IL18

Gene Summary

Gene:IL18; interleukin 18
Aliases: IGIF, IL-18, IL-1g, IL1F4
Location:11q22.2-q22.3
Summary:The protein encoded by this gene is a proinflammatory cytokine that augments natural killer cell activity in spleen cells, and stimulates interferon gamma production in T-helper type I cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-18
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL18 (cancer-related)

Medina L, Rabinovich A, Piura B, et al.
Expression of IL-18, IL-18 binding protein, and IL-18 receptor by normal and cancerous human ovarian tissues: possible implication of IL-18 in the pathogenesis of ovarian carcinoma.
Mediators Inflamm. 2014; 2014:914954 [PubMed] Free Access to Full Article Related Publications
Proinflammatory cytokine IL-18 has been shown to be elevated in the sera of ovarian carcinoma patients. The aim of the study was to examine the levels and cellular origin of IL-18, IL-18 binding protein, and IL-18 receptor in normal and cancerous ovarian tissues. Ovarian tissue samples were examined by immunohistochemical staining for IL-18, IL-18BP, and IL-18R and mRNA of these cytokines was analyzed with semiquantitative PT-PCR. IL-18 levels were significantly higher in cancerous ovarian tissues (P = 0.0007), IL-18BP levels were significantly higher in normal ovarian tissues (P = 0.04), and the ratio of IL-18/IL-18BP was significantly higher in cancerous ovarian tissues (P = 0.036). Cancerous ovarian tissues expressed significantly higher IL-18 mRNA levels (P = 0.025), while there was no difference in the expression of IL-18BP mRNA and IL-18R mRNA between cancerous and normal ovarian tissues. IL-18 and IL-18BP were expressed dominantly in the epithelial cells of both cancerous and normal ovarian tissues, while IL-18R was expressed dominantly in the epithelial cells of cancerous ovarian tissues but expressed similarly in the epithelial and stromal cells of normal cancerous tissues. This study indicates a possible role of IL-18, IL-18BP, and IL-18R in the pathogenesis of epithelial ovarian carcinoma.

Surovtseva MN, Vainer AS, Berezina OV, et al.
Analysis of the association of polymorphic loci rs917997 in IL18RAP gene and rs187238 in IL18 gene with the risk for non-Hodgkin's malignant lymphomas in Novosibirsk population.
Bull Exp Biol Med. 2014; 157(1):66-9 [PubMed] Related Publications
We analyzed the association of polymorphic variants of rs917997 (G/A) locus in IL18RAP gene and rs187238 (G/C) locus in IL18 gene with the risk of malignant non-Hodgkin's lymphomas in Novosibirsk population. Allele and genotype frequencies of the above loci were determined in patients (243 persons) and control group (371 persons) and compared using χ(2) test. None of the analyzed loci showed statistically significant association with the risk of malignant non-Hodgkin's lymphomas.

Uzan B, Poglio S, Gerby B, et al.
Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression.
EMBO Mol Med. 2014; 6(6):821-34 [PubMed] Free Access to Full Article Related Publications
Development of novel therapies is critical for T-cell acute leukaemia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleukin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xenografted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development.

Liu Z, Zhao F, He JJ
Hepatitis C virus (HCV) interaction with astrocytes: nonproductive infection and induction of IL-18.
J Neurovirol. 2014; 20(3):278-93 [PubMed] Related Publications
Hepatitis C virus (HCV) infection causes the central nervous system (CNS) abnormalities in more than 50 % of chronically infected subjects. However, the underlying mechanisms are largely unknown. In this study, we characterized the HCV interactions with astrocytes, one of the putative HCV target cells in the brain. We demonstrated that primary human astrocytes (PHA) were very inefficiently infected by HCV, either in the cell-free form or through cell-cell contact. We then determined the potential restriction steps of HCV infection and replication in these cells. PHA expressed all known HCV receptors but failed to support HCV entry. HCV IRES-mediated RNA translation was functional in PHA and further enhanced by miR122 expression. Nevertheless, PHA did not support HCV replication regardless of miR122 expression. To our great surprise, we found that HCV exposure induced robust IL-18 expression in PHA and exhibited direct neurotoxicity. Taken together, these results showed that astrocytes did not support productive HCV infection and replication, but HCV interactions with astrocytes and neurons alone might be sufficient to cause CNS dysfunction.

Guo XG, Xia Y
The Interleukin-18 promoter -607C>A polymorphism contributes to nasopharyngeal carcinoma risk: evidence from a meta-analysis including 1,886 subjects.
Asian Pac J Cancer Prev. 2013; 14(12):7577-81 [PubMed] Related Publications
The interleukin-18 promoter -607C>A gene polymorphism may be related to nasopharyngeal carcinoma (NPC) risk but the results of individual studies remain conflicting. A meta-analysis including 1,886 subjects from five individual studies was therefore performed to provide a more accurate estimation. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by fixed- or random-effects models. A significant relationship between interleukin-18 promoter -607C>A gene polymorphism and NPC was found in a dominant genetic model (OR: 1.351, 95% CI: 1.089-1.676, P=0.006, Pheterogeneity=0.904), a homozygote model (OR: 1.338, 95% CI: 1.023-1.751, P=0.034, Pheterogeneity=0.863), and a heterozygote model (OR: 1.357, 95% CI: 1.080-1.704, P=0.009, Pheterogeneity=0.824). No significant association was detected in either an allelic genetic model (OR: 1.077, 95% CI: 0.960-1.207, 0.207, Pheterogeneity=0.844) or a recessive genetic model (OR: 1.093, 95% CI: 0.878-1.361, P=0.425, Pheterogeneity=0.707). In conclusion, a significant association was found between interleukin-18 promoter -607C>A gene polymorphism and NPC risk. Individuals with the C allele of interleukin-18 promoter -607C>A gene polymorphism have a higher risk of NPC development.

