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Background: Aberrant deoxyribonucleic acid (DNA) contributes to inflammasome orchestrated progression of chronic inflammatory diseases like diabetes and periodontitis. The purpose of the present study was to estimate salivary levels of DNA sensing inflammasomes, absent in melanoma 2 (AIM2), interferon γ inducible protein (IFI16), and cytokine interleukin 18 (IL18) in individuals with periodontitis, diabetes, and healthy controls and interpret its association with periodontal and diabetic parameters. Methods: Salivary levels of AIM2, IFI16, and IL18 were estimated by enzyme linked immunosorbent assay (ELISA) in a total of 120 individuals (n = 30 in each group), namely, healthy (Group 1), periodontitis (Group 2), diabetes (Group 3), and diabetes with periodontitis (Group 4). Correlations of inflammasome levels and periodontal clinical parameters—plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment level (CAL), and periodontal inflamed surface area (PISA) were performed. Multiple regression was carried out to predict AIM2 and IFI16 with various independent variables. Results: The mean salivary levels of AIM2, IFI16, and IL18 were highest in diabetes with periodontitis (Group 4) and least in healthy (Group 1) and statistically significant between the groups (p = 0.000). Significant positive correlation between clinical periodontal parameters and AIM2, IFI16, and IL18 was present (p ≤ 0.05). Multiple regression showed glycated hemoglobin (HbA1C) (p = 0.002), GI (p = 0.016), PISA (p = 0.002), and CAL (p = 0.004) were significant predictors of AIM2, while HbA1C (p = 0.012), PISA (p = 0.003), and CAL (p = 0.007) predicted IFI16. Conclusion: The results of the present study showed higher levels of AIM2, IFI16, and IL18 in saliva of individuals with diabetes and periodontitis. HbA1C, PISA, and CAL were significant independent predictors of salivary AIM2 and IFI16 levels. [ABSTRACT FROM AUTHOR]

The inflammasome is a cytosolic multiprotein complex that plays a crucial role in inflammation and cell death. The sensor proteins in the inflammasome complex detect various microbial and endogenous stimuli, leading to subsequent caspase activation. The activation of caspases results in the maturation of pro‐inflammatory cytokines IL‐1β and IL‐18 or pyroptosis. Inflammasome dysfunction is associated with the pathogenesis of various diseases, including autoimmune disease and cancer. It appears that the interactions between the gut microbiota and the inflammasome play crucial roles in the gastrointestinal tract. The gut microbiota induces the expression and activation of inflammasome proteins, which contribute to both homeostasis and disease in the gut. Likewise, although controversial, mounting evidence suggests that inflammasome activation can modulate the composition of the gut microbiota, which, in turn, affects disease progression. In this review, we summarize the current concepts and recent insights linking the inflammasome and gut commensal microorganisms. We describe how the reciprocal interaction between the inflammasome and the commensal microbiota relates to physiological and pathophysiological consequences in the host. [ABSTRACT FROM AUTHOR]

Objectives: Accumulated evidence suggests that Pin1 contributes to oncogenesis of diverse cancers. However, the underlying mechanism of oncogenic function of Pin1 in PDAC requires further exploration. Materials and Methods: IHC was performed using PDAC tissues. Western blot, PCR, immunofluorescence and transwell were performed using cell lines. GSEA were applied for possible downstream pathways. ChIP assay and dual luciferase were used for assessment of transcriptional activity. Results: Both Pin1 and IL‐18 levels are increased in primary PDAC tissues and that their levels are positively correlated. High expression of IL‐18 is a predictor of poor prognoses. Pin1 promoted pancreatic cancer cell proliferation and motility by increasing IL‐18 expression, while Pin1 knockdown also inhibited the tumour‐promoting effect of IL‐18. Both Pin1 and IL‐18 could enhance the NFκB activity in pancreatic cancer cells. When bound to the p65 protein, Pin1 promoted p65 phosphorylation and its nuclear translocation. In the nucleus, Pin1 and p65 simultaneously bound to the IL‐18 promoter and enhanced IL‐18 transcription. In addition, recruitment of p65 to the IL‐18 promoter was decreased in Pin1‐silenced cells. Conclusions: Our study improves the understanding of Pin1 in tumour‐promoting inflammation in PDAC, which is a hallmark of cancer; Pin1 interacted with p65 in PDAC and enhanced NF‐κB signalling and downstream transcriptional activation of IL‐18, with increased IL‐18 continuously activating NF‐κB signalling, which then forms a positive feedback loop. [ABSTRACT FROM AUTHOR]

