation levels of NLRP3 inflammasome components, including NLRP3, an apoptosis-associated speck-like protein (ASC) containing caspase activation and recruitment domain (CARD) and caspase-1 (CAS1), were significantly upregulated. In addition, we found interleukin (IL)-1ß activity increased while IL-18 activity decreased in the retinas of oxygen-induced ischemic retinopathy (OIR) mice. MCC950, an inhibitor of NLRP3, reversed the IL-1ß/IL-18 activation pattern, inhibited the formation of retinal neovascularization (RNV), decreased the number of acellular capillaries and reduced leakage of retinal vessels. Moreover, MCC950 could regulate the expression of endothelial cell- and pericyte function-associated molecules, such as vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1, VEGFR2, matrix metalloproteinase (MMP)2, MMP9, tissue inhibitor of metalloproteinases (TIMP)1, TIMP2, platelet-derived growth factor receptor-ß (PDGFR-ß), platelet-derived growth factor-B (PDGF-B), and angiopoietin2 (Ang2). In vitro, recombinant human (r)IL-18 and rIL-1ß regulated the expression of endothelial cell- and pericyte function-associated molecules and the proliferation and migration of endothelial cells and pericytes. We therefore determined that inhibiting the NLRP3 inflammasome with MCC950 can regulate the function of endothelial cells and pericytes by reversing the IL-1ß/IL-18 activation pattern to ameliorate RNV and leakage; thereby opening new avenues to treat RNV-associated ocular diseases.

c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells.

RORγt+ group 3 innate lymphoid cells (ILC3s) maintain intestinal homeostasis through secretion of type 3 cytokines such as interleukin (IL)-17 and IL-22. However, CCR6- ILC3s additionally co-express T-bet allowing for the acquisition of type 1 effector functions. While T-bet controls the type 1 programming of ILC3s, the molecular mechanisms governing T-bet are undefined. Here, we identify c-Maf as a crucial negative regulator of murine T-bet+ CCR6- ILC3s. Phenotypic and transcriptomic profiling of c-Maf-deficient CCR6- ILC3s revealed a hyper type 1 differentiation status, characterized by overexpression of ILC1/NK cell-related genes and downregulation of type 3 signature genes. On the molecular level, c-Maf directly restrained T-bet expression. Conversely, c-Maf expression was dependent on T-bet and regulated by IL-1ß, IL-18 and Notch signals. Thus, we define c-Maf as a crucial cell-intrinsic brake in the type 1 effector acquisition which forms a negative feedback loop with T-bet to preserve the identity of CCR6- ILC3s.

Interaction between hyperphosphorylated tau and pyroptosis in forskolin and streptozotocin induced AD models.

Amyloid-ß (Aß) activating the pyroptotic cell pathway has been reported to act as a component in the progression of Alzheimer's disease (AD). As another major pathophysiological protein process in AD, the abnormal hyperphosphorylation of tau proteins exerts neurotoxic effects through a variety of mechanisms. However, data describing the relationship between hyperphosphorylated tau proteins and pyroptosis are very scarce. In this study, we used two hyperphosphorylated tau models, intracerebroventricular (ICV) forskolin (FSK, a PKA activator) rat model and ICV-streptozotocin (STZ) rat model; also, FSK and STZ treated PC12 cells as in vitro models to test the relationship between hyperphosphorylated tau proteins and pyroptosis. We found that FSK and STZ significantly increased the hyperphosphorylated tau level, pyroptosis-related protein in PC12 cell and rats' brain, and inhibited the activity of caspase-1 by caspase-1 inhibitor, caspase-1 siRNA, or incubated with Interleukin(IL)-1ß/IL-18 neutralizing antibody could notably alleviate the FSK and STZ induced PC12 cells damage and improve the cognitive disorder in ICV-FSK and ICV-STZ rats. Suppressed the level of hyperphosphorylated tau by LiCl also significantly decreased caspase-1 activity and the content of inflammatory cytokines in FSK or STZ treated PC12 cells. In summary, our results demonstrated that inflammasomes mediated pyroptosis at least one underlying pathogenic mechanism for the neurotoxicity induced by hyperphosphorylated tau in PC12 cells and dementia rats. IL-1ß and IL-18, the downstream of caspase-1, in turn increased hyperphosphorylated tau while spreading neuroinflammation.