El-Saghire H, Vandevoorde C, Ost P, et al.
Intensity modulated radiotherapy induces pro-inflammatory and pro-survival responses in prostate cancer patients.
Int J Oncol. 2014; 44(4):1073-83 [PubMed] Free Access to Full Article Related Publications
Intensity modulated radiotherapy (IMRT) is one of the modern conformal radiotherapies that is widely used within the context of cancer patient treatment. It uses multiple radiation beams targeted to the tumor, however, large volumes of the body receive low doses of irradiation. Using γ-H2AX and global genome expression analysis, we studied the biological responses induced by low doses of ionizing radiation in prostate cancer patients following IMRT. By means of different bioinformatics analyses, we report that IMRT induced an inflammatory response via the induction of viral, adaptive, and innate immune signaling. In response to growth factors and immune-stimulatory signaling, positive regulation in the progression of cell cycle and DNA replication were induced. This denotes pro-inflammatory and pro-survival responses. Furthermore, double strand DNA breaks were induced in every patient 30 min after the treatment and remaining DNA repair and damage signaling continued after 18-24 h. Nine genes belonging to inflammatory responses (TLR3, SH2D1A and IL18), cell cycle progression (ORC4, SMC2 and CCDC99) and DNA damage and repair (RAD17, SMC6 and MRE11A) were confirmed by quantitative RT-PCR. This study emphasizes that the risk assessment of health effects from the out-of-field low doses during IMRT should be of concern, as these may increase the risk of secondary cancers and/or systemic inflammation.

Miller JM, Thompson JK, MacPherson MB, et al.
Curcumin: a double hit on malignant mesothelioma.
Cancer Prev Res (Phila). 2014; 7(3):330-40 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1β. Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation.

Miyoshi H, Morishita A, Tani J, et al.
Expression profiles of 507 proteins from a biotin label-based antibody array in human colorectal cancer.
Oncol Rep. 2014; 31(3):1277-81 [PubMed] Related Publications
Molecular-targeted therapy is one of the most promising therapies for patients with advanced-stage colorectal cancer (CRC). However, a wide range of proteins have unknown expression levels in CRC. The purpose of the present study was to determine the expression levels of various proteins related to colorectal carcinogenesis and cancer development. We examined the expression levels of 507 target proteins using a biotin label-based antibody array in 6 human CRC tissues. We also analyzed the clinicopathological features of CRC patients. In CRC tissues, IL-1α, GRO, Glut5, MIG, ICAM-5, VE-cadherin, uPA and Leptin R were increased when compared to levels in normal colon tissues. MPIF-1/CCL23, FGF R5, MIP2, SAA and IL-18 Rβ were strongly upregulated in rectal cancer when compared to the levels in non-rectal cancer. These data suggest that differential protein expression profiles exist under different conditions, including carcinogenesis and CRC localization. Therefore, an exhaustive analysis of protein expression levels using a biotin label-based antibody protein array is a potentially useful tool for identifying novel individual therapies for CRC patients.

Tsai HT, Hsin CH, Hsieh YH, et al.
Impact of interleukin-18 polymorphisms -607A/C and -137G/C on oral cancer occurrence and clinical progression.
PLoS One. 2013; 8(12):e83572 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: The purpose of this study was to identify gene polymorphisms of interleukin-18 (IL-18) -607A/C and -137G/C specific to patients with oral cancer susceptibility and clinicopathological status.
METHODOLOGY AND PRINCIPAL FINDINGS: A total of 1,126 participants, including 559 healthy people and 567 patients with oral cancer, were recruited for this study. Allelic discrimination of -607A/C (rs1946518) and -137G/C (rs187238) polymorphisms of the IL-18 gene was assessed by a real-time PCR with the TaqMan assay. There was no significant association between IL-18 -607A/C polymorphism and oral cancer risk. However, among alcohol consumers, people with A/A homozygotes of IL-18 -607A/C polymorphism had a 2.38-fold (95% CI=1.17-4.86; p=0.01) increased risk of developing oral cancer compared with those with C/C homozygotes. The participants with G/C heterozygotes of IL-18 -137 polymorphism had a 1.64-fold (95% CI: 1.08-2.48; p=0.02) increased risk of developing oral cancer compared with those with G/G wild type homozygotes. Both sets of statistics were determined after adjusting for confounding factors. Among people who had exposure to oral cancer-related environmental risk factors such as areca, alcohol, and tobacco consumption, the adjusted odd ratios and 95% confidence intervals were increased to a 2.02-fold (95% CI=1.01-4.04; p=0.04), 4.04 (95% CI=1.65-9.87; p=0.002) and a 1.66-fold (95% CI=1.00-2.84; p=0.05) risk of developing oral cancer. However, patients with G/C alleles of IL-18 -137 were correlated with a lower clinical stage (AOR=0.59; 95% CI=0.39-0.89; p=0.01), smaller tumor size (AOR=0.56; 95% CI=0.35-0.87; p=0.01), and non-lymph node metastasis (AOR=0.51; 95% CI=0.32-0.80; p=0.003).
CONCLUSION: IL-18 -137 G/C gene polymorphism may be a factor that increases the susceptibility to oral cancer, as well as a protective factor for oral cancer progression. The interactions of gene to oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development.

