Diagnostic accuracy of interleukin-33 for tuberculous pleural effusion: A systematic review and meta-analysis.

BACKGROUND: The detection of interleukin 33 (IL-33) in pleural effusion may be more sensitive in diagnosing tuberculous pleural effusion (TPE). The present study aimed to assess the accuracy of pleural IL-33 for the diagnosis of TPE by means of meta-analysis and systematic review of relevant studies. METHOD: After retrieving the published studies, the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and a summary receiver operating characteristic curve were assessed to estimate the usefulness of pleural IL-33 in diagnosing TPE using meta-analysis with a random-effects model. We also performed meta-regression and subgroup analysis. RESULTS: A total of 639 patients from 6 studies were analyzed. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.87 (95% confidence interval [CI], 0.82-0.91), 0.76 (95% CI, 0.72-0.80), 6.54 (95% CI, 2.65-16.15), 0.17 (95% CI, 0.10-1.27), and 45.40 (95% CI, 12.83-160.70) respectively. The area under the curve was 0.94. The composition of the included population was the main cause of heterogeneity and subgroup analysis showed that pleural IL-33 had a higher specificity (0.93, 95% CI 0.87-0.96) when used for differential diagnosis between TPE and malignant pleural effusion. CONCLUSION: The detection of IL-33 alone in pleural effusion seems to not be an efficient diagnostic marker for TPE but may serve as a novel biomarker to differentiate between TPE and malignant pleural effusion.

The impact of airborne endotoxin exposure on rheumatoid arthritis-related joint damage, autoantigen expression, autoimmunity, and lung disease.

Airborne biohazards are risk factors in the development and severity of rheumatoid arthritis (RA) and RA-associated lung disease, yet the mechanisms explaining this relationship remain unclear. Lipopolysaccharide (LPS, endotoxin) is a ubiquitous inflammatory agent in numerous environmental and occupational air pollutant settings recognized to induce airway inflammation. Combining repetitive LPS inhalation exposures with the collagen induced arthritis (CIA) model, DBA1/J mice were assigned to either: sham (saline injection/saline inhalation), CIA (CIA/saline), LPS (saline/LPS 100 ng inhalation), or CIA + LPS for 5 weeks. Serum anti-citrullinated (CIT) protein antibody (ACPA) and anti-malondialdehyde-acetaldehyde (MAA) antibodies were strikingly potentiated with co-exposure (CIA + LPS). CIT- and MAA-modified lung proteins were increased with co-exposure and co-localized across treatment groups. Inhaled LPS exacerbated arthritis with CIA + LPS > LPS > CIA versus sham. Periarticular bone loss was demonstrated in CIA and CIA + LPS but not in LPS alone. LPS induced airway inflammation and neutrophil infiltrates were reduced with co-exposure (CIA + LPS). Potentially signaling transition to pro-fibrotic processes, there were increased infiltrates of activated CD11c+CD11b+ macrophages and transitioning CD11c+CD11bint monocyte-macrophage populations with CIA + LPS. Moreover, several lung remodeling proteins including fibronectin and matrix metalloproteinases as well as complement C5a were potentiated with CIA + LPS compared to other treatment groups. IL-33 concentrations in lung homogenates were enhanced with CIA + LPS with IL-33 lung staining driven by LPS. IL-33 expression was also significantly increased in lung tissues from patients with RA-associated lung disease (N = 8) versus controls (N = 7). These findings suggest that patients with RA may be more susceptible to developing interstitial lung disease following airborne biohazard exposures enriched in LPS.

Particulate matter exposure is highly correlated to pediatric asthma exacerbation.

Asthma is a heterogeneous disease in which environmental factors play an important role, and the effect of particulate matter (PM) on the occurrence and severity of asthma is drawing more attention. This study aims to identify the correlation between PM and pediatric asthma exacerbation and explore the potential mechanisms. The asthma visits data (N = 16,779,739) in a university-based tertiary children's hospital from January 2013 to December 2017 were collected, and the relationship between asthma visits and local PM concentration was analyzed. For further study, we established a house dust mite (HDM)-induced allergic airway inflammation model with PM intervention. We detected a correlation between PM concentration and pediatric asthma visits, especially in children under 6 years old. The in vivo data showed that PM aggravated HDM-induced airway inflammation, and IL-33 neutralizing antibody exerted a protective role. Our study suggests that PM is a risk factor in promoting pediatric asthma exacerbation, in which IL-33 might be a promising target.