The diagnosis of acute kidney injury (AKI) is frequently established on modifications in serum creatinine (SCr). The discriminative and prognostic aptitudes of serum cystatin-C as well as N-acetylglucosaminidase (NAG) and Interleukin-18 (IL-18) were inspected for the estimation of AKI. In this study twelve rats were alienated into two groups: control group received saline, second group received cadmium chloride at a dose (2.4 mg Cd/kg/day, i.p) for 30 days. Blood urea nitrogen (BUN), SCr, and IL-18 serum level were measured in addition to serum and tissue content of cystatin-C and NAG. AKI model showed significant increase in BUN, creatinine, and IL-18. RT-PCR showed upregulation of cystatin-C gene besides significant increase of its level in serum. Additionally, tissue content of NAG was significantly increased. Our findings may provide that grouping of several biomarkers for diagnosis of AKI is a more valuable diagnostic tool than single-marker measurement. [ABSTRACT FROM AUTHOR]

ABSTRACT Autoimmune bullous diseases (AIBDs)-associated interstitial lung disease (ILD) is extremely rare. Pemphigus vulgaris (PV) is an intraepidermal autoimmune blistering disease caused by circulating autoantibodies against desmoglein. To date, PV-associated ILD has rarely been reported in English literature. We report a rare association of PV and ILD. A 53-year-old Chinese female with PV for 8 months developed ILD after a relapse of PV for 2 months due to discontinuation of oral prednisone by herself. She was successfully treated by systemic methylprednisolone. Taken previously reported bullous pemphigoid-associated ILD and linear IgA/IgG bullous dermatosis-associated ILD together, in general, AIBDs-associated ILD occurs when AIBDs relapse or are not controlled, responds well to systemic corticosteroids, and has a relatively better prognosis when compared with rheumatoid arthritis- or dermatomyositis-associated ILD. [ABSTRACT FROM AUTHOR]

ABSTRACT Most animal experiments on cosmetics safety are prohibited and since March 2013, this obligation includes sensitization tests. However, until now there has been no validated alternative in vitro method. In this work, 400 compounds used in the cosmetic industry were selected to cover the greatest diversity of structures, biological activities and sensitizing potential. These molecules were submitted to a series of tests aimed at reproducing essential steps in sensitization and to distinguish between sensitization and irritations, i.e., transcutaneous permeation (factor A), haptenation (factor B), sensitization cytokines production (factor C) and acute toxicity (factor D). The transcutaneous diffusion was measured on human skin explants using Franz cells. Haptenation was tested in solution on human serum albumin. Sensitization cytokine production was investigated by measurement of interleukin-18 release by keratinocytes. Acute toxicity was determined using an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide75 cell viability test. As only sufficiently stable, soluble and detectable compounds are usable, 33, 72, 68 and 68 molecules were finally tested on factors A, B, C and D, respectively, and 32 were completely screened by the four factors. The individual correlation of the four factors with the reference in vivo tests was limited but the combination of these factors led to a correlation between in vivo and in vitro assays of 81.2% and the safety of the test (risk of false negative) reached 96.8%. The techniques employed are simple and inexpensive and this model of four tests appears as a promising technique to evaluate in vitro the skin sensitization potential of unknown molecules. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Interleukin 18 (IL-18), a member of the IL-1 family of cytokines, is an important regulator of innate and acquired immune responses. It signals through its ligand-binding primary receptor IL-18Rα and accessory receptor IL-18Rβ. Here we report the crystal structure of IL-18 with the ectodomain of IL-18Rα, which reveals the structural basis for their specific recognition. It confirms that surface charge complementarity determines the ligand-binding specificity of primary receptors in the IL-1 receptor family. We suggest that IL-18 signaling complex adopts an architecture similar to other agonistic cytokines and propose a general ligand-receptor assembly and activation model for the IL-1 family. [ABSTRACT FROM AUTHOR]