Tsirakis G, Roussou P, Pappa CA, et al.
Increased serum levels of MIP-1alpha correlate with bone disease and angiogenic cytokines in patients with multiple myeloma.
Med Oncol. 2014; 31(1):778 [PubMed] Related Publications
Many cytokines possess variable roles in the pathogenesis of multiple myeloma. Macrophage inflammatory protein-1alpha (MIP-1alpha) is an osteoclast-activating factor with a major role in myeloma bone disease. The aim of the study was to examine its participation in the angiogenic process of the disease. We measured, by enzyme-linked immunosorbent assays, its serum levels in 56 newly diagnosed myeloma patients, in several skeletal grades and stages of the disease and in 25 healthy controls. Concurrently, we measured serum levels of the angiogenic cytokines basic-fibroblast growth factor, hepatocyte growth factor and interleukin-18. All the above cytokines were higher in myeloma patients (p < 0.001 for all cases) and were increasing in parallel with disease stage (p < 0.001 for all cases) and skeletal grade (p < 0.04 for MIP-1alpha and p < 0.001 for the other cases). Moreover, positive correlations between MIP-1alpha and all the angiogenic cytokines were noted (p < 0.001 for all cases). MIP-1alpha seems to be a predominant factor responsible for the enhancement of bone resorption and increased angiogenesis. The positive correlation between MIP-1alpha and the angiogenic chemoattractants supports the involvement of these factors in the biology of myeloma cell growth. Moreover, they could be used as possible therapeutic targets as well as markers of disease activity.

Villalobos X, Rodríguez L, Prévot J, et al.
Stability and immunogenicity properties of the gene-silencing polypurine reverse Hoogsteen hairpins.
Mol Pharm. 2014; 11(1):254-64 [PubMed] Related Publications
Gene silencing by either small-interference RNAs (siRNA) or antisense oligodeoxynucleotides (aODN) is widely used in biomedical research. However, their use as therapeutic agents is hindered by two important limitations: their low stability and the activation of the innate immune response. Recently, we developed a new type of molecule to decrease gene expression named polypurine reverse Hoogsteen hairpins (PPRHs) that bind to polypyrimidine targets in the DNA. Herein, stability experiments performed in mouse, human, and fetal calf serum and in PC3 cells revealed that the half-life of PPRHs is much longer than that of siRNAs in all cases. Usage of PPRHs with a nicked-circular structure increased the binding affinity to their target sequence and their half-life in FCS when bound to the target. Regarding the innate immune response, we determined that the levels of the transcription factors IRF3 and its phosphorylated form, as well as NF-κB were increased by siRNAs and not by PPRHs; that the expression levels of several proinflammatory cytokines including IL-6, TNF-α, IFN-α, IFN-ß, IL-1ß, and IL-18 were not significantly increased by PPRHs; and that the cleavage and activation of the proteolytic enzyme caspase-1 was not triggered by PPRHs. These determinations indicated that PPRHs, unlike siRNAs, do not activate the innate inflammatory response.

Xu Y, Li H, Chen W, et al.
Mycoplasma hyorhinis activates the NLRP3 inflammasome and promotes migration and invasion of gastric cancer cells.
PLoS One. 2013; 8(11):e77955 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Mycoplasma hyorhinis (M.hyorhinis, M.hy) is associated with development of gastric and prostate cancers. The NLRP3 inflammasome, a protein complex controlling maturation of important pro-inflammatory cytokines interleukin (IL)-1β and IL-18, is also involved in tumorigenesis and metastasis of various cancers.
METHODOLOGY/PRINCIPAL FINDINGS: To clarify whether M.hy promoted tumor development via inflammasome activation, we analyzed monocytes for IL-1β and IL-18 production upon M.hy challenge. When exposed to M.hy, human monocytes exhibited rapid and robust IL-1β and IL-18 secretion. We further identified that lipid-associated membrane protein (LAMP) from M.hy was responsible for IL-1β induction. Applying competitive inhibitors, gene specific shRNA and gene targeted mice, we verified that M.hy induced IL-1β secretion was NLRP3-dependent in vitro and in vivo. Cathepsin B activity, K(+) efflux, Ca(2+) influx and ROS production were all required for the NLRP3 inflammasome activation by M.hy. Importantly, it is IL-1β but not IL-18 produced from macrophages challenged with M.hy promoted gastric cancer cell migration and invasion.
CONCLUSIONS: Our data suggest that activation of the NLRP3 inflammasome by M.hy may be associated with its promotion of gastric cancer metastasis, and anti-M.hy therapy or limiting NLRP3 signaling could be effective approach for control of gastric cancer progress.