Deletion of interleukin-18 attenuates abdominal aortic aneurysm formation.

BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is a common disease; however, its exact pathogenesis remains unknown, and no specific medical therapies are available. Interleukin (IL)-18 plays a crucial role in atherosclerotic plaque destabilization and is a strong predictor of cardiovascular death. Here, we investigated the role of IL-18 in AAA pathogenesis using an experimental mouse model. METHODS AND RESULTS: After infusion of angiotensin II (Ang II) for 4 weeks and ß-aminopropionitrile (BAPN) for 2 weeks, 58% of C57/6J wild-type (WT) mice developed AAA associated with enhanced expression of IL-18; however, disease incidence was significantly lower in IL-18-/- mice than in WT mice (p < 0.01), although no significant difference was found in systolic blood pressure between WT mice and IL-18-/- mice in this model. Additionally, IL-18 deletion significantly attenuated Ang II/BAPN-induced macrophage infiltration, macrophage polarization into inflammatory M1 phenotype, and matrix metalloproteinase (MMP) activation in abdominal aortas, which is associated with reduced expression of osteopontin (OPN). CONCLUSIONS: These findings indicate that IL-18 plays an important role in the development of AAA by enhancing OPN expression, macrophage recruitment, and MMP activation. Moreover, IL-18 represents a previously unrecognized therapeutic target for the prevention of AAA formation.

IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential.

Interleukin (IL)-18 and IL-22 are key components of cytokine networks that play a decisive role in (pathological) inflammation, host defense, and tissue regeneration. Tight regulation of cytokine-driven signaling, inflammation, and immunoactivation is supposed to enable nullification of a given deleterious trigger without mediating overwhelming collateral tissue damage or even activating a cancerous face of regeneration. In fact, feedback regulation by specific cytokine opponents is regarded as a major means by which the immune system is kept in balance. Herein, we shine a light on the interplay between IL-18 and IL-22 and their opponents IL-18 binding protein (IL-18BP) and IL-22BP in order to provide integrated information on their biology, pathophysiological significance, and prospect as targets and/or instruments of therapeutic intervention.

MARK4 (Microtubule Affinity-Regulating Kinase 4)-Dependent Inflammasome Activation Promotes Atherosclerosis-Brief Report.

OBJECTIVE: MARK4 (microtubule affinity-regulating kinase 4) regulates NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome activation. The aim of the study is to examine the role of MARK4 in hematopoietic cells during atherosclerosis. METHODS AND RESULTS: We show increased MARK4 expression in human atherosclerotic lesions compared with adjacent areas. MARK4 is coexpressed with NLRP3, and they colocalize in areas enriched in CD68-positive but α-SMA (α-smooth muscle actin)-negative cells. Expression of MARK4 and NLRP3 in the atherosclerotic lesions is associated with the production of active IL (interleukin)-1ß and IL-18. To directly assess the role of hematopoietic MARK4 in NLRP3 inflammasome activation and atherosclerotic plaque formation, Ldlr (low-density lipoprotein receptor)-deficient mice were lethally irradiated and reconstituted with either wild-type or Mark4-deficient bone marrow cells, and were subsequently fed a high-fat diet and cholesterol diet for 9 weeks. Mark4 deficiency in bone marrow cells led to a significant reduction of lesion size, together with decreased circulating levels of IL-18 and IFN-γ (interferon-γ). Furthermore, Mark4 deficiency in primary murine bone marrow-derived macrophages prevented cholesterol crystal-induced NLRP3 inflammasome activation, as revealed by reduced caspase-1 activity together with reduced production of IL-1ß and IL-18. CONCLUSIONS: MARK4-dependent NLRP3 inflammasome activation in the hematopoietic cells regulates the development of atherosclerosis.

Implication of Interleukin-12/15/18 and Ruxolitinib in the Phenotype, Proliferation, and Polyfunctionality of Human Cytokine-Preactivated Natural Killer Cells.