Interleukin (IL)-33 is dispensable for Schistosoma mansoni worm maturation and the maintenance of egg-induced pathology in intestines of infected mice.

BACKGROUND: Schistosomes are trematode worms that dwell in their definitive host's blood vessels, where females lay eggs that need to be discharged into the environment with host excreta to maintain their life-cycle. Both worms and eggs require type 2 immunity for their maturation and excretion, respectively. However, the immune molecules that orchestrate such immunity remain unclear. Interleukin (IL)-33 is one of the epithelium-derived cytokines that induce type 2 immunity in tissues. The aim of this study was to determine the role of IL-33 in the maturation, reproduction and excretion of Schistosoma mansoni eggs, and in the maintenance of egg-induced pathology in the intestines of mice. METHODS: The morphology of S. mansoni worms and the number of eggs in intestinal tissues were studied at different time points post-infection in S. mansoni-infected IL-33-deficient (IL-33-/-) and wild-type (WT) mice. IL-5 and IL-13 production in the spleens and mesenteric lymph nodes were measured. Tissue histology was performed on the terminal ilea of both infected and non-infected mice. RESULTS: Worms from IL-33-/- and WT mice did not differ morphologically at 4 and 6 weeks post-infection (wpi). The number of eggs in intestinal tissues of IL-33-/- and WT mice differed only slightly. At 6 wpi, IL-33-/- mice presented impaired type 2 immunity in the intestines, characterized by a decreased production of IL-5 and IL-13 in mesenteric lymph nodes and fewer inflammatory infiltrates with fewer eosinophils in the ilea. There was no difference between IL-33-/- and WT mice in the levels of IL-25 and thymic stromal lymphopoietin (TSLP) in intestinal tissues. CONCLUSIONS: Despite its ability to initiate type 2 immunity in tissues, IL-33 alone seems dispensable for S. mansoni maturation and its absence may not affect much the accumulation of eggs in intestinal tissues. The transient impairment of type 2 immunity observed in the intestines, but not spleens, highlights the importance of IL-33 over IL-25 and TSLP in initiating, but not maintaining, locally-induced type 2 immunity in intestinal tissues during schistosome infection. Further studies are needed to decipher the role of each of these molecules in schistosomiasis and clarify the possible interactions that might exist between them.

Metabolic and immunological evaluation of patients with indeterminate and cardiac forms of Chagas disease.

ABSTRACT: Chagas disease affects approximately 7 million people, causing disability and mortality in the most productive life stages of infected individuals. Considering the lifestyle of the world population, metabolic syndrome is a synergistic factor for an increased cardiovascular risk of patients with Chagas disease.This study transversally evaluated the metabolic and immunological profiles of patients with indeterminate (IF) and cardiac (CF) forms of Chagas disease and their correlations with left ventricular dysfunction (LVD).Clinical and electrical bioimpedance analysis, levels of cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-17, IL-10, and IL-33) and adipocytokines (adiponectin, leptin, and resistin), metabolic syndrome components, and brain natriuretic peptide (BNP) levels were assessed in 57 patients (13 IF and 44 CF) with a mean age of 61.63 ±â€Š12.1 years. Chest x-ray, electrocardiogram, and echocardiogram were performed to classify the clinical forms.The CF group had a higher number of individuals with metabolic syndrome components blood pressure altered, while more participants in the CF group with LVD had low high-density lipoprotein (HDL) levels. The IF group had more participants with a higher waist-to-hip ratio (WHR). No significant difference was observed between metabolic syndrome, cytokine and adipocytokine level, and clinical forms of the disease or in relation to LVD.Individuals with the IF showed metabolic and immunological profiles compatible with increased disease control, whereas those with CF showed marked inflammatory immune response.