Background and Aim Symptomatic gallstone disease ( SGSD) induced several inflammatory responses and affected extrahepatic bile ducts. Although the pathology and environmental risk factors of gallstone disease are well documented, immune or inflammatory responses in SGSD development are still inconclusive. Interleukin 18 ( IL18) is a pro-inflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of the induction of interferon-γ. In this study, we investigated whether polymorphisms of the IL18 gene were associated with SGSD susceptibility. Methods Genomic DNA was isolated from the whole blood samples of 445 patients with SGSD and 1121 gallstone-free controls. The IL18 rs549908 T> G, rs5744247 C> G, rs187238 G> C, rs1946518 T> G, and rs360719 A> G polymorphisms were genotyped using predeveloped TaqMan allelic discrimination assay. Results We found IL18 rs5744247 G allele conferred protection against SGSD in female patients (odds ratio = 0.75, corrected P-value = 0.015). Haplotype analysis revealed that TGGTA protected females from SGSD development (odds ratio = 0.75, corrected P-value = 0.02). Conclusions Based on our findings, IL18 rs5744247 C> G polymorphism could be a potential genetic marker to predict SGSD susceptibility in Han Chinese women. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (11): 994-1001 Background Interleukin 18(IL-18) is a pro-atherosclerotic cytokine. Elevated IL-18 levels and the genetic variation of the IL-18 have been previously linked with acute coronary events and cardiovascular mortality among patients with coronary artery disease (CAD). We studied the possible association between the IL-18 gene polymorphism and cardiovascular mortality during follow-up among Finnish patients who had undergone a clinical exercise stress test, in addition to the possible effect on the expression of angiography-verified CAD. Materials and methods A total of 2152 patients of the Finnish Cardiovascular Study (cohort study) were followed up for 6·3 years and cardiovascular mortality was recorded. Angiography was performed on 461 patients. Genotyping of five common single nucleotide polymorphisms (SNPs) of the IL-18 gene was performed using the 5′nuclease assay for allelic discrimination with the ABI Prism 7900HT Sequence Detection System. Results Among the study population, IL-18 gene polymorphism did not associate with cardiovascular mortality. According to adjusted binary regression analysis, the male carriers of one major haplotype (the only ones carrying the t allele of the +127 C/t SNP) had a lower occurrence rate for significant CAD defined as > 50% stenosis in at least one of the main branches of the coronary arteries (OR 0·495, 95% CI 0·862-0·284, P = 0·041). No associations were observed among women. The sex-by-genotype interaction was significant ( P = 0·033). Conclusions The IL-18 gene was not found to associate significantly with mortality. Among patients who had coronary angiography, one major haplotype of the IL-18 gene has a gender-dependent different impact on the expression of CAD. [ABSTRACT FROM AUTHOR]