A brief in vitro stimulation of natural killer (NK) cells with interleukin (IL)-12, IL-15, and IL-18 endow them a memory-like behavior, characterized by higher effector responses when they are restimulated after a resting period of time. These preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have several properties that make them a promising tool in cancer immunotherapy. In the present study, we have described the effect that different combinations of IL-12, IL-15, and IL-18 have on the generation of human CIML NK cells. Our data points to a major contribution of IL-15 to CIML NK cell-mediated cytotoxicity against target cells. However, the synergistic effect of the three cytokines grant them the best polyfunctional profile, that is, cells that simultaneously degranulate (CD107a) and produce multiple cytokines and chemokines such as interferon γ, tumor necrosis factor α, and C-C motif chemokine ligand 3. We have also analyzed the involvement of each cytokine and their combinations in the expression of homing receptors CXCR4 and CD62L, as well as the expression of CD25 and IL-2-induced proliferation. Furthermore, we have tested the effects of the Jak1/2 inhibitor ruxolitinib in the generation of CIML NK cells. We found that ruxolitinib-treated CIML NK cells expressed lower levels of CD25 than non-treated CIML NK cells, but exhibited similar proliferation in response to IL-2. In addition, we have also found that ruxolitinib-treated NK cells displayed reduced effector functions after the preactivation, which can be recovered after a 4 days expansion phase in the presence of low doses of IL-2. Altogether, our results describe the impact that each cytokine and the Jak1/2 pathway have in the phenotype, IL-2-induced proliferation, and effector functions of human CIML NK cells.

Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy.

When pathogenic stresses are recognized by innate immune cells, inflammasomes are assembled and caspase-1 is activated, resulting in the conversion of pro-IL-18 into mature IL-18. Because natural killer (NK) cells express IL-18 receptors, IL-18 may play roles in immune functions of NK cells. In the present study, we examined the effect of IL-18 on NK cells derived from lung cancer patients and healthy adult volunteers. When peripheral blood NK cells were stimulated with IL-2, the cells formed clusters beginning on day 5-6 and proliferated thereafter, in which the number of NK cells increased by 10-fold in 10 days. When IL-18 was added, cell clusters were observed as early as on day 4 and NK cells proliferated vigorously. On day 10, the expansion rate was 56-fold on average, showing that IL-18 promoted the expansion of NK cells. It was also notable that IL-18 enhanced the expression of CD80, CD86, HLA-DR and HLA-DQ on NK cells, suggesting that IL-18 conferred NK cells an APC-like phenotype. When cellular cytotoxicity was determined, APC-like NK cells efficiently killed tumor cells and anti-tumor activity was augmented by the addition of tumor antigen-specific mAbs. In addition, IFN-γ was produced by APC-like NK cells in response to tumor cells, and the cytokine production was further enhanced by mAbs. Taken together, IL-18 not only promoted the expansion of NK cells, but also changed the phenotype of NK cells. IL-2/IL-18-induced NK cells might, therefore, serve as a bridge between innate immunity and adaptive immunity and be useful for cancer immunotherapy.

Immuno-detection of Immature and Bioactive Forms of the Inflammatory Cytokine IL-18.

Gastric cancer (GC) is the third most lethal cancer worldwide, and like many other types of cancers, it is associated with precursory chronic inflammatory responses. In the context of many inflammation-associated cancers such as GC, activation of the innate immune response by infectious microbes and/or host-derived molecules is often characterized by production of the cytokines interleukin (IL)-1ß and IL-18, which can often have divergent and opposing (i.e., pro or anti) roles in inflammation and oncogenesis. The processing of these mature bioactive cytokines from their inactive precursor polypeptides is dependent upon the enzyme Caspase-1, which is part of multiprotein complexes called "inflammasomes." Considering the recent mounting evidence for the role of IL-18 in the pathogenesis of GC, here, we describe a Western blotting technique used on genetic mouse models for GC to detect and characterize both pro-Il-18 and mature IL-18 proteins.

The P2X7 receptor-NLRP3 inflammasome complex predicts the development of non-Hodgkin's lymphoma in Sjogren's syndrome: a prospective, observational, single-centre study.

