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INTERLEUKIN 18 PROPROTEIN
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1: Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2010 Aug, 30(8)
[Relationship between liver damage and serum levels of IL-18, TNF-alpha and NO in patients with acute pancreatitis.]
[Abstract]OBJECTIVE: To study the relationship between liver damage and the serum levels of interleukin-18 (IL-18), tumor necrosis factor-alpha (TNF-alpha) and NO in patients with acute pancreatitis (AP). METHODS: Eighty-seven AP patients were divided into mild AP (MAP) and severe AP (SAP) groups, with 50 healthy subjects serving as the controls. The serum levels of IL-18 and TNF-alpha were determined by ELISA, and NO level was measured by nitrate reductase method. The serum levels of ALT, AST, TB, ALB, LDH, AKP and gamma-GT were also measured. RESULTS: The incidence of liver damage was 62.06% in these patients. The serum markers of the liver function differed significantly between the AP patients and the control subjects and between SAP and MAP groups before the treatment (P<0.01). The ALB level in SAP group increased significantly after the treatment (P<0.01), and the other indices of the liver function all decreased in both MAP and SAP groups (P<0.01). The serum levels of IL-18, TNF-alpha and NO were higher in the AP patient than in the control subjects (P<0.01), and decreased significantly after the treatment (P<0.01). In AP patients with liver damage, the levels of IL-18, TNF-alpha and NO were obviously higher than those in patients without liver damage and the control group (P<0.01). In AP patients with liver damage, the serum levels of IL-18, TNF-alpha, and NO were positively correlated to ALT and AST levels, and IL-18 was positively correlated to TNF-alpha and NO. CONCLUSION: AP patients have high incidence of liver damage, which is obviously severer in SAP than in MAP patients. The serum levels of IL-18, TNF-alpha and NO are positively correlated to the severity of liver damage in the AP patients, and can be used as indictors for early diagnosis, evaluation of the severity and prognosis of liver damage.
2: Nephron. Experimental nephrology, 2010 Jul 28, 116(4)
Stimulation of Mesangial Cells by Angiotensin II and Lipopolysaccharide Increases Expression of Interleukin-18, but Not IL-18 Receptor.
[Abstract]Background/Aims: Mesangial cell (MC) hyperplasia is associated with several kidney diseases. Experimental studies confirm upregulation of IL-18 in glomerular disease and renal allograft rejection. We evaluated whether MCs express IL-18 and IL-18 receptor-alpha (IL-18Ralpha) with and without stimulation by LPS, AngII and PDGF. Methods: Glomeruli were isolated using Dynabeads perfusion. MCs were cultured by glomerular explantation. IL-18 and IL-18Ralpha expression were detected by RT-PCR, ELISA and flow cytometry. Results: Significantly higher levels of IL-18 expression were detected in isolated glomeruli, compared to cortical tissue devoid of glomeruli, and in MCs, compared to tubular cells (both p < 0.01). Increased IL-18 expression was detected in MCs, but not podocytes, endothelial cells or tubular cells in response to LPS stimulation. IL-18 mRNA and protein expression were significantly upregulated by AngII (p < 0.05) and LPS (p < 0.01), but not PDGF-BB, in primary MCs and a MC line (MES13). IL-18Ralpha mRNA was almost undetectable in MCs treated with or without LPS, AngII and PDGF-BB. IL-18Ralpha protein was not detected by flow cytometry. Conclusions: MCs express IL-18, which was significantly increased after LPS and AngII stimulation, but do not express appreciable levels of IL-18Ralpha. MC-derived IL-18 is unlikely to be an autocrine mediator in glomerular disease given the lack of IL-18Ralpha.
3: Molecular medicine (Cambridge, Mass.), 2010 Jul 12, 89(1)
Overexpression of IL-18 Aggravates Cardiac Fibrosis and Diastolic Dysfunction in Fructose-fed Rats.
[Abstract]Inflammation plays an important role in the pathophysiology of metabolic syndrome (MS). We determined whether the overexpression of interleukin-18 (IL-18) could aggravate left ventricular (LV) remodeling and diastolic dysfunction in fructose-fed rats (FFRs). To create an animal model for MS, male Wistar rats received 10% fructose in water for eight months. We used an adenovirus encoding rat IL-18 to overexpress IL-18 in FFRs by intravenous administration. IL-18 overexpression led to increases in collagen volume fraction (CVF) and collagen deposition. LV systolic function was unaltered. But the LV end-diastolic pressure (LVEDP) and the time constant of isovolumic relaxation (tau) were increased. Peak negative value of time derivative of LV pressure (-dp/dt) was decreased. Isovolumic relaxation time (IVRT) and myocardial index (MI) as assessed by echocardiography were increased. Overexpression of IL-18 leads to aggravate LV remodeling and dysfunction in FFRs. Attenuation of inflammatory process may provide a novel therapeutic strategy in treating metabolic cardiomyopathy.
4: Journal of immunology (Baltimore, Md. : 1950), 2010 Jul 19, 89(1)
Inflammation in the CNS and Th17 Responses Are Inhibited by IFN-{gamma}-Induced IL-18 Binding Protein.