Interleukin-18 (IL-18) is an inflammation-related cytokine that plays a central role both in innate defense reactions and in Th1 activation and specific immune responses. Increased levels of IL-18 can be detected in biological fluids and organs of individuals affected by several autoimmune pathologies, as well as in autoimmune animal models. In this review, the role of IL-18 in systemic lupus erythematosus (SLE) is critically examined, including its possible role in the pathogenesis of disease. In SLE, increased levels of IL-18 have been found in serum/plasma of affected persons, which positively correlated with disease severity. The possibility that circulating IL-18 levels are predictive of renal damage has been proposed, suggesting that IL-18 may be a prognostic marker of renal involvement useful to identify patients at risk of renal failure. The evaluation of urinary levels of free active IL-18 indeed suggests a correlation with the degree of renal involvement. The possible pathogenic role of IL-18 in lupus has been studied in a mouse model of progressive disease, which makes possible the identification, at the level of the different affected organs, of IL-18 changes preceding disease development and those appearing after disease onset. It can be concluded that IL-18 has a multifaceted role in autoimmune lupus, being apparently involved both in the effector phases of the late organ damage and, in some organs, in the initial pathogenic events. Therapeutic strategies targeting IL-18 in autoimmunity are under development. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic, inflammatory skin disease with a high prevalence and complex pathogenesis. The skin of AD patients is usually colonized by Staphylococcus aureus ( S. aureus); its exotoxins may trigger or enhance the cutaneous inflammation. Several mediators are related to the AD immune imbalance and interleukin-18 (IL-18), an inflammatory cytokine, may play a role in the atopic skin inflammation. Aims: To evaluate peripheral blood mononuclear cells (PBMC) proliferation response to staphylococcal enterotoxins A (SEA) and B (SEB) and the levels of IL-18 in adults with AD. Methods: Thirty-eight adult patients with AD and 33 healthy controls were analysed. PBMC were stimulated with SEA and SEB, phytohemaglutinin (PHA), pokeweed (PWM), tetanus toxoid (TT) and Candida albicans (CMA). IL-18 secretion from PBMC culture supernatants and sera were measured by ELISA. Results: A significant inhibition of the PBMC proliferation response to SEA, PHA, TT and CMA of AD patients was detected ( P ≤ 0.05). Furthermore, increased levels of IL-18 were detected both in sera and non-stimulated PBMC culture supernatants from AD patients ( P ≤ 0.05). Conclusions: A decreased PBMC proliferation response to distinct antigens and mitogens (TT, CMA, SEA and PHA) in adults with AD suggest a compromised immune profile. IL-18 secretion from AD upon stimulation was similar from controls, which may indicate a diverse mechanism of skin inflammation maintained by Staphylococcus aureus. On the other hand, augmented IL-18 secretion from AD sera and non-stimulated cell culture may enhance the immune dysfunction observed in AD, leading to constant skin inflammation. [ABSTRACT FROM AUTHOR]

To evaluate the balance of interleukin IL18 and its endogenous antagonist IL18 binding protein ( IL18BP) in patients with idiopathic thrombocytopenic purpura (ITP), plasma IL18, IL18BP, interferon gamma ( IFNG) and IL4 levels, as well as platelet counts were measured in patients with active ITP ( n = 23), ITP in remission ( n = 21) and in healthy subjects ( n = 24) by enzyme linked immunosorbent assay (ELISA). Using real-time quantitative polymerase chain reaction, the mRNA expression of IL18, IL18BP, IFNG, IL4, T-box ( TBX21) and GATA-binding protein 3( GATA3) were studied in all subjects. The results showed that IL18 and IFNG protein and mRNA levels were significantly increased in patients with active ITP than in control subjects, but that IL18BP were not significantly elevated in ITP patients, which resulted in an elevated ratio of IL18/IL18BP in patients with active disease. During remission stages, the levels of these cytokines were comparable to those of healthy controls. The elevated levels of IL18/IL18BP in plasma during active stages of disease suggest a possible role in the pathogenesis and course of ITP. [ABSTRACT FROM AUTHOR]

Background/Aims: Injury and activation of tubular proximal epithelial cells (TEC) play central roles in renal tubulointerstitial fibrosis (TIF), but its mechanisms remain obscure. Interleukin 18 (IL-18) is overproduced during chronic kidney diseases (CKD), but how IL-18 affects the biological behaviour of TEC is not clear. The aim of the present study is to reveal the role of IL-18 in renal TIF. Methods: The expressions of IL-18 and IL-18 receptor in TEC were detected by immunohistochemical staining in vivo and by reverse transcriptase polymerase chain reaction (RT-PCR) in vitro. TEC line (HK-2 cells) were incubated without or with IL-18. Cell proliferation and cell cycle were evaluated by methyl thiazolyl tetrazolium assay and flow cytometric analysis, respectively. Cell apoptosis was assessed by Hoechst 33258 staining. Expression of α-smooth muscle actin was evaluated by RT-PCR, immunocytochemical staining and flow cytometric analysis, respectively. Type I collagen, fibronectin, MCP-1 and RANTES in cultured supernatants were measured by enzyme-linked immunosorbent assay. Results: IL-18 expression in TEC increased significantly in CKD state. IL-18 receptor was constitutively expressed in normal proximal TEC, and its expression increased strongly in CKD state. Proliferation and cell cycle of HK-2 cells were not affected by IL-18. Cell apoptosis, α-smooth muscle actin expression, type I collagen and fibronectin production as well as MCP-1 secretion were promoted by IL-18 in dosage- and/or time-dependent manners, but RANTES secretion was not affected. Conclusion: IL-18 may play a crucial role in the process of TIF by promoting TEC injury and activation, and could be a target of the therapeutic approaches against TIF. [ABSTRACT FROM AUTHOR]