Cellular context of IL-33 expression dictates impact on anti-helminth immunity.

Interleukin-33 (IL-33) is a pleiotropic cytokine that can promote type 2 inflammation but also drives immunoregulation through Foxp3+Treg expansion. How IL-33 is exported from cells to serve this dual role in immunosuppression and inflammation remains unclear. Here, we demonstrate that the biological consequences of IL-33 activity are dictated by its cellular source. Whereas IL-33 derived from epithelial cells stimulates group 2 innate lymphoid cell (ILC2)-driven type 2 immunity and parasite clearance, we report that IL-33 derived from myeloid antigen-presenting cells (APCs) suppresses host-protective inflammatory responses. Conditional deletion of IL-33 in CD11c-expressing cells resulted in lowered numbers of intestinal Foxp3+Treg cells that express the transcription factor GATA3 and the IL-33 receptor ST2, causing elevated IL-5 and IL-13 production and accelerated anti-helminth immunity. We demonstrate that cell-intrinsic IL-33 promoted mouse dendritic cells (DCs) to express the pore-forming protein perforin-2, which may function as a conduit on the plasma membrane facilitating IL-33 export. Lack of perforin-2 in DCs blocked the proliferative expansion of the ST2+Foxp3+Treg subset. We propose that perforin-2 can provide a plasma membrane conduit in DCs that promotes the export of IL-33, contributing to mucosal immunoregulation under steady-state and infectious conditions.

The Ca2+-dependent pathway contributes to changes in the subcellular localization and extracellular release of interleukin-33.

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family and plays critical roles in facilitating type-2 immune responses. IL-33 is localized in the nucleus and released to the extracellular milieu during cell death, although the precise mechanisms underlying IL-33 mobilization remain unclear. Here, we found that nigericin, a toxin derived from Streptomyces hygroscopicus, promoted IL-33 translocation from the nucleus to the cytosol before extracellular release. This translocation was inhibited by chelating Ca2+ with EGTA or membrane protection by glycine treatment. Ca2+ ionophore A23187 stimulation caused IL-33 translocation to the cytoplasm but was not sufficient for extracellular release. However, IL-33 release was induced by detergent treatment, which indicates that membrane rupture is required for IL-33 release. The pore-forming pyroptosis executor gasdermin D was cleaved following nigericin stimulation, and overexpression of the cleaved gasdermin D-N-terminal fragment that forms the membrane pore sufficiently induced IL-33 release, which was blocked by EGTA and glycine. Together, these findings suggest that Ca2+-dependent signals and gasdermin D pore formation are required for robust IL-33 production.

IL-33 and its increased serum levels as an alarmin for imminent pulmonary complications in polytraumatized patients.

Background: According to recently published findings, we hypothesized that serum interleukin-33 (IL-33) may qualify for predicting pulmonary complications in polytraumatized patients. Methods: One hundred and thirty patients (age ≥ 18 years, ISS ≥ 16) were included in our prospective analysis after primary admission to our level I trauma center during the first post-traumatic hour. Serum samples immediately after admission and on day 2 after trauma were obtained and analyzed. Results: Median initial IL-33 levels (in picograms per milliliter) were higher in polytrauma victims (1) with concomitant thoracic trauma [5.08 vs. 3.52; p = 0.036], (2) sustaining parenchymal lung injury (PLI) [5.37 vs. 3.71; p = 0.027], and (3) developing acute respiratory distress syndrome (ARDS) [6.19 vs. 4.48; p = 0.003], compared to the respective rest of the study group. The median initial IL-33 levels were higher in patients experiencing both PLI and ARDS compared to those sustaining PLI and not developing ARDS [6.99 vs. 4.69; p = 0.029]. ROC statistics provided an AUC of 0.666 (p = 0.003) and a cut-off value of 4.77 (sensitivity, 71.8%; specificity, 75.7%) for predicting ARDS. Moreover, a higher initial median IL-33 level was revealed in the deceased compared to the survivors [12.25 vs. 4.72; p = 0.021]. ROC statistics identified the initial level of IL-33 as a predictor of death with 11.19 as cut-off value (sensitivity, 80.0%; specificity, 80.0%; AUC = 0.805; p = 0.021). Conclusions: Following tissue damage, IL-33 is abundantly released in the serum of polytraumatized patients immediately after their injuries occurred. As initial IL-33 levels were particularly high in individuals experiencing both PLI and ARDS, IL-33 release after trauma seems to be involved in the promotion of ARDS and might serve already at admission as a solid indicator of impending death in polytraumatized patients.