Yang X, Qiu MT, Hu JW, et al.
Association of interleukin-18 gene promoter -607 C>A and -137G>C polymorphisms with cancer risk: a meta-analysis of 26 studies.
PLoS One. 2013; 8(9):e73671 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Evidence suggest that IL-18 gene polymorphisms may be risk factors for several cancers. Increasing studies investigating the association between IL-18 gene promoter polymorphisms (-607 C>A and -137G>C) and cancer risk have yielded conflicting results.
METHODOLOGY/PRINCIPAL FINDINGS: We performed a meta-analysis of 26 studies including 4096 cases and 5222 controls. We assessed the strength of the association of IL-18 gene promoter -607 C>A and -137G>C polymorphisms with cancer risk and performed sub-group analyses by cancer types, ethnicities, source of controls and sample size. The pooled results revealed a significant increased risk of cancer susceptibility for -607 C>A (CA vs. CC: OR = 1.19, 95%CI: 1.04, 1.37, Pheterogeneity = 0.033; CA/AA vs. CC: OR = 1.17, 95% CI: 1.01, 1.34, Pheterogeneity = 0.007), but no significant association for -137 G>C was observed with overall cancer risk. Sub-group analyses revealed that an increased risk of nasopharyngeal carcinoma was both found for -607 C>A (CA/AA vs. CC: OR = 1.32, 95% CI: 1.04, 1.69, Pheterogeneity = 0.823) and -137G>C (GC/CC vs. GG: OR = 1.57, 95%CI: 1.26, 1.96, Pheterogeneity = 0.373). Consistent with the results of the genotyping analyses, the -607A/-137C and -607C/-137C haplotypes were associated with a significantly increased risk of nasopharyngeal carcinoma as compared with the -607C/-137G haplotype (-607A/-137C vs. -607C/-137G: OR = 1.26, 95%CI: 1.13, 1.40; Pheterogeneity = 0.569; -607C/-137C vs. -607C/-137G: OR = 1.14, 95%CI: 1.03, 1.27; Pheterogeneity = 0.775). As for gastrointestinal cancer, we also found that -607 C>A polymorphism was significantly associated with increased cancer risk (CA/AA vs. CC: OR = 1.25, 95% CI: 1.05, 1.50, Pheterogeneity = 0.458). Further sub-group analysis revealed that -137G>C polymorphism contributed to cancer risk in Asians but not in Caucasians (GC/CC vs. GG: OR = 1.31, 95%CI: 1.05, 1.64, Pheterogeneity<0.001).
CONCLUSIONS: The meta-analysis results suggest that IL-18 gene promoter -607 C>A polymorphism is significantly associated with overall cancer risk, especially in nasopharyngeal carcinoma and gastrointestinal cancer; and the -137 G>C polymorphism is associated with increased overall cancer risk in Asian populations and also significantly increases the risk of nasopharyngeal carcinoma.

Hughes L, Ruth K, Rebbeck TR, Giri VN
Genetic variation in IL-16 miRNA target site and time to prostate cancer diagnosis in African-American men.
Prostate Cancer Prostatic Dis. 2013; 16(4):308-14 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Men with a family history of prostate cancer and African-American men are at high risk for prostate cancer and in need of personalized risk estimates to inform screening decisions. This study evaluated genetic variants in genes encoding microRNA (miRNA) binding sites for informing of time to prostate cancer diagnosis among ethnically diverse, high-risk men undergoing prostate cancer screening.
METHODS: The Prostate Cancer Risk Assessment Program (PRAP) is a longitudinal screening program for high-risk men. The eligibility includes men aged between 35 and 69 years with a family history of prostate cancer or African descent. Participants with 1 follow-up visit were included in the analyses (n=477). Genetic variants in genes encoding miRNA binding sites (ALOX15 (arachidonate 15-lipooxygenase), IL-16, IL-18 and RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)) previously implicated in prostate cancer development were evaluated. Genotyping methods included Taqman SNP Genotyping Assay or pyrosequencing. Cox models were used to assess time to prostate cancer diagnosis by risk genotype.
RESULTS: Among 256 African Americans with one follow-up visit, the TT genotype at rs1131445 in IL-16 was significantly associated with earlier time to prostate cancer diagnosis vs the CC/CT genotypes (P=0.013), with a suggestive association after correction for false discovery (P=0.065). Hazard ratio after controlling for age and PSA for TT vs CC/CT among African Americans was 3.0 (95% confidence interval: 1.26-7.12). No association with time to diagnosis was detected among Caucasians by IL-16 genotype. No association with time to prostate cancer diagnosis was found for the other miRNA target genotypes.
CONCLUSIONS: Genetic variation in IL-16 encoding miRNA target site may be informative of time to prostate cancer diagnosis among African-American men enrolled in prostate cancer risk assessment, which may inform individualized prostate cancer screening strategies in the future.