BACKGROUND: P2X7 receptor (P2X7R), trigger of acute inflammatory responses via the NLRP3 inflammasome, is hyperfunctioning in patients with Sjögren's syndrome (SS), where it stimulates IL-18 production. Some patients with SS develop a mucosa-associated lymphoid tissue non-Hodgkin's lymphoma (MALT-NHL). OBJECTIVES: To prospectively evaluate the involvement and the putative prognostic role of this inflammatory pathway in the development of MALT-NHL. METHODS: A total of 147 women with SS have been prospectively followed for a mean of 52 months, relating the expression and function of the P2X7R-inflammasome axis in salivary glands and circulating lymphomonocytes to the prognosis and the degree of the disease. RESULTS: At baseline, gene expression of P2X7R and of the inflammasome components NLRP3, caspase-1 and IL-18 increased according to the presence of germinative centres and was higher in autoantibody-positive individuals and strongly higher in those developing a MALT-NHL over the follow-up. Glandular expression of IL-18 was threefold higher in MALT-NHL than in controls or in the other patients with SS. P2X7R did not colocalize with generic markers of inflammatory infiltrate, like CD20, being selectively expressed by epithelial cells. P2X4R, sharing functional characteristics with P2X7R, did not differ in SS and controls. The increased P2X7R gene and protein expression was tissue specific, no difference being observed in peripheral lymphomonocytes between SS with MALT-NHL and SS not developing MALT-NHL. CONCLUSION: We propose the P2X7R-inflammasome axis as a novel potential pathway involved in both SS exocrinopathy and lymphomagenesis, reinforcing the hypothesis of a key role of IL-18, via its increased P2X7R-mediated production, in the pathogenesis of lymphoproliferative malignancies, and opening novel opportunities for the early diagnosis of lymphoproliferative complications and the development of potential targeted therapies.

Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation.

RATIONALE: A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown. OBJECTIVE: Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC. RESULTS AND METHODS: The iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients' sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs. CONCLUSION: Our data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation.

The Proinflammatory Cytokine Interleukin 18 Regulates Feeding by Acting on the Bed Nucleus of the Stria Terminalis.

UNLABELLED: The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra(-/-)), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons. SIGNIFICANCE STATEMENT: Loss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.

Interleukin 18 (IL-18) as a target for immune intervention.

Interleukin 18 (IL-18) is a pleiotropic cytokine involved in the regulation of innate and acquired immune response. In the milieu of IL-12 or IL-15, IL-18 is a potent inducer of IFN-gamma in natural killer (NK) cells and CD4 T helper (Th) 1 lymphocytes. However, IL-18 also modulates Th2 and Th17 cell responses, as well as the activity of CD8 cytotoxic cells and neutrophils, in a host microenvironment-dependent manner. It is produced by various hematopoietic and nonhematopoietic cells, including dendritic cells and macrophages. In an organism, bioactivity of the cytokine depends on the intensity of IL-18 production, the level of its natural inhibitory protein - IL-18BP (IL-18 binding protein) and the surface expression of IL-18 receptors (IL-18R) on the responding cells. This review summarizes the biology of the IL-18/IL-18BP/IL-18R system and its role in the host defense against infections. The prospects for IL-18 application in immunotherapeutic or prophylactic interventions in infectious and non-infectious diseases are discussed.

IL-18 and Cutaneous Inflammatory Diseases.

Interleukin (IL)-18, an IL-1 family cytokine, is a pleiotropic immune regulator. IL-18 plays a strong proinflammatory role by inducing interferon (IFN)-γ. Previous studies have implicated IL-18 in the pathogenesis of various diseases. However, it is not well understood biologic activities of IL-18 in the diverse skin diseases. Here, we have reviewed the expression and function of IL-18 in skin diseases including inflammatory diseases. This article provides an evidence-based understanding of the role of IL-18 in skin diseases and its relationship with disease activities.

Interleukin-1 Family Cytokines in Liver Diseases.

The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases.

The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.

The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver.

Aldosterone-induced cardiomyocyte growth, and fibroblast migration and proliferation are mediated by TRAF3IP2.

