Gene Summary

Gene:IL1RN; interleukin 1 receptor antagonist
Aliases: DIRA, IRAP, IL1F3, IL1RA, MVCD4, IL-1RN, IL-1ra, IL-1ra3, ICIL-1RA
Summary:The protein encoded by this gene is a member of the interleukin 1 cytokine family. This protein inhibits the activities of interleukin 1, alpha (IL1A) and interleukin 1, beta (IL1B), and modulates a variety of interleukin 1 related immune and inflammatory responses. This gene and five other closely related cytokine genes form a gene cluster spanning approximately 400 kb on chromosome 2. A polymorphism of this gene is reported to be associated with increased risk of osteoporotic fractures and gastric cancer. Four alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-1 receptor antagonist protein
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
Show (30)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 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.

  • Sensitivity and Specificity
  • Genetic Predisposition
  • Interleukin-6
  • Interleukin 1 Receptor Antagonist Protein
  • Statistics, Nonparametric
  • Staging
  • Vulvar Cancer
  • Thailand
  • Prostatic Hyperplasia
  • Polymorphism
  • Minisatellite Repeats
  • Xenograft Models
  • Chromosome 2
  • Interleukin-1beta
  • Case-Control Studies
  • Alleles
  • Adenocarcinoma
  • Cytokines
  • Helicobacter pylori and cancer
  • Haplotypes
  • Asian Continental Ancestry Group
  • Promoter Regions
  • Helicobacter Infections
  • European Continental Ancestry Group
  • Single Nucleotide Polymorphism
  • Interleukin-1
  • Cervical Cancer
  • Adolescents
  • Stomach Cancer
  • Cancer Gene Expression Regulation
  • Receptors, Interleukin-1
  • TNF
  • Genotype
  • Sialoglycoproteins
  • Ultraviolet Rays
  • Risk Factors
  • Sweden
  • Polymerase Chain Reaction
  • Odds Ratio
  • Smoking
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: IL1RN (cancer-related)

Chittezhath M, Dhillon MK, Lim JY, et al.
Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression.
Immunity. 2014; 41(5):815-29 [PubMed] Related Publications
Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.

Golozar A, Beaty TH, Gravitt PE, et al.
Oesophageal squamous cell carcinoma in high-risk Chinese populations: Possible role for vascular epithelial growth factor A.
Eur J Cancer. 2014; 50(16):2855-65 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Mechanisms involved in wound healing play some role in carcinogenesis in multiple organs, likely by creating a chronic inflammatory milieu. This study sought to assess the role of genetic markers in selected inflammation-related genes involved in wound healing (interleukin (IL)-1a, IL-1b, IL-1 Receptor type I (IL-1Ra), IL-1 Receptor type II (IL-1Rb), tumour necrosis factor (TNF)-α, tumour necrosis factor receptor superfamily member (TNFRSF)1A, nuclear factor kappa beta (NF-kB)1, NF-kB2, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, hypoxia induced factor (HIF)-1α, vascular endothelial growth factor (VEGF)A and P-53) in risk to oesophageal squamous cell carcinoma (OSCC).
METHODS: We genotyped 125 tag single nucleotide polymorphism (SNP)s in 410 cases and 377 age and sex matched disease-free individuals from Nutritional Intervention Trial (NIT) cohort, and 546 cases and 556 controls individually matched for age, sex and neighbourhood from Shanxi case-control study, both conducted in high-risk areas of north-central China (1985-2007). Cox proportional-hazard models and conditional logistic regression models were used for SNPs analyses for NIT and Shanxi, respectively. Fisher's inverse test statistics were used to obtain gene-level significance.
RESULTS: Multiple SNPs were significantly associated with OSCC in both studies, however, none retained their significance after a conservative Bonferroni adjustment. Empiric p-values for tag SNPs in VEGFA in NIT were highly concentrated in the lower tail of the distribution, suggesting this gene may be influencing risk. Permutation tests confirmed the significance of this pattern. At the gene level, VEGFA yielded an empiric significance (P=0.027) in NIT. We also observed some evidence for interaction between environmental factors and some VEGFA tag SNPs.
CONCLUSION: Our finding adds further evidence for a potential role for markers in the VEGFA gene in the development and progression of early precancerous lesions of oesophagus.

Di Mitri D, Toso A, Chen JJ, et al.
Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.
Nature. 2014; 515(7525):134-7 [PubMed] Related Publications
Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.