[Abstract]Inflammatory responses are essential for immune protection but may also cause pathology and must be regulated. Both Th1 and Th17 cells are implicated in the pathogenesis of autoimmune inflammatory diseases, such as multiple sclerosis. We show in this study that IL-18-binding protein (IL-18bp), the endogenous inhibitor of the Th1-promoting cytokine IL-18, is upregulated by IFN-gamma in resident microglial cells in the CNS during multiple sclerosis-like disease in mice. Test of function by overexpression of IL-18bp in the CNS using a viral vector led to marked reduction in Th17 responses and robust inhibition of incidence, severity, and histopathology of disease, independently of IFN-gamma. The disease-limiting action of IL-18bp included suppression of APC-derived Th17-polarizing cytokines. IL-18bp thus acts as a sensor for IFN-gamma and can regulate both Th1 and Th17 responses in the CNS.
5: Medical oncology (Northwood, London, England), 2010 May 20, 24(4)
Review and pooled analysis of studies on -607(C/A) and -137(G/C) polymorphisms in IL-18 and cancer risk.
[Abstract]Interleukin-18 (IL-18) is a pleiotropic, pro-inflammatory cytokine with dual effects on tumor development and progression. The -607(C/A) and -137(G/C) polymorphisms in IL-18 gene region have been implicated in cancer risk; however, data from published studies with individually low statistical power are conflicting. To clarify the role of IL-18 -607(C/A) and -137(G/C) genotype in global cancer, we examined all the available published studies through a pooled analysis approach. Overall, IL-18 -607A allele was associated with increased total cancer risk when compared with -607C allele (OR = 1.14, 95% CI = 1.01-1.28, P = 0.010), as well as in the heterozygote comparison (OR = 1.10, 95% CI = 1.04-1.15, P = 0.256) and the dominant model (OR = 1.07, 95% CI = 1.03-1.11, P = 0.124). Furthermore, IL-18 -137(G/C) polymorphism was associated with increased nasopharyngeal carcinoma risk. In the stratified analysis for -607(C/A) polymorphism, a significantly increased cancer risk in Asian population was found, as well as subgroup in source of control. Similar results were found in the stratified analysis for -137(G/C) polymorphism. Our pooled analysis supported that IL-18 is a good candidate for large-scale epidemiological case-control studies that may be a low-penetrance susceptibility biomarker for cancer.
6: Journal of immunology (Baltimore, Md. : 1950), 2010 Mar 29, 44(2)
Activation of Naive NK Cells in Response to Listeria monocytogenes Requires IL-18 and Contact with Infected Dendritic Cells.
[Abstract]The mechanisms for NK cell activation during infection by intracellular bacterial pathogens are not clearly defined. To dissect how Listeria monocytogenes infection elicits NK cell activation, we evaluated the requirements for activation of naive splenic NK cells by infected bone marrow-derived dendritic cells (BMDCs). We found that NK cell activation in this setting required infection of BMDCs by live wild type bacteria. NK cells were not activated when BMDCs were infected with a live hemolysin deficient (Deltahly) strain. Neutralization of IL-12, TNF-alpha, or caspase-1 each dramatically reduced NK cell IFN-gamma production in response to live wt L. monocytogenes infection. Addition of recombinant IL-18, but not IL-1beta, reversed the effects of caspase-1 inhibition. Recombinant IL-18 also restored NK cell activation by BMDCs infected with Deltahly L. monocytogenes, which produced IL-12 but not IL-18. IL-18 acted on NK cells because MyD88 expression was required in responding NK cells, but not infected BMDC. However, secreted cytokines were not sufficient for activation of naive NK cells by infected BMDCs. Rather, NK cell activation additionally required contact between infected BMDCs and NK cells. These data suggest that the activation of NK cells during L. monocytogenes infection requires both secreted cytokines and ligation of NK activating receptors during direct contact with infected DCs.
7: Journal of clinical immunology, 2010 Mar 27, 44(2)
TL1A Selectively Enhances IL-12/IL-18-Induced NK Cell Cytotoxicity against NK-Resistant Tumor Targets.
[Abstract]INTRODUCTION: TL1A (TNFSF15) augments IFN-gamma production by IL-12/IL-18 responsive human T cells. Its ligand, death domain receptor 3 (DR3), is induced by activation on T and NK cells. Although IL-12/IL-18 induces DR3 expression on most NK cells, addition of TL1A minimally increases IFN-gamma production. METHODS: (51)Chromium release and flow cytometric analysis were used to determine whether the TL1A-DR3 pathway is implicated in tumor cell lysis. Our aim was to determine whether the TL1A-DR3 pathway is implicated in tumor cell lysis. RESULTS: TL1A had no additional effect on IL-12/IL-18-induced cytotoxicity against an NK-susceptible tumor (K562); however, it promoted cytotoxicity against NK-resistant targets susceptible to lysis only by activated NK cells. DISCUSSION: With IL-12/IL-18 activation, TL1A increased CD107a expression on NK cells which led to enhanced lysis of Daudi by PBMC and purified NK cells. To a lesser degree, TL1A increased lysis of colorectal adenocarcinoma epithelial derived lines (WiDr and SW837) by IL-12/IL-18-activated cells. CONCLUSION: TL1A increased cytotoxicity of IL-12/IL-18-activated NK cells against target cells dependent on NK activation for lysis and could function in vivo as a key co-activator of NK cytotoxicity.
8: Arthritis research & therapy, 2010 Mar 23, 12(2)
Association between IL-18 gene polymorphisms and biopsy-proven giant cell arteritis.