Xia P, Zhou M, Dong DS, et al.
Association of polymorphisms in interleukin-18 and interleukin-28B genes with outcomes of hepatitis B virus infections: a meta-analysis.
Tumour Biol. 2014; 35(2):1129-37 [PubMed] Related Publications
Several polymorphisms in the interleukin-18 (IL-18) and nterleukin-28B (IL-28B) genes have been reported to influence hepatitis B virus (HBV) infection. However, the published findings have been conflicting. We conducted meta-analyses of randomized, controlled trials to address the association of IL-18 or IL-28B polymorphisms and the outcomes of HBV infection. Weipu, Wanfang, CNKI, MEDLINE, PubMed, EMBASE, and Cochrane Library databases were employed to search for citations using the MeSH terms as "interleukin-18"/"interleukin-28B" AND "HBV" AND "gene" AND "polymorphism" without any restriction in language and publication year. Meta-analysis was conducted by RevMan 5.0 software. The results showed that the IL28B rs8099917 AA genotype (AA vs AC + CC: odds ratio (OR) = 0.63, 95 % confidence interval (CI) = 0.46-0.87) was associated with a decreased risk of hepatocellular carcinoma (HCC). Carriage of IL28B rs12979860 CC genotype was associated with an increased risk for developing liver cirrhosis among patients with HBV infection (CC vs CT + TT: OR = 1.39, 95 % CI = 1.04-1.85). Further well-designed large studies are warranted to confirm the mechanisms by which these are involved in these outcomes of HBV infection.

Carbotti G, Barisione G, Orengo AM, et al.
The IL-18 antagonist IL-18-binding protein is produced in the human ovarian cancer microenvironment.
Clin Cancer Res. 2013; 19(17):4611-20 [PubMed] Related Publications
PURPOSE: Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-γ production, T-helper 1 responses, and antitumor effects. In turn, IFN-γ stimulates IL-18-binding protein production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immunotherapy, here, we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo.
EXPERIMENTAL DESIGN: Expression and production of IL-18BP in EOC cell lines, primary ovarian carcinomas, and the corresponding normal tissues, patients' serum, and ascites were investigated by immunochemistry, ELISA, screening of gene expression profiles, and reverse-transcription PCR.
RESULTS: Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells. Release of IL-18BP was detectable in EOC sera and to a greater extent in the ascites, indicating production at the tumor site. Indeed, immunochemical analyses on cells isolated from the ascites and on tumor sections indicated that IL-18BP is expressed in both tumor cells and tumor-associated leukocytes, which displayed a CD3-CD20-NKp46-CD13+CD14low phenotype. EOC cell lines do not constitutively express IL-18BP. However, its release is inducible both by IFN-γ stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment. In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity.

Ponomareva L, Liu H, Duan X, et al.
AIM2, an IFN-inducible cytosolic DNA sensor, in the development of benign prostate hyperplasia and prostate cancer.
Mol Cancer Res. 2013; 11(10):1193-202 [PubMed] Related Publications
UNLABELLED: Close links have been noted between chronic inflammation of the prostate and the development of human prostatic diseases such as benign prostate hyperplasia (BPH) and prostate cancer. However, the molecular mechanisms that contribute to prostatic inflammation remain largely unexplored. Recent studies have indicated that the IFN-inducible AIM2 protein is a cytosolic DNA sensor in macrophages and keratinocytes. Upon sensing DNA, AIM2 recruits the adaptor ASC and pro-CASP1 to assemble the AIM2 inflammasome. Activation of the AIM2 inflammasome cleaves pro-interleukin (IL)-1β and pro-IL-18 and promotes the secretion of IL-1β and IL-18 proinflammatory cytokines. Given that human prostatic infections are associated with chronic inflammation, the development of BPH is associated with an accumulation of senescent cells with a proinflammatory phenotype, and the development of prostate cancer is associated with the loss of IFN signaling, the role of AIM2 in mediating the formation of prostatic diseases was investigated. It was determined that IFNs (α, β, or γ) induced AIM2 expression in human prostate epithelial cells and cytosolic DNA activated the AIM2 inflammasome. Steady-state levels of the AIM2 mRNA were higher in BPH than in normal prostate tissue. However, the levels of AIM2 mRNA were significantly lower in clinical tumor specimens. Accordingly, constitutive levels of AIM2 mRNA and protein were lower in a subset of prostate cancer cells as compared with BPH cells. Further, the cytosolic DNA activated the AIM2 inflammasome in the androgen receptor-negative PC3 prostate cancer cell line, suggesting that AIM2-mediated events are independent of androgen receptor status.
IMPLICATIONS: The AIM2 inflammasome has a fundamental role in the generation of human prostatic diseases.

Naumnik W, Naumnik B, Niewiarowska K, et al.
Angiogenic axis angiopoietin-1 and angiopoietin-2/Tie-2 in non-small cell lung cancer: a bronchoalveolar lavage and serum study.
Adv Exp Med Biol. 2013; 788:341-8 [PubMed] Related Publications
Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), ligands for the Tie-2 receptor expressed on endothelial cells, play a critical role in angiogenesis, in concert with vascular endothelial growth factor (VEGF). Angiogenesis is important for tumor growth and development and also is implicated in the pathogenesis of interstitial lung diseases. The aim of this study was to evaluate the concentration of Ang-1, Ang-2, Tie-2, interleukin-18 (IL-18), transforming growth factor beta-1 (TGF β1), and VEGF domain in both serum and bronchoalveolar lavage fluid (BALF) of lung cancer patients before chemotherapy. We studied 45 non-small cell lung cancer (NSCLC) patients (M/F; 38/7; mean age 62 ± 4 years). The age-matched control groups consisted of 15 sarcoidosis (BBS), 15 hypersensivity pneumonitis (HP), and 15 healthy subjects. The patients with NSCLC had a significantly higher level of Ang-1 compared with the BBS and healthy subjects, and a higher level of Ang-2 compared with the healthy subjects in both serum and BALF. BALF level of IL-18 was lower in the NSCLC than that in the HP group, but higher than that in the BBS patients. Serum level of IL-18 was higher in the NSCLC than in the healthy subjects. The NSCLC group had lower VEGF in BALF than that in healthy subjects. Receiver-operating characteristics (ROC) curves were applied to find the cut-off the serum levels of Ang-1 and Ang-2 levels in BALF. We did not find any correlation between the levels of Ang-1, Ang-2, Tie-2, and the stage of tumor or treatment response (prospectively). We conclude that the angiogenic axis Ang-1 and Ang-2/Tie-2 may play an important role in lung cancer development and their concentrations may be a useful marker at the time of initial diagnosis of lung cancer.