The concentration of interleukin-33 in heart failure with reduced ejection fraction.

OBJECTIVE: Despite several improvements in the management of heart failure (HF), it is still an incurable and a progressive disease. Several trials demonstrated that the process of inflammation may be responsible for initiation and progression of HF. The aim of the present study was to investigate the role of interleukin-33 (IL-33) in the pathogenesis of HF and to assess whether disease etiology and course of the disease affect the expression of cytokines. METHODS: The study included 155 (106 male and 49 female) patients with systolic HF with a mean left ventricle ejection fraction of 32.13+-12.8% and 60 (36 male and 24 female) healthy individuals. IL-33 concentrations were evaluated using enzyme-linked immunosorbent assay. RESULTS: The concentration of IL-33 was statistically significantly lower in patients with HF than in healthy subjects, 16.91 (0-81.00) pg/mL and 92.51 (33.61-439.61) pg/mL, respectively. Patients with HF with ischemic etiology had lower concentration of IL-33 (10.75 pg/mL) than subjects with HF with non-ischemic etiology (21.05 pg/mL). Patients with stable HF (10.46 pg/mL) had lower IL-33 levels than those with unstable HF (19.02 pg/mL). CONCLUSION: The concentrations of IL-33 were lower in patients with HF than in healthy controls, which may play an important role of above cytokine in HF development and progression. In addition, interleukin concentrations varied depending on the etiology and severity of the course of the disease.

Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure.

Chitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) (Chia) deficiency on host defense during acute exposure to the fungal pathogen Aspergillus fumigatus as well as its contribution to A. fumigatus-associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels in A. fumigatus conidia, which emerged at the highest level during hyphal transition. In response to acute A. fumigatus challenge, Chia-/- mice unexpectedly demonstrated lower A. fumigatus lung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin-33 (IL-33) levels yet increased IL-1ß and prostaglandin E2 (PGE2) production, a phenotype that we reported previously to promote the induction of IL-17A and IL-22. During chronic A. fumigatus exposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses.

Interleukin-33 overexpression reflects less aggressive tumour features in large-duct type cholangiocarcinomas.

AIMS: The aim of the present study was to elucidate the clinicopathological significance of interleukin (IL)-6 and IL-33 expression in intrahepatic cholangiocarcinomas (iCCAs) and perihilar cholangiocarcinomas (pCCAs). METHODS AND RESULTS: IL-6 and IL-33 mRNA expression levels were examined in iCCAs (n = 55) and pCCAs (n = 32) by the use of quantitative real-time polymerase chain reaction and a highly sensitive in-situ hybridisation protocol (RNAscope), and expression levels were correlated with clinicopathological features. According to a recently proposed classification scheme, iCCAs were separated into small-duct (n = 33) and large-duct (n = 22) types. IL-6 and IL-33 expression levels were higher in large-duct iCCAs and pCCAs than in small-duct iCCAs, and there was a positive correlation between the expression levels of these cytokines. Double in-situ hybridisation/immunostaining showed that IL-6 mRNA was expressed in actin-positive (myo)fibroblasts, whereas IL-33 mRNA was mainly produced by CD31-positive endothelial cells. With the average expression level as a cut-off point, cases were classified as IL-6high and IL-6low or IL-33high and IL-33low . In the combined cohort of large-duct iCCAs and pCCAs, IL-6high and IL-6low cholangiocarcinomas shared many features, whereas IL-33high cases had less aggressive characteristics than IL-33low cases, as shown by lower tumour marker concentrations, smaller tumour sizes, less common vascular invasion, lower pT stages, and higher lymphocyte/monocyte ratios in blood. KRAS mutations were slightly less common in IL-33high cases than in IL-33low cases (9% versus 29%; P = 0.061). The strong expression of IL-33 in tissue appeared to be an independent favourable prognostic factor. CONCLUSIONS: IL-33high cholangiocarcinomas may represent a unique, less aggressive carcinogenetic process of the large bile ducts.