[Abstract]ABSTRACT: INTRODUCTION: The objective was to investigate the potential implication of the IL18 gene promoter polymorphisms in the susceptibility to giant cell arteritis (GCA). METHODS: A total of 212 patients diagnosed with biopsy-proven GCA were included in this study. DNA from patients and matched controls was obtained from peripheral blood. Samples were genotyped for the IL18 -137 G>C (rs187238), the IL18 -607 C>A (rs1946518) and the IL18-1297 T>C (rs360719) gene polymorphisms by polymerase chain reaction, using a pre-designed TaqMan allele discrimination assay. RESULTS: No significant association between the IL18 -137 G>C polymorphism and GCA was found. However, the IL18 -607 allele A was significantly increased in GCA patients compared to controls (47.8% vs. 40.9% in patients and controls respectively; P= 0.02; OR: 1.32; 95% CI 1.04 to 1.69). It was due to an increased frequency of homozygosity for the IL18 -607 A/A genotype in patients with GCA (20.4%) compared to controls (13.4%) (IL18 -607 A/A versus IL18 -607 A/C plus IL18 -607 C/C genotypes: P= 0.04; OR: 1.59; 95% CI 1.02 to 2.46). Also, the IL18-1297 allele C was significantly increased in GCA patients (30.7%) compared to controls (23.0%) (P= 0.003; OR: 1.48; 95% CI 1.13 to 1.95). In this regard, an increased susceptibility to GCA was observed in individuals carrying the IL18-1297 C/C or the IL18-1297 C/T genotypes compared to those carrying the IL18-1297 T/T genotype (IL18-1297 C/C plus IL18-1297 T/C versus IL18-1297 T/T genotype in GCA patients compared to controls: P= 0.005; OR: 1.61; 95% CI: 1.15 to 2.25). We also found an additive effect of the IL18 -1297 and -607 polymorphisms with TLR4 Asp299Gly polymorphism. The OR for GCA was 1.95 for combinations of genotypes with one or two risk alleles, whereas carriers [greater than or equal to] 3 risk alleles have an OR of 3.7. CONCLUSIONS: Our results show for the first time an implication of IL18 gene promoter polymorphisms in the susceptibility to biopsy-proven GCA. In addition, an additive effect between the associated IL18 and TLR4 genetic variants was observed.
9: Infection and immunity, 2010 Mar 15,
YopJ-promoted cytotoxicity and systemic colonization is associated with higher levels of murine IL-18, IFN{gamma} and neutrophils in a live vaccine model of Yersinia pseudotuberculosis infection.
[Abstract]Several Yersinia species have been utilized as live attenuated vaccines to prime protective immunity against Yersiniae and other pathogens. A type III secretion system effector known as YopJ in Y. pseudotuberculosis and Y. pestis and YopP in Y. enterocolitica has been shown to regulate host immune responses to live Yersinia vaccines. YopJ/P kills macrophages and dendritic cells, reduces their production of TNFalpha and IL-12, and promotes systemic colonization in mouse models of intestinal Yersinia infection. Furthermore, YopP activity decreases antigen presentation by dendritic cells, and a yopP mutant of a live Y. enterocolitica carrier vaccine elicited effective priming of CD8 T cells to a heterologous antigen in mice. These results suggest that YopJ/P activity suppresses both innate and adaptive immune responses to live Yersinia vaccines. Here, a sublethal intragastric mouse infection model using wild-type and catalytically inactive yopJ mutant strains of Y. pseudotuberculosis was developed to further investigate how YopJ action impacts innate and adaptive immune responses to a live vaccine. Surprisingly, YopJ-promoted cytotoxicity and systemic colonization was associated with significant increases in neutrophils in spleens and the pro-inflammatory cytokines IL-18 and IFNgamma in serum of mice vaccinated with Y. pseudotuberculosis. Secretion of IL-18 accompanied YopJ-mediated killing of macrophages infected ex vivo with Y. pseudotuberculosis, suggesting a mechanism by which this effector directly increases pro-inflammatory cytokine levels in vivo. Mice vaccinated with the wild-type or yopJ mutant produced similar levels of antibodies to Y. pseudotuberculosis antigens and were equally resistant to lethal intravenous challenge with Y. pestis. The findings indicate that a pro-inflammatory, rather than anti-inflammatory, process accompanies YopJ-promoted cytotoxicity, leading to increased systemic colonization by Y. pseudotuberculosis and potentially enhancing adaptive immunity to a live vaccine.
10: Clinical rheumatology, 2010 Feb 8,
Expressions of IL-18 and its binding protein in peripheral blood leukocytes and kidney tissues of lupus nephritis patients.
[Abstract]To investigate the expressions of IL-18 and its binding protein (IL-18BP) in peripheral blood leukocytes and kidney tissues in patients with lupus nephritis (LN). SYBR-green-dye-I-based real-time quantitative PCR method was used to compare the gene expression levels (indicated as 2(-DeltaDeltaCT) value) of IL-18 and IL-18BP in the peripheral blood leucocytes of LN patients and those in normal controls. Serum levels of IL-18 were measured with ELISA method. Immunohistochemical evaluation of IL-18 and Il-18BP expression in LN was carried out on frozen renal biopsy sections. IL-18BP mRNA expression levels in LN patients were significantly lower than those of normal controls (P < 0.01). Serum levels of IL-18 in LN patients were significantly higher than those of normal controls (P < 0.01). It is noticeable that serum IL-18 levels in the patients treated with glucocorticoids and cyclophosphamide was lower than those treated with glucocorticoids only or glucocorticoids and other immune inhibitors such as chloroquine/hydroxychloroquine and azathioprine. Expression of IL-18 in renal glomeruli was higher in type-IV and type-V LN patients than in type-III LN patients. LN patients present lower IL-18BP mRNA expression and higher serum levels of IL-18 than those in normal controls. The preponderance of IL-18 in glomeruli from LN patients indicates IL-18 may be concerned with the local inflammation. Up-regulation of IL-18BP expression and control of the biological activity of IL-18 may be a therapeutic approach to LN patients.