Liang TJ, Ma H, Wang CX, et al.
The -137G>C polymorphism in interleukin-18 promoter region and cancer risk: evidence from a meta-analysis of 21 studies.
Tumour Biol. 2013; 34(6):3483-90 [PubMed] Related Publications
Interleukin-18 (IL-18) is a key cytokine responsible for immune response and involved in the process of cancer development. The association of -137G>C polymorphism in the promoter region of IL-18 with cancer risk is still elusive based on current genetic association studies. We performed this meta-analysis to determine whether the -137G>C polymorphism is associated with cancer risk. A comprehensive search was conducted for databases of PubMed, EMBASE, and China National Knowledge Infrastructure. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength. Publication bias was detected by Egger's and Begg's test. Twenty-one eligible studies including 3,498 cancer patients and 5,222 controls were identified and analyzed. In the overall analysis, no significant association between -137G>C polymorphism and cancer risk was observed. In the sub-group analyses of ethnicities, the -137G>C polymorphism significantly increased cancer risk in Asian population (GC/CC vs. GG: OR = 1.313, 95% CI = 1.053-1.638, heterogeneity P < 0.001) but not in Caucasian population. Further stratified analyses showed that the variant -137C allele was significantly associated with increased risk of nasopharyngeal carcinoma (C vs. G: OR = 1.484, 95% CI = 1.193-1.847, heterogeneity P = 0.213). No publication bias was detected. We provide evidence that the -137G>C polymorphism in IL-18 promoter region significantly increases cancer risk in Asian population but not in Caucasian population, and the variant -137C allele is associated with increased risk of nasopharyngeal carcinoma.

Mertens LS, Neuzillet Y, Horenblas S, van Rhijn BW
Biomarkers for assessing therapeutic response in bladder cancer.
Arch Esp Urol. 2013; 66(5):495-504 [PubMed] Related Publications
Reliable markers for assessing therapeutic response are needed to select the most effective treatment strategy for bladder cancer patients. We analyzed the role of biomarkers predicting response of non-muscle invasive bladder cancer (NMIBC) on BCG induction, and of non-organ confined muscle invasive bladder cancer (MIBC) on neoadjuvant chemotherapy. A critical, non-structured review of the literature was conducted. For assessing BCG therapy outcome, measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed. Measurements of urinary interleukins IL-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels seem promising as well. Immunohistochemical markers (ie, TP53, Ki-67, and Rb)display contradictory results and seem unsuitable. Gene polymorphisms need to be studied more thoroughly before their clinical relevance can be determined. Regarding assessing and predicting response of MIBC to neoadjuvant chemotherapy, a set of potent markers has been studied. However, no conclusive evidence is yet available on their additional value over the established clinicopathological variables. Prospective trials are needed to validate the clinical benefit of molecular markers to predict response to BCG (NMIBC) and neoadjuvant chemotherapy (MIBC) before predictive biomarkers can become part of clinical practice.

Tanaka S, Aida K, Nishida Y, Kobayashi T
Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes.
Endocr J. 2013; 60(7):837-45 [PubMed] Related Publications
Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes.