Li S, Wang W, Zhang N, et al.
IL-1β mediates MCP-1 induction by Wnt5a in gastric cancer cells.
BMC Cancer. 2014; 14:480 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BACKGROUND: Both Wnt5a overexpression and macrophage infiltration have been implicated in inflammation and cancer. The aim of this study is to reveal the involvement of Wnt5a in macrophage recruitment in gastric cancer.
METHODS: mRNA expression in gastric cancer tissues and cells was investigated by real-time PCR. Protein secretion by gastric cancer cells was determined by ELISA. PcDNA3.1-Wnt5a expression vector and Wnt5a siRNA vector were used to overexpress and silence Wnt5a expression in gastric cells, respectively. Macrophage migration was analyzed by transwell, and macrophage cytoskeleton was stained with FITC-phalloidin.
RESULTS: Wnt5a was overexpressed in gastric cancer tissues, and correlated with monocyte chemotactic protein 1 (MCP-1) and interleukin 1β (IL-1β), respectively. In gastric cancer cells, Wnt5a induced MCP-1 expression, which was mediated by IL-1β. Conditioned medium from gastric cancer cells transfected with Wnt5a stimulated macrophage chemotaxis and cytoskeletal changes via MCP-1, which were suppressed by recombinant IL-1 receptor antagonist (rIL-1Ra).
CONCLUSIONS: These results suggest that Wnt5a is involved in macrophage recruitment by upregulating MCP-1, and IL-1Ra may be used to inhibit macrophage recruitment in gastric cancer.

Gonzalez-Hormazabal P, Musleh M, Bustamante M, et al.
Role of cytokine gene polymorphisms in gastric cancer risk in Chile.
Anticancer Res. 2014; 34(7):3523-30 [PubMed] Related Publications
AIM: To assess the role of pro- and anti-inflammatory polymorphisms in gastric cancer susceptibility.
PATIENTS AND METHODS: We genotyped 12 polymorphisms in eight cytokine genes (Interleukin-1β -IL1B-, IL8, IL17A, IL17F, IL32, tumor necrosis factor-α -TNF-, IL1RN, IL10) in a case-control study of 147 patients with gastric cancer and 172 controls.
RESULTS: Single polymorphism analysis revealed an association between the IL10 -592C>A single nucleotide polymorphism and cases with moderately- or well-differentiated tumors [AA vs. GG, odds ratio (OR)=3.01; 95% confidence interval (CI)=1.08-8.50]. We further analyzed gene-gene interactions using a combined attribute network implemented in multifactor dimensionality reduction software. The analysis revealed an interaction between IL8 -251A>T and IL32 rs28372698 SNPs among cases with moderately- or well-differentiated tumors. Homozygosity for both IL8 -251T and IL32 T alleles increases the odds for developing gastric cancer up to 2.63-fold (OR=2.63; 95% CI=1.15-6.03). This association was higher compared to the homozygosity for the IL8-251 T allele alone (OR=1.11; 95% CI=0.51-2.43) or the IL32 T allele alone (OR=1.21; 95% CI=0.54-2.72).
CONCLUSION: These findings suggest that IL10 -592C>A increases the odds for developing gastric cancer. An interaction between IL8 -251A>T and IL32 rs28372698 SNPs is also proposed.

Wu S, Hu G, Chen J, Xie G
Interleukin 1β and interleukin 1 receptor antagonist gene polymorphisms and cervical cancer: a meta-analysis.
Int J Gynecol Cancer. 2014; 24(6):984-90 [PubMed] Related Publications
OBJECTIVES: Previous studies investigating the association between interleukin 1β (IL-1β) and its receptor antagonist (IL-1RN) polymorphism and cervical cancer risk have reported controversial results. Thus, we examined these associations by performing meta-analyses.
METHODS AND MATERIALS: Fourteen studies testing the association between IL-1β and/or IL-1RN gene polymorphisms and cervical cancer were examined: 5 studies of IL-1β-511C/T, 3 studies of IL-1β-31T/C, and 6 studies of IL-1RN. Overall and ethnicity-specific summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for cervical cancer associated with these polymorphisms were estimated using fixed- and random-effects models. Heterogeneity and publication bias were evaluated.
RESULTS: Meta-analysis of all 6 studies showed variant genotypes of IL-1RN to be associated with an elevated cervical cancer risk (RN2/RN2 vs RN1/RN1: OR, 2.64; 95% CI, 1.29-