11: Arthritis and rheumatism, 2010 Jan 7, 23(1)
Blocking ERK1/2 reduces TNF-alpha-induced-IL-18 bioactivity in rheumatoid arthritis synovial fibroblasts by induction of IL-18BPa Role of ERK1/2 in IL-18 bioactivity regulation.
[Abstract]OBJECTIVE.: To examine the mechanism of regulation of interleukin-18 (IL-18) bioactivity by IL-18 binding protein (IL-18BP) induction. METHODS.: Levels of IL-18 and IL-18BPa expression were determined by enzyme-linked immunosorbent assays (ELISA) in osteoarthritis (OA) and rheumatoid arthritis (RA) synovial fluids, followed by free IL-18 calculation. IL-18 and IL-18BPa synthesis in RA synovial fibroblasts treated with pro- and anti-inflammatory cytokines were assessed by qRT-PCR and ELISA, respectively, followed by IL-18 bioactivity determination using KG-1 cells. Chemical signaling inhibitors and antisense oligonucleotides were used for validation of the signal transduction pathways involved in IL-18BPa/IL-18 regulation. TNF-alpha-induced caspase-1 activity was determined by a colorimetric assay. RESULTS.: IL-18BPa was lower in RA synovial fluid than in OA synovial fluid (n=8; P < 0.05) and free IL-18 was higher in RA synovial fluid than in OA synovial fluid. TNF-alpha induced RA synovial fibroblast IL-18BPa and IL-18 in a time dependent manner (P < 0.05). Evaluation of signaling pathways suggested that TNF-alpha induced IL-18 production through extracellular signal-regulated kinases (ERK)1/2, protein kinase C (PKC)delta, and Src pathways, whereas IL-18BPa synthesis was mediated through nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB), PKC, Src, and c-Jun N-terminal kinases (JNK) pathways. Furthermore, addition of exogenous IL-18BPa-Fc reduced the RA synovial fibroblast phosphorylation of ERK1/2 induced by TNF-alpha. CONCLUSION.: These results suggest that IL-18BPa reduces IL-18 bioactivity induced by TNF-alpha, by regulating the ERK1/2 pathway in RA synovial fibroblasts. Targeting IL-18 bioactivity by induction or addition of IL-18BPa may provide another therapeutic option in the management of RA.
12: Viral immunology, 2010 Feb, 23(1)
Serum IL-18 and IL-18BP Levels in Patients with Chikungunya Virus Infection.
[Abstract]Abstract Chikungunya virus infection has recently emerged in several countries. The inflammatory response is suggested to be involved in the pathology observed in this infectious disease. Interleukin-18 (IL-18) is an inducer of interferon-gamma (IFN-gamma) production and has been shown to play a role in several inflammatory diseases. IL-18 binding protein (IL-18BP) is a natural regulator of IL-18. In this study, we determined the levels of IL-18 and IL-18BP in patients with Chikungunya virus infection. Acute and convalescent sera were collected from each patient. The levels of both IL-18 and IL-18BP were measured by ELISA assays. IL-18 and IL-18BP levels were higher in patients than in controls. In addition, the level of IL-18 was higher in convalescent than in acute sera. However, the level of IL-18BP was lower in convalescent than in acute sera. These data suggest that production of both IL-18 and IL-18BP was induced following Chikungunya virus infection. IL-18BP was increased to regulate the activity of IL-18. The ratio of IL-18 to IL-18BP was higher in convalescent than in acute sera. The lower level of IL-18BP in convalescent sera was probably due to loss following IL-18 neutralization. Our data suggest that Chikungunya virus infection promotes the T helper-1 (Th-1) response by inducing IL-18 production. Manipulation of IL-18 and IL-18BP levels could be a promising therapeutic approach to alleviate symptoms in patients with Chikungunya virus infection.
13: The Journal of investigative dermatology, 2009 Oct 29, 32(5)
IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway.
[Abstract]Excessive accumulation of collagen contributes to the fibrotic process. Several experimental studies have shown that IFN-gamma is effective in preventing fibrogenesis. IL-18, originally identified as an IFN-gamma-inducing factor, is a key mediator of inflammation and host defense responses. In this study, we investigated the regulatory effect of IL-18 on the expression of type I and III collagen genes in dermal fibroblasts. The exposure of human dermal fibroblasts (HDFs) to IL-18 resulted in a reduction of collagen gene expression and production. Also, IL-18 inhibited the fibrogenic cytokine transforming growth factor (TGF)-beta-induced collagen gene expression. Next, to determine the molecular mechanism involved in this regulation, we showed that IL-18-regulated collagen expression was blocked by small interfering RNA (siRNA)-mediated Ets-1 knockdown. Furthermore, we showed that IL-18 induced phosphorylation of extracellular signal-regulated kinase (ERK) within 10 minutes and that the ERK inhibitor PD98059 blocked the inhibitory effect of IL-18. IL-18 also inhibited the production of collagen in systemic sclerosis (SSc) dermal fibroblasts. Our data indicate that IL-18 downregulates collagen production in HDF directly via Ets-1 and the ERK pathway, suggesting that IL-18 may exert antifibrotic activities in dermal fibroblasts.Journal of Investigative Dermatology advance online publication, 29 October 2009; doi:10.1038/jid.2009.302.