The aim of this work was to analyse apoptosis rate, measured by the serum levels of proapoptotic interleukin (IL)-18 and of soluble Fas (sFas), as well as of anti-inflammatory IL-10, in patients with chronic hepatitis C, at baseline and after treatment with interferon alpha and ribavirin. Twenty-seven patients with biopsy-proven chronic hepatitis C were studied, at baseline and after treatment with interferon alpha (21 cases) or pegylated interferon (6 cases) plus ribavirin. A group of 15 healthy sex- and age-matched individuals was selected as control. Serum concentrations of sFas, IL-10 and IL-18 were determined by ELISA in sandwich. The relationship of these molecules to necro-inflammatory and fibrotic activity was evaluated. Evolution of the serum concentrations of these molecules was analysed after treatment. Significantly increased serum concentrations of sFas were detected in patients with chronic hepatitis, compared with controls. Levels of this molecule were significantly correlated with necroinflammatory activity. Likewise, concentrations of IL-10 were significantly increased in the group of patients, compared with controls. Treatment with interferon and ribavirin induced a significant decrease of IL-18 concentration independently of the viral response. In contrast, levels of sFas decreased only in those patients with sustained response to therapy. Finally, baseline levels of IL-10 were significantly increased in patients without response to treatment, compared with those with sustained response, but the concentration did not change with the treatment. Increased serum levels of IL-10 are a negative prognostic marker of response to hepatitis C treatment. A significant decrease of apoptotic rate, as determined by sFas, can be expected in patients with a response to therapy. [ABSTRACT FROM AUTHOR]

A homologue of interleukin 18 has been identified from rainbow trout, Oncorhynchus mykiss. The trout IL-18 gene spans 3.7 kb and consists of six exons and five introns, sharing the same gene organization with its human counterpart. The putative translated protein is 199 amino acids in length with no predicted signal peptide. Analysis of the multiple sequence alignment reveals a conserved ICE cut site, resulting in a mature peptide of 162 amino acids. The trout IL-18 shares 41­45% similarity with known IL-18 molecules and contains an IL-1 family signature motif. It is constitutively expressed in a wide range of tissues including brain, gill, gut, heart, kidney, liver, muscle, skin and spleen. Transcription is not modulated by lipopolysaccharide, poly(I:C) or trout recombinant IL-1β in primary head kidney leucocyte cultures and RTS-11 cells, a macrophage cell line. However, expression is downregulated by lipopolysaccharide and rIL-1β in RTG-2 cells, a fibroblast-like cell line. An alternatively spliced form of IL-18 mRNA has also been found and translates into a 182 amino acid protein with a 17 amino acid deletion in the precursor region of the authentic form. This alternatively spliced form is also widely expressed although much lower than the authentic form. Interestingly, its expression is upregulated by lipopolysaccharide and poly(I:C), but is not affected by rIL-1β in RTG-2 cells. The present study suggests that alternative splicing may play an important role in regulating IL-18 activities in rainbow trout. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation (BMT) is mediated by grafted T lymphocytes after their polarization into type 1 T cells. Interleukin (IL)-18, a novel immunoregulatory cytokine, strongly stimulates type 1 T cells, therefore we postulated that IL-18 may be involved in the pathogenesis of aGVHD. Using an enzyme-linked immunosorbent assay (ELISA), we serially measured serum levels of IL-18 in 37 patients with haematological malignancy before and after allogeneic BMT. Patients with aGVHD had high levels of IL-18 that strongly correlated with the severity of aGVHD. We also found that they showed reduced serum levels of IL-18 after appropriate treatment or at a state of resolution. IL-18 levels were not affected by the pretransplant regimen, engraftment or bacterial infection. Compared with circulating interferon (IFN)-γ or IL-12 levels, serum levels of IL-18 showed a more sensitive and specific correlation with the disease status of aGVHD. These findings suggest that IL-18 may play important roles in the pathogenesis of aGVHD and that measurement of serum IL-18 levels can be useful indicator of aGVHD. [ABSTRACT FROM AUTHOR]