Crende O, Sabatino M, Valcárcel M, et al.
Metastatic lesions with and without interleukin-18-dependent genes in advanced-stage melanoma patients.
Am J Pathol. 2013; 183(1):69-82 [PubMed] Related Publications
IL-18 is an immune-stimulating cytokine that promotes experimental melanoma metastasis via vascular endothelial growth factor (VEGF)-induced very late antigen (VLA)-4. We studied genes associated with the ability of melanoma cells to allow metastasis under IL-18 effects, and we verified their expression in metastatic lesions from patients with melanoma. Human melanoma cell lines with and without the IL-18 receptor (IL-18R)/VEGF/VLA-4-expressing phenotype were identified, and their metastatic potential was studied in nude mice. RNA from untreated and IL-18-treated melanoma phenotypes was hybridized to a cDNA microarray, and their signature genes were studied. RNA from primary and metastatic lesions from patients with melanoma was hybridized to a cDNA microarray to identify lesions with the transcript patterns of melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype. IL-18R/VEGF/VLA-4-expressing A375 and 1182 melanoma cells produced a higher metastasis number than 526 and 624.28 melanoma cells, not using this prometastatic pathway. Melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype had distinct transcript patterns. However, the type I transcriptional cluster, including cutaneous and lymph node metastases, but not the type II cluster, not including cutaneous metastases, had signature genes from IL-18-treated melanoma cells with, but not without, the IL-18R/VEGF/VLA-4 phenotype. Metastatic melanoma lesions with and without IL-18-dependent genes were identified, suggesting that melanoma metastasis developed via inflammation-dependent and inflammation-independent mechanisms. Signature genes from melanomas with and without the IL-18R/VEGF/VLA-4 phenotype may serve as diagnostic biomarkers of melanoma predisposition to prometastatic effects of IL-18.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Zhang S, Saha B, Kodys K, Szabo G
IFN-γ production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells.
J Hepatol. 2013; 59(3):442-9 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND & AIMS: Interferon-γ (IFN-γ), a cytokine produced by activated natural killer cells (NK) and T lymphocytes, is an important regulator of innate and adaptive immunity during hepatitis C virus (HCV) infection. However, the cellular sources and mechanisms of IFN-γ induction in HCV-infection are not fully understood.
METHODS: We cultured normal human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and JFH-1 HCV-infected HuH7.5 (JFH-1/HuH7.5) cells.
RESULTS: We found that PBMCs produced large amounts of IFN-γ after co-culture with JFH-1/HuH7.5 cells. Using intracellular cytokine staining, we confirmed that NK cells and NKT cells (to a lesser extent) were the major IFN-γ producers within PBMCs. Purified NK/NKT cells did not produce IFN-γ in response to JFH-1/HuH7.5 cells and depletion of accessory (HLA-DR(+)) cells prevented IFN-γ induction in PBMCs. Through selective cell depletion of dendritic cells or monocytes from PBMCs, we determined that plasmacytoid dendritic cells (pDCs) were indispensable for NK-IFN-γ induction and the presence of monocytes was needed for maximal NK-IFN-γ induction. We further revealed that NK-IFN-γ induction depended on pDC-derived IFN-α while other IFN-γ inducing cytokines, IL-12, and IL-18, played minimal roles. Close contact between JFH-1/HuH7.5 cells and NK cells was required for IFN-γ production and monocyte-derived IL-15 significantly augmented IFN-γ induction.
CONCLUSIONS: We discovered a novel mechanism where NK cells interact with pDCs and monocytes, efficiently producing IFN-γ in response to HCV-infected cells. This indicates that co-operation between NK cells and accessory cells is critical for IFN-γ production and regulation of immunity during HCV infection.

Teixeira AC, Mendes CT, Marano LA, et al.
Alleles and genotypes of polymorphisms of IL-18, TNF-α and IFN-γ are associated with a higher risk and severity of hepatocellular carcinoma (HCC) in Brazil.
Hum Immunol. 2013; 74(8):1024-9 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. We evaluated the association of alleles and genotypes of polymorphisms of IL-18 (-607C/A and -137G/C), IFN-γ (+874T/A) and TNF-α (-238G/A and -308G/A) with the risk and severity of HCC. One-hundred-and-twelve patients with HCC and 202 healthy controls were studied. Single nucleotide polymorphisms (SNPs) were amplified by PCR with specific primers and the products were submitted to polyacrylamide gel electrophoresis and stained with silver. We evaluated tumor presentation, tumor size and presence of metastasis. Significant higher risk of HCC was associated with: alleles IL-18 -607(*)A (P=0.0235; OR=1.48; 95%CI=1.06-2.08); TNF-α -238(*)A (P=0.0025; OR=2.12; 95%CI=1.32-3.40) and TNF-α -308(*)A (P=0.0351; OR=1.82; 95%CI=1.07-3.08); and genotypes IL-18-607AA (P=0.0048; OR=3.03; 95%CI=1.40-6.55); TNF-α -238GA (P=0.0011; OR=2.44; 95%CI=1.45-4.12); and TNF-α -308GA (P=0.0031; OR=2.51; 95%CI=1.39-4.51). Significant association was found between multinodular HCC and IL-18 -607(*)C allele (P=0.029; OR=2.40, 95%CI: 1.09-5.28), and IL-18 -607CC genotype (P=0.028; OR=3.5, 95%CI: 1.24-9.86). Diffuse HCC was significantly associated with IFN-γ +874TA genotype (P=0.044; OR=3.6, 95%CI: 1.03-12.47). The IL-18 -137(∗)C allele showed a significant association with the presence of metastasis. Thus, IL-18 -607(*)A and TNF-α (-238(*)A and -308(*)A) alleles may confer susceptibility to HCC, while IL-18 -607(*)C and -137(*)C alleles more severe disease.

Yang YC, Chang TY, Chen TC, et al.
Genetic variants in interleukin-18 gene and risk for cervical squamous cell carcinoma.
Hum Immunol. 2013; 74(7):882-7 [PubMed] Related Publications
Cervical cancer is strongly associated with infection of oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for progression to cervical cancer. It is now recognized that host immunogenetic background participates in the control of HPV infection and development of cervical cancer. Interleukin-18 (IL-18) is a multifunctional cytokine that induces interferon-gamma secretion and plays a central role in antitumor immunity. The aim of this study is to determine if potentially functional polymorphisms in IL-18 gene are associated with risk of HPV-induced cervical cancer in Taiwanese women. Pre-Developed TaqMan Allelic Discrimination Assay was used to genotype IL-18 -1297 T/C, -607 C/A, -380 C/G, -137 G/C, and +105 A/C polymorphisms in a hospital-based study of 470 women with cervical squamous cell carcinoma (CSCC) and 722 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined by PCR. None of the polymorphisms or any haplotype was found to have significant differences in distribution among all subjects with CSCC, those with HPV-16 positive CSCC, and controls. Our results suggest that the IL-18 -1297 T/C, -607 C/A, -380 C/G, -137 G/C, and +105 A/C polymorphisms are not associated with susceptibility to CSCC in Taiwanese women.