14: Journal of reproductive immunology, 2009 Oct 21, 32(5)
Modulation of innate immunity by IL-18.
[Abstract]IL-18 is expressed in various reproductive organs and its expression in the uterus fluctuates in linkage with menstrual cycle, implantation, pregnancy and delivery. However, the roles of this cytokine in reproduction remain obscure. IL-18 is a pleiotropic cytokine and exerts apparently complicated and sometimes paradoxical functions in immune and inflammatory responses, and a consensus understanding of its action has not been attained. Recent investigations reveal that IL-18 activates anti-apoptotic signals and promotes both survival and proliferation of activated lymphocytes as well as various cells exposed to different stressors. Especially, IL-18 enhances the expansion of NK and gammadelta T cells isolated from the circulation and stimulated in various ways. The expansion of gammadelta T cells, stimulated by zoledronate and IL-2, was strongly promoted by exogenous IL-18 and was inhibited by neutralizing anti-IL-18 receptor antibody. The expansion of gammadelta T cells was coincident with an increased number of CD11c+ cells. The gammadelta T cells that expanded in the presence of zoledronate, IL-2 and IL-18 exhibited the phenotype of effector memory cells characterized as CD44+ CD27- CD45RA- cells. In addition, they expressed NKG2D, perforin, CD94, CD25 and CD122, and 30-40% of them were positive for CD56. Incubation of expanded gammadelta T cells with IL-18 induced production of GM-CSF, IFNgamma and TNFalpha at much higher levels than those incubated without IL-18. They showed strong cytotoxicity against tumor cells, including mesothelioma cells, and inhibited growth of mesothelioma xenografts in mice. These observations suggest that IL-18 can efficiently promote expansion of gammadelta T cells with potent cytotoxicity.
15: Journal of immunotherapy (Hagerstown, Md. : 1997), 2009 Oct 6,
IL-18 Paradox in Pancreatic Carcinoma: Elevated Serum Levels of Free IL-18 are Correlated With Poor Survival.
[Abstract]The role of the proinflammatory interleukin (IL)-18 in cancer progression remains controversial; we thus examined the hypothesis that impaired antitumor immune response in pancreatic carcinoma patients is related to elevated levels of its natural inhibitor IL-18 binding protein (BP) and/or to alteration in the IL-18 receptor complex expression and function. IL-18 and IL-18 binding protein isoform a (BPa) was assessed in pancreatic carcinoma patients at various disease stages, and after surgery/chemotherapy; free bioactive IL-18 concentrations were calculated. IL-18 receptor complex expression in lymphocyte subsets was analyzed and signaling function was assessed versus healthy donors. Carcinoma cells exhibited below normal IL-18BPa expression and above normal IL-18 expression. Circulating IL-18BPa and IL-18 were above controls. Unexpectedly, free unbound IL-18 serum levels were correlated with disease severity and poor survival. IL-18BPa levels were unchanged by surgery but free IL-18 levels were elevated. Gemcitabine with 5-fluorouracile or oxaliplatin, but not alone, increased IL-18 and free IL-18 levels statistically significantly, without affecting IL-18BPa. Spontaneous/induced IL-18 receptor alpha and receptor beta expression in peripheral blood lymphocyte subsets from patients with advanced disease were near-normal, although CD4 and CD8 cells were fewer in percentage, and fully functional in inducing interferon-gamma. IL-18 is proposed as novel adjuvant cancer therapy, but free IL-18 levels are increased in the blood of pancreatic carcinoma patients, despite elevated IL-18BP levels, and are associated with poor survival; this highlights recent experimental insights into the prometastatic and proangiogenic effects of IL-18, and suggests that careful preclinical studies are needed to determine the proper application of IL-18 in cancer therapy.
16: Immunological investigations, 2009, 38(3-4)
TLR4 and IL-18 gene variants in chronic periodontitis: impact on disease susceptibility and severity.
[Abstract]The aim of the study was to assess whether genotypes in the Toll-like receptor 4 gene and in the promoter of the interleukin-18 gene are associated with the susceptibility to chronic periodontitis. 108 chronic periodontitis patients and 76 controls were genotyped for c.896A>G/1196C>T (TLR4 gene) and for c.-368G>C/ c.-838C>A (IL-18 promoter). There were no significant differences in genotype and allele distributions between the study groups. Periodontitis severity in patients with TLR4 c.896AG/1196CT genotype was significantly higher than wildtype carriers. The percentage of teeth with clinical attachment loss > or = 5 mm was 77.3% and 58.8%, respectively (p < or = 0.006, t-test). All subjects were further classified into carriers and non-carriers of at least one variant of each gene. A logistic regression analysis adjusted for gender, smoking, and age showed no association between gene variant carrier status and periodontitis (OR = 1.98, 95% CI 0.61-6.39). The results did not show that IL-18 and TLR4 variants have an effect on the susceptibility to chronic periodontitis. Considering the low number of periodontitis patients carrying TLR4 variants (11%), a comparison of the periodontitis severity depending on the genotype has to be interpreted cautiously.
17: Proceedings of the National Academy of Sciences of the United States of America, 2009 Oct 13, 106(41)
IL-18 binding protein-expressing mesenchymal stem cells improve myocardial protection after ischemia or infarction.
[Abstract]IL-18 is a proinflammatory cytokine known to cause tissue injury by inducing inflammation and cell death. Increased levels of IL-18 are associated with myocardial injury after ischemia or infarction. IL-18-binding protein (IL-18BP), the naturally occurring inhibitor of IL-18 activity, decreases the severity of inflammation in response to injury. In the present study, mesenchymal stem cells (MSCs) derived from mice transgenic for over expression of human IL-18BP were tested in rat models of global myocardial ischemia and acute myocardial infarction. Improved myocardial function is associated with production of VEGF, and in vitro, IL-18BP MSCs secreted higher levels of constitutive VEGF compared to wild-type MSCs. Whereas IL-18 increased cell death and reduced VEGF in wild-type MSCs, IL-18BP MSCs were protected. In an isolated heart model, intracoronary infusion of IL-18BP MSCs before ischemia increased postischemic left ventricular (LV) developed pressure to 79.5 + or - 9.47 mmHg compared to 59.3 + or - 7.8 mmHg in wild-type MSCs and 37.8 + or - 5 mmHg in the vehicle group. Similarly, using a coronary artery ligation model, intramyocardial injection of IL-18BP MSCs improved LV ejection fraction to 67.8 + or - 1.76% versus wild-type MSCs (57.4 + or - 1.33%) and vehicle (39.2 + or - 2.07%), increased LV fractional shortening 1.25-fold over wild-type MSCs and 1.95-fold over vehicle, decreased infarct size to 38.8 + or - 2.16% compared to 46.4 + or - 1.92% in wild-type MSCs and 60.7 + or - 2.2% in vehicle, reduced adverse ventricular remodeling, increased myocardial VEGF production, and decreased IL-6 levels. This study provides the concept that IL-18BP genetically modified stem cells improve cardioprotection over that observed with unmodified stem cells.
18: Breast cancer research and treatment, 2009 Oct 3, 106(41)
Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-alpha in a model of metastatic breast cancer.
[Abstract]Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy.
19: Journal of the American Society of Nephrology : JASN, 2009 Sep 17, 128(1 Suppl)
IL-18 and Urinary NGAL Predict Dialysis and Graft Recovery after Kidney Transplantation.
[Abstract]Current methods for predicting graft recovery after kidney transplantation are not reliable. We performed a prospective, multicenter, observational cohort study of deceased-donor kidney transplant patients to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL), IL-18, and kidney injury molecule-1 (KIM-1) as biomarkers for predicting dialysis within 1 wk of transplant and subsequent graft recovery. We collected serial urine samples for 3 d after transplant and analyzed levels of these putative biomarkers. We classified graft recovery as delayed graft function (DGF), slow graft function (SGF), or immediate graft function (IGF). Of the 91 patients in the cohort, 34 had DGF, 33 had SGF, and 24 had IGF. Median NGAL and IL-18 levels, but not KIM-1 levels, were statistically different among these three groups at all time points. ROC curve analysis suggested that the abilities of NGAL or IL-18 to predict dialysis within 1 wk were moderately accurate when measured on the first postoperative day, whereas the fall in serum creatinine (Scr) was not predictive. In multivariate analysis, elevated levels of NGAL or IL-18 predicted the need for dialysis after adjusting for recipient and donor age, cold ischemia time, urine output, and Scr. NGAL and IL-18 quantiles also predicted graft recovery up to 3 mo later. In summary, urinary NGAL and IL-18 are early, noninvasive, accurate predictors of both the need for dialysis within the first week of kidney transplantation and 3-mo recovery of graft function.
20: Immunology, 2009 Sep, 128(1 Suppl)
A synergistic interferon-gamma production is induced by mouse hepatitis virus in interleukin-12 (IL-12)/IL-18-activated natural killer cells and modulated by carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a receptor.
[Abstract]The production of interferon-gamma (IFN-gamma) by infiltrating natural killer (NK) cells in liver is involved in the control of mouse hepatitis virus (MHV) infection. The objectives of this study were to identify the mechanisms used by MHV type 3 to modulate the production of IFN-gamma by NK cells during the acute hepatitis in susceptible C57BL/6 mice. Ex vivo and in vitro experiments revealed that NK cells, expressing carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a (the MHV receptor), can produce a higher level of IFN-gamma in the presence of both L2-MHV3 and interleukin-12 (IL-12)/IL-18. The synergistic production of IFN-gamma by NK cells depends on viral replication rather than viral fixation only, because it is inhibited or not induced in cells infected with ultraviolet-inactivated viruses and in cells from Ceacam1a(-/-) mice infected with virulent viruses. The synergistic IFN-gamma production involves the p38 mitogen-activated protein kinase (MAPK) rather than the extracellular signal-regulated kinase-1/2 MAPK signalling pathway. However, the signal triggered through the engagement of CEACAM1a decreases the production of IFN-gamma, when these molecules are cross-linked using specific monoclonal antibodies. These results suggest that control of acute hepatitis by IFN-gamma-producing NK cells may depend on both production of IL-12 and IL-18 in the liver environment and viral infection of NK cells.