IL-33 and Its Receptor ST2 after Inhaled Allergen Challenge in Allergic Asthmatics.

BACKGROUND: Previous murine models have demonstrated interleukin (IL)-33 to be an important mediator of type-2 inflammation and to promote airway hyperresponsiveness in allergic asthma. A number of inflammatory cells produce IL-33 and eosinophils express ST2 mRNA. The relationship between IL-33 and eosinophils in allergic asthma, however, remains unclear. OBJECTIVE: The aim of this work was to evaluate in vitro the effect of allergen inhalation on IL-33 levels and expression of its receptor (ST2L) on eosinophils in allergic asthmatics, and the effect of IL-33 stimulation on eosinophil activity. METHODS: Plasma and sputum IL-33, soluble ST2 (sST2) levels, and ST2L expression on eosinophils were measured in 10 healthy controls and 10 allergic asthmatics. Asthmatics underwent allergen and diluent inhalation challenges. Blood and sputum samples were collected to measure IL-33, sST2, and ST2L eosinophil expression before and 24 h after allergen inhalation. Purified blood eosinophils from allergic asthmatics were incubated overnight with IL-33 to assess ST2 and intracellular IL-5 expression. RESULTS: Baseline levels of IL-33 in sputum and sST2 in plasma and sputum were similar in allergic asthmatics compared to healthy controls. In addition, there was no difference in blood or sputum eosinophil ST2L expression in healthy controls versus allergic asthmatics. Eosinophil ST2L expression was significantly increased 24 h postallergen inhalation in allergic asthmatics. In vitro stimulation of human eosinophils with IL-33 and LPS significantly increased eosinophil ST2L expression and IL-33 stimulation increased intracellular IL-5 expression, which was attenuated by treatment with sST2 and ST2 blockade. CONCLUSION AND CLINICAL RELEVANCE: In mild asthmatics, there was a significant upregulation of ST2 surface expression on eosinophils from blood and sputum following allergen inhalation challenge. In vitro, IL-33 stimulation of eosinophils increases both ST2 membrane expression and IL-5 production. These results support a role for IL-33 in causing allergen-induced eosinophilia. Blockade of IL-33 and ST2 signaling may present a novel therapeutic avenue for asthma treatment.

Calycosin Suppresses Epithelial Derived Initiative Key Factors and Maintains Epithelial Barrier in Allergic Inflammation via TLR4 Mediated NF-κB Pathway.

BACKGROUND/AIMS: Calycosin is a bioactive component of Astragali Radix, a Chinese herb for treating allergy. We have previously demonstrated that calycosin effectively inhibited allergic inflammation efficiently. The aim of this study was to explore the mechanism of calycosin on epithelial cells in allergic inflammation. METHODS: An initial stage of atopic dermatitis (AD) model in which mice were just sensitized with FITC, was established in vivo and immortalized human keratinocytes (HaCaT cells) were utilized in vitro. Initiative key cytokines, TSLP and IL-33, were measured by ELISA, qPCR, immunofluorescence and Western blot. The junctions in epithelial cells were observed by electron microscopy and tight junctions (TJs) (Occludin and ZO-1) were assessed by Western blot and immunofluorescence. TLR4, MyD88, TAK1, TIRAP and NF-κB were measured by qPCR or Western blot. RESULTS: The results showed that TSLP and IL-33 were inhibited significantly by calycosin in the initial stage of AD model. Simultaneously, calycosin attenuated the separated gap among the epithelial cells and increased the expression of TJs. TSLP/IL-33 and TJs were similarly affected in LPS-stimulated HaCaT cells in vitro. Meanwhile, calycosin not only inhibited the expressions of TLR4, MyD88, TAK1 and TIRAP, but also reduced NF-κB activation in vitro and in vivo. An NF-κB inhibitor enhanced the expressions of TJs and reduced that of TSLP/IL-33 in LPS-stimulated HaCaT cells. CONCLUSION: These results indicated that calycosin reduced the secretion of TSLP/IL-33 and attenuated the disruption of epithelial TJs by inhibiting TLR4 mediated NF-κB signaling pathway. These findings help to understand the beneficial effects of calycosin on AD, and to develop effective preventive or therapeutic strategies to combat this disease and other epithelial barrier deletion-mediated allergic diseases.

IL-33 Attenuates Sepsis by Inhibiting IL-17 Receptor Signaling through Upregulation of SOCS3.

BACKGROUND/AIMS: Sepsis is a systemic inflammatory response during infection. There are limited therapeutic options for sepsis patients. Interleukin (IL)-33 has been reported recently with a beneficial effect in mouse sepsis. METHODS: In this study, we initiated a clinical study to measure serum levels of pro-inflammatory cytokines including IL-33 in sepsis patients. Next, we employed cecal ligation and puncture (CLP) to study the role of IL-33 during sepsis. To further dissect the molecular mechanism, we used in vivo knockout models and in vitro knockdown murine embryonic fibroblasts (MEFs) to investigate the cross-talk between IL-33 and IL-17 signaling, and to identify the potential downstream mediators. RESULTS: IL-33 and IL-17 were upregulated in both clinical and experimental sepsis. In CLP, IL-33 (-/-) mice showed higher mortality rate, and IL-33 treatment improved the survival rate. Elevated proinflammatory cytokines in sepsis were related to IL-17 from γδT cells. IL-33 treatment suppressed production of these cytokines by targeting IL-17 signaling both in vivo and in vitro. Finally, IL-33 was shown to inhibit the IL-17 pathway via activating suppressor of cytokine signaling (SOCS)-3. CONCLUSION: Collectively, the results suggest that IL-33 plays a negative regulatory role in sepsis progression by inhibiting IL-17 pathway through activating SOCS3. This finding would inspire a new therapeutic strategy for treating sepsis.

Interleukin-33 in children with asthma: A systematic review and meta-analysis

Background: Previous studies have shown that serum interleukin 33 serving as an ‘alarmin’ is increased in children with asthma. The objective of this study was to assess the validity of serum IL33 test for early diagnosis of childhood asthma. Methods: A literature search was performed in June 2016 using PubMed, Embase, the Cochrane Library and other Chinese Medical Databases to identify studies. The search terms used were ‘cytokine’, ‘interleukin-33’, ‘asthma’ and ‘children’. The meta-analysis was performed using Review Manager 5.3 software. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs). Results: A total of eight studies were included into this meta-analysis, involving 330 asthmatic children and 248 healthy children. The meta-analysis results revealed that the serum IL33 level was higher in asthmatic children compared to that in healthy children (SMD = 1.29, 95%CI = 0.53-2.05, P = 0.0009), with significant heterogeneity across studies (I2 = 94% and P < 0.00001). Conclusions: The meta-analysis showed that serum IL33 is a helpful biomarker for early diagnosis of childhood asthma. However, owing to lack of enough data, the increased serum concentration of IL33 cannot be an indicator for the asthma severity (AU)

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Saliva, Serum Levels of Interleukin-21, -33 and Prostaglandin E2 in Patients with Generalised Aggressive or Chronic Periodontitis.

PURPOSE: This cross-sectional study aims to evaluate saliva, serum levels of interleukin-21 (IL-21), IL-33, and prostaglandin E2 (PGE2) in patients with generalised chronic periodontitis or aggressive periodontitis. MATERIALS AND METHODS: Before initiation of any periodontal treatment, saliva and serum samples were collected and clinical periodontal measurements were recorded from 94 participants (25 aggressive periodontitis patients, 25 chronic periodontitis patients, 44 periodontally healthy individuals). IL-21, IL-33 and PGE2 levels in serum and saliva samples were determined by ELISA. Data were tested statistically using Kruskal-Wallis, Mann-Whitney U-, and Spearman-rho rank tests. RESULTS: Saliva IL-33 levels were statistically significantly higher in the chronic than the aggressive group (p < 0.05). Serum IL-33, saliva and serum IL-21 and PGE2 levels were similar in the two periodontitis groups. Saliva IL-33 levels correlated with age in the chronic periodontitis group (p < 0.05). Statistically significant positive correlations were found between serum, saliva PGE2 levels and plaque index (p < 0.05). IL-33 and IL-21 levels in serum samples positively correlated in the periodontitis groups (p < 0.05). CONCLUSION: IL-21 and PGE2 analysis did not exhibit discriminating data between generalised chronic and aggressive periodontitis, but the present findings support the role of these cytokines in periodontitis. Statistically significantly higher saliva IL-33 levels in the chronic periodontitis group warrant further research.

Cardiokines as Modulators of Stress-Induced Cardiac Disorders.

Almost 30 years ago, the protein, atrial natriuretic peptide, was identified as a heart-secreted hormone that provides a peripheral signal from the myocardium that communicates to the rest of the organism to modify blood pressure and volume under conditions of heart failure. Since then, additional peripheral factors secreted by the heart, termed cardiokines, have been identified and shown to coordinate this interorgan cross talk. In addition to this interorgan communication, cardiokines also act in an autocrine/paracrine manner to play a role in intercellular communication within the myocardium. This review focuses on the roles of newly emerging cardiokines that are mainly increased in stress-induced cardiac diseases. The potential of these cardiokines as clinical biomarkers for diagnosis and prognosis of cardiac disorders is also discussed.

Role of the IL-33-ST2 axis in sepsis.

Sepsis remains a major clinical problem with high morbidity and mortality. As new inflammatory mediators are characterized, it is important to understand their roles in sepsis. Interleukin 33 (IL-33) is a recently described member of the IL-1 family that is widely expressed in cells of barrier tissues. Upon tissue damage, IL-33 is released as an alarmin and activates various types of cells of both the innate and adaptive immune system through binding to the ST2/IL-1 receptor accessory protein complex. IL-33 has apparent pleiotropic functions in many disease models, with its actions strongly shaped by the local microenvironment. Recent studies have established a role for the IL-33-ST2 axis in the initiation and perpetuation of inflammation during endotoxemia, but its roles in sepsis appear to be organism and model dependent. In this review, we focus on the recent advances in understanding the role of the IL-33/ST2 axis in sepsis.

IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis.

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b+ GR1+ and CD11b+ F4/80+ myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. © 2016 Wiley Periodicals, Inc.

The role of IL-25 and IL-33 in chronic rhinosinusitis with or without nasal polyps.

The role of IL-25 and IL-33 in the aetiology and pathogenesis of nasal polyps has been controversial in the literature. The objective of the study is to detect serum and tissue levels of IL-25 and IL-33 in patients with (CRSwNP) or without (CRSsNP) nasal polyps using enzyme-linked immunosorbent assay (ELISA). Study group consisted of 20 CRSwNP and 20 CRSsNP patients. Control group comprised of 20 volunteers who had been operated with septum deviation without any additional sinonasal pathology, allergy, systemic disease, or medication use. All groups preoperatively underwent paranasal CT examinations and sinonasal pathologies were recorded based on Lund-Mackay radiological staging system. IL-25 and IL-33 levels in serum and tissue samples were analyzed using the ELISA method. Serum IL-25 and IL-33 levels in CRSsNP, CRSwNP, and control groups did not differ statistically significantly (p = 0.345 and p = 0.338). Any statistically significant difference was not detected in mean tissue IL-25 levels among CRSsNP, CRSwNP, and control groups (p = 0.698). Mean tissue IL-33 level in the CRSwNP group was statistically significantly lower when compared with those of CRSsNP and control groups (p < 0.001 and p < 0.001, respectively). A statistically significant negative correlation was detected between tissue IL-33 levels and Lund-Mackay CT scores (r = -0.436 and p = 0.005). In the present study, we conceivably contributed to scarce number of studies conducted on this issue and we think that further studies will better clarify the role of IL-25 and IL-33 in the development of nasal polyps.