Sustained activation of the Renin-Angiotensin-Aldosterone System (RAAS) contributes to the pathogenesis of heart failure. Aldosterone (Aldo) is known to induce both myocardial hypertrophy and fibrosis through oxidative stress and proinflammatory pathways. Here we have investigated whether Aldo-mediated cardiomycocyte hypertrophy is dependent on TRAF3IP2, an upstream regulator of IKK and JNK. We also investigated whether the pro-mitogenic and pro-migratory effects of Aldo on cardiac fibroblasts are also mediated by TRAF3IP2. Aldo induced both superoxide and hydrogen peroxide in isolated adult mouse cardiomyocytes (CM), and upregulated TRAF3IP2 expression in part via the mineralocorticoid receptor and oxidative stress. Silencing TRAF3IP2 blunted Aldo-induced IKKß, p65, JNK, and c-Jun activation, IL-18, IL-6 and CT-1 upregulation, and cardiomyocyte hypertrophy. In isolated adult mouse cardiac fibroblasts (CF), Aldo stimulated TRAF3IP2-dependent IL-18 and IL-6 production, CTGF, collagen I and III expression, MMP2 activation, and proliferation and migration. These in vitro results suggest that TRAF3IP2 may play a causal role in Aldo-induced adverse cardiac remodeling in vivo, and identify TRAF3IP2 as a potential therapeutic target in hypertensive heart disease.

Role of Chitinase 3-Like-1 in Interleukin-18-Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung.

Chitinase 3-like 1 (Chi3l1), which is also called YKL-40 in humans and BRP-39 in mice, is the prototypic chitinase-like protein. Recent studies have highlighted its impressive ability to regulate the nature of tissue inflammation and the magnitude of tissue injury and fibroproliferative repair. This can be appreciated in studies that highlight its induction after cigarette smoke exposure, during which it inhibits alveolar destruction and the genesis of pulmonary emphysema. IL-18 is also known to be induced and activated by cigarette smoke, and, in murine models, the IL-18 pathway has been shown to be necessary and sufficient to generate chronic obstructive pulmonary disease-like inflammation, fibrosis, and tissue destruction. However, the relationship between Chi3l1 and IL-18 has not been defined. To address this issue we characterized the expression of Chi3l1/BRP-39 in control and lung-targeted IL-18 transgenic mice. We also characterized the effects of transgenic IL-18 in mice with wild-type and null Chi3l1 loci. The former studies demonstrated that IL-18 is a potent stimulator of Chi3l1/BRP-39 and that this stimulation is mediated via IFN-γ-, IL-13-, and IL-17A-dependent mechanisms. The latter studies demonstrated that, in the absence of Chi3l1/BRP-39, IL-18 induced type 2 and type 17 inflammation and fibrotic airway remodeling were significantly ameliorated, whereas type 1 inflammation, emphysematous alveolar destruction, and the expression of cytotoxic T lymphocyte perforin, granzyme, and retinoic acid early transcript 1 expression were enhanced. These studies demonstrate that IL-18 is a potent stimulator of Chi3l1 and that Chi3l1 is an important mediator of IL-18-induced inflammatory, fibrotic, alveolar remodeling, and cytotoxic responses.

Interleukin-18 increases TLR4 and mannose receptor expression and modulates cytokine production in human monocytes.

Interleukin-18 is a proinflammatory cytokine belonging to the interleukin-1 family of cytokines. This cytokine exerts many unique biological and immunological effects. To explore the role of IL-18 in inflammatory innate immune responses, we investigated its impact on expression of two toll-like receptors (TLR2 and TLR4) and mannose receptor (MR) by human peripheral blood monocytes and its effect on TNF-α, IL-12, IL-15, and IL-10 production. Monocytes from healthy donors were stimulated or not with IL-18 for 18 h, and then the TLR2, TLR4, and MR expression and intracellular TNF-α, IL-12, and IL-10 production were assessed by flow cytometry and the levels of TNF-α, IL-12, IL-15, and IL-10 in culture supernatants were measured by ELISA. IL-18 treatment was able to increase TLR4 and MR expression by monocytes. The production of TNF-α and IL-10 was also increased by cytokine treatment. However, IL-18 was unable to induce neither IL-12 nor IL-15 production by these cells. Taken together, these results show an important role of IL-18 on the early phase of inflammatory response by promoting the expression of some pattern recognition receptors (PRRs) that are important during the microbe recognition phase and by inducing some important cytokines such as TNF-α and IL-10.