21: Journal of immunology (Baltimore, Md. : 1950), 2009 Sep 1, 183(5)
IL-12p40 and IL-18 play pivotal roles in orchestrating the cell-mediated immune response to a poxvirus infection.
[Abstract]A strong cell-mediated immune response is critical for controlling viral infections and is regulated by a number of cytokines, including IL-12 and IL-18. Indeed, some viruses have evolved to specifically target these pathways to counter the host immune response. Orthopoxviruses, including ectromelia virus, encode immune evasion molecules that specifically target IL-18 and IFN-gamma. We hypothesized that IL-12 and IL-18 are pivotal for induction of IFN-gamma production and subsequent generation of an effective host response to ectromelia virus infection. In this study, we demonstrate that absence of both IL-12p40 and IL-18 resulted in increased susceptibility to infection that was associated with skewing of the cytokine response to Th2 and a reduction in NK and CTL responses. The decrease in CTL response correlated with a defect in CD8(+) T cell proliferation and lower numbers of virus-specific CD8(+) T cells. Lack of either IL-12p40 and/or IL-18 was also associated with reduced numbers of CD8(+) T cells at sites of infection and with an increase in the numbers of splenic T regulatory cells. Taken together, our data indicate that IL-12p40 and IL-18 act in concert and play an important antiviral role through the up-regulation of IFN-gamma production and cell-mediated immune responses.
22: Veterinary immunology and immunopathology, 2009 Dec 15, 132(2-4)
Construction and immunogenicity of a DNA vaccine containing clumping factor A of Staphylococcus aureus and bovine IL18.
[Abstract]Selection of potent cytokine adjuvants is important for the development of Staphylococcus aureus DNA vaccines. Several potential cytokines have been proven to induce enhanced immune responses in animal models and clinical tests. There is still no reported use of IL18 as an adjuvant to design DNA vaccines against S. aureus. In this study, we cloned the main fibronectin binding protein gene (a fragment from clumping factor A, ClfA(221-550)) of S. aureus and bovine interleukin 18 (bIL18). Then recombinant plasmids were constructed based on the eukaryotic expression vector pVAX1 with or without bIL18. Indirect immunofluorescence assays in transfected HeLa cells indicated that the recombinant DNAs (rDNAs) could be expressed correctly and had antigenicity. BALB/c mice were used as experimental models to examine the immunogenicity of rDNAs in vivo. The ClfA(221-550) rDNA provoked antibody production. The bIL18 rDNA induced production of the Th1 type cytokines IL2 and IFNgamma, and ClfA(221-550) and bIL18 synergistically stimulated T-lymphocyte proliferation. The data demonstrated that bIL18 is a potent adjuvant that could be used to enhance cellular immunity.
23: Kidney international, 2009 Sep, 76(5)
IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis.
[Abstract]Ureteral obstruction results in renal fibrosis in part due to inflammatory injury. The role of interleukin-18 (IL-18), an important mediator of inflammation, in the genesis of renal fibrosis was studied using transgenic mice overexpressing human IL-18-binding protein. In addition, HK-2 cells were analyzed following direct exposure to IL-18 compared to control media. Two weeks after ureteral obstruction, the kidneys of wild-type mice had a significant increase in IL-18 production, collagen deposition, alpha-smooth muscle actin and RhoA expression, fibroblast and macrophage accumulation, chemokine expression, and transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha) production, whereas E-cadherin expression was simultaneously decreased. The transgenic mice with neutralized IL-18 activity exhibited significant reductions in these indicators of obstruction-induced renal fibrosis and epithelial- mesenchymal transition, without demonstrating alterations in TGF-beta1 or TNF-alpha activity. Similarly, the HK-2 cells exhibited increased alpha-smooth muscle actin expression and collagen production, and decreased E-cadherin expression in response to IL-18 stimulation without alterations in TNF-alpha or TGF-beta1 activity. Our study demonstrates that IL-18 is a significant mediator of obstruction-induced renal fibrosis and epithelial- mesenchymal transition independent of downstream TGF-beta1 or TNF-alpha production.
24: Acta tropica, 2009 Sep, 111(3)
IL-18 enhances protective effect in mice immunized with a Schistosoma japonicum FABP DNA vaccine.
[Abstract]Two recombinant plasmids, pVAX/SjFABP and pVAX/mIL-18 containing Schistosoma japonicum 14 kDa fatty acid binding protein (SjFABP) and murine IL-18, were constructed and evaluated for their ability to induce immune responses and to protect against S. japonicum challenge in mice. Mice were intramuscularly immunized twice at three-weekly intervals, and challenged with S. japonicum cercariae at 4 weeks after the last vaccination. All animals vaccinated with pVAX/SjFABP alone or plus pVAX/mIL-18 developed specific anti-SWAP ELISA antibody and T lymphocyte proliferation. Co-injection of pVAX/mIL-18 significantly increased the production of IFN-gamma and IL-2 compared with pVAX/SjFABP alone, indicating that IL-18 enhances the Th1-dominant immune response. The challenge experiment showed that co-injection of plasmid encoding IL-18 significantly enhances protective effect against S. japonicum infection, as demonstrated by worm reduction rates and the hepatic egg reduction rates 45 days post-challenge. These results indicated that IL-18 may become a novel vaccine adjuvant for development of vaccines against schistosomiasis.
25: Autoimmunity reviews, 2009 Sep, 9(1)
IL-18 and skin inflammation.
[Abstract]IL-18 belongs to the IL-1 family of cytokines and has recently regained interest in the context of inflammasome activation. The inflammasome dependent caspase 1 cleaves pro-IL-18 into the active form - similar to what is known for IL-1ss. Still, the action and importance of IL-18 are not completely understood. There are several indications that it plays a pathogenetically important role in chronic inflammatory conditions of epithelial organs (such as skin, gut, kidney) and importantly also in responses against self. Here, we summarise current knowledge on the role of IL-18 in human skin inflammation with a focus on its role in Cutaneous Lupus Erythematosus (CLE). There is evidence that IL-18 plays a role in CLE upstream of TNFalpha. In CLE but not normal keratinocytes IL-18 strongly induces TNFalpha release, which then results in apoptosis. Blocking TNFalpha in vitro prevents apoptosis of keratinocytes but anti-TNFalpha therapy is not applicable in LE conditions. We will discuss potential approaches to control IL-18 in skin inflammation.
26: American journal of respiratory cell and molecular biology, 2009 Dec, 41(6)
Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice.
[Abstract]Administration of several chemotherapeutic drugs, such as bleomycin, busulfan, and gefitinib, often induces lethal lung injury. However, the precise mechanisms responsible for this drug-induced lung injury are still unclear. In the present study, we examined the role of the proinflammatory cytokines IL-18 and IL-1beta in the mechanism of bleomycin-induced lung injury. We performed immunohistochemical analysis of IL-18 and IL-18 receptor (R) alpha chain expression in the lungs of five patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-18Ralpha was observed in the lungs of all five patients with bleomycin-induced lung injury. To support the data obtained from patient samples, the levels of IL-1beta and IL-18 mRNA and protein, pulmonary inflammation, and lung fibrosis were examined in mouse models of bleomycin-induced lung injury. Intravenous administration of bleomycin induced the expression of IL-1beta and IL-18 in the serum and lungs of wild-type C57BL/6 mice. IL-18-producing F4/80(+) neutrophils, but not CD3(+) T cells, were greatly increased in the lungs of treated mice. Moreover, bleomycin-induced lung injury was significantly attenuated in caspase-1(-/-), IL-18(-/-), and IL-18Ralpha(-/-) mice in comparison with control mice. Thus, our results provide evidence for an important role of IL-1beta and IL-18 in chemotherapy-induced lung injury.
27: Infection and immunity, 2009 Feb 17, 17(1)
IL-18 Related Genes are Induced during the Contraction Phase but do not Play Major Roles in Regulating the Dynamics or Function of the T Cell Response to L. monocytogenes Infection.
[Abstract]Proinflammatory cytokines such as IFN-gamma impact aspects of T cell responses after infection including expansion, contraction and memory formation. IL-18 functions as a proinflammatory cytokine by stimulating the production of IFN-gamma from multiple cell types and accentuating the development of Th1 CD4 T cell responses. Focused microarray analyses revealed upregulation of IL18 and IL-18 receptor genes in CD8 T cells during the contraction phase. Based on these data we investigated if and how signaling through the IL-18 receptor would influence the development and kinetics of Ag-specific CD8 and CD4 T cell responses following infection. IL-18Ralpha(-/-) and IL-18(-/-) mice developed a similar magnitude of Ag-specific CD8 T cells after L. monocytogenes infection as Wt B6 mice both in frequency and in total numbers of cells. The kinetics of expansion, contraction and memory CD8 T cell maintenance were also similar. When IL-18Ralpha deficiency was isolated to Ag-specific CD8 T cells alone, the kinetics of the expansion and contraction phases were also normal. These basic findings were confirmed in response to vaccinia virus infection. In contrast, the expansion of Ag-specific CD4 T cells was slightly curtailed by the absence of IL-18Ralpha; however, contraction and the maintenance of memory were not altered. Importantly, both memory Ag-specific CD8 and CD4 T cells generated in the absence of IL-18Ralpha expanded appropriately after secondary antigen exposure and were protective indicating that signaling through the IL-18 receptor is not required for normal T cell response kinetics and survival of immunized mice against a lethal L. monocytogenes infection.
28: Revista espa?ola de enfermedades digestivas : organo oficial de la Sociedad Espa?ola de Patolog¨ªa Digestiva, 2008 Dec, 100(12)
[Interleukin 18 (IL-18) and other immunological parameters as markers of severity in acute pancreatitis]
[Abstract]OBJECTIVE: Our aim was to prospectively compare the behavior of interleukin 18 (IL-18) levels and other immunological parameters during the first week of hospitalization between acute pancreatitis patients with and without severity criteria, as well as between patients with and without late pseudocyst development. PATIENTS AND METHODS: In 36 patients with acute pancreatis we compared sTNF-RI, IL-1Ra, IL-6, and IL-18 levels at days 1, 2, 3 and 7 after hospitalization between mild pancreatitis, severe pancreatitis, and a "control" group (13 patients) with uncomplicated biliary colic, as well as between patients with and without pseudocyst. RESULTS: On comparing mild to severe pancreatitis, IL-18 was significantly higher only the first day in severe pancreatitis, while the other parameters were steadily higher after the second day. In patients developing pseudocyst, IL-18 was also noticeably higher the first day. CONCLUSIONS: IL-18 appears to be the earliest marker of complications and severity in acute pancreatitis at both the systemic and local level (pseudocyst).