Liu JM, Liu JN, Wei MT, et al.
Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population.
Genet Mol Res. 2013; 12(1):820-9 [PubMed] Related Publications
Interleukin-18 (IL-18) has been implicated in a wide variety of cellular functions that affect the biological response to tumors. However, there is insufficient evidence to prove that IL-18 gene variants are associated with risk of prostate cancer. We examined a possible association between two promoter polymorphisms, -137G/C (rs187238) and -607C/A (rs1946518), in the IL-18 gene and prostate cancer occurrence and prognosis in Han Chinese. We used a high-resolution melting method to genotype these two polymorphisms in 375 Chinese Han patients with prostate cancer and in 400 age-matched healthy controls. A hundred and eighty-one prostate cancer patients who had been receiving androgen deprivation therapy, including operational and medical castration, were enrolled to follow-up in this study. Carriers of the GG genotype of the -137G/ C polymorphism had a 2.165-times higher risk of prostate cancer progression than carriers of GC [95% confidence interval (CI) = 1.270-3.687]. Patients with the GG genotype at clinical stages III and IV also had significantly lower rates of progression-free survival (relative risk = 2.174, 95%CI = 1.211-3.906). However, we found no significant association of genotype or allele distributions of these two polymorphisms with occurrence of prostate cancer. We conclude that there is evidence that the IL-18 gene promoter polymorphism -137G/ C influences the prognosis of prostate cancer patients in androgen deprivation therapy, although neither of the two SNPs contributes to prostate cancer development.

White KL, Vierkant RA, Fogarty ZC, et al.
Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome.
Cancer Epidemiol Biomarkers Prev. 2013; 22(5):987-92 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
BACKGROUND: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.
METHODS: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates.
RESULTS: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined.
CONCLUSIONS: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies.
IMPACT: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.

Jaiswal PK, Singh V, Srivastava P, Mittal RD
Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population.
Gene. 2013; 519(1):128-34 [PubMed] Related Publications
IL-12 and IL-18 are immunomodulatory cytokines that play important roles in host immune response against cancers. Variation in DNA sequence in gene promoter may lead to altered IL-18 production and/or activity, and hence can modulate an individual's susceptibility to BC. To test this hypothesis, we investigated the relationship of IL-18 gene promoter -137 G/C and -607C/A polymorphisms and IL12 (-16974) A/C with the risk of BC in North Indian population. Polymorphisms in IL-18 and IL-12 genes were analyzed in 200 BC patients and 200 age, ethnicity and sex-matched controls, using restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) and amplification refractory mutation specific-polymerase chain reaction (ARMS) method. The concentrations of IL-18 in serum were determined by ELISA. Significant association was observed with IL18 (-137) G/C heterozygous genotype (GC) with 1.96 folds risk of BC as well at C allele carrier and variant C allele having 2 fold and 1.6 fold risk for BC respectively. IL18 (-607) C/A, heterozygous CA genotype also showed a high risk (OR=1.59) for BC. While IL12 (-16974) A/C heterozygote genotype and C allele carrier demonstrated reduced risk of BC. Hetero genotype of IL18 (-137) G/C was associated with risk of recurrence (HR=2.35) in superficial BC patients receiving BCG treatment thus showing least survival. The distributions of IL-18 gene haplotypes were not significantly different between patients and controls. Serum IL-18 levels were significantly higher in BC patients than in the healthy subjects (p=0.025). Serum IL-18 levels was also significantly associated with IL18 (-137) G/C in heterozygous genotype (GC) (p=0.048). Our results suggest that IL-18 gene polymorphism contributes to bladder cancer risk whereas IL-12 is protective. A relation between IL18 (-137) G/C in heterozygous genotype with elevated IL-18 serum level and bladder cancer risk has been registered in the present study.

Kuppala MB, Syed SB, Bandaru S, et al.
Immunotherapeutic approach for better management of cancer--role of IL-18.
Asian Pac J Cancer Prev. 2012; 13(11):5353-61 [PubMed] Related Publications
Interleukin-18 (IL-18) is an immune-stimulatory cytokine with antitumor activity in preclinical models. It plays pivotal roles in linking inflammatory immune responses and tumor progression and is a useful candidate in gene therapy of lymphoma or lymphoid leukemia. A phase I study of recombinant human IL-18 (rhIL-18) in patients with advanced cancer concluded that rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. Some viruses can induce the secretion of IL-18 for immune evasion. The individual cytokine activity might be potentiated or inhibited by combinations of cytokines. Here we focus on combinational effects of cytokines with IL-18 in cancer progression. IL-18 is an important non-invasive marker suspected of contributing to metastasis. Serum IL-18 may a useful biological marker as independent prognostic factor of survival. In this review we cover roles of IL-18 in immune evasion, metastasis and angiogenesis, applications for chemotherapy and prognostic or diagnostic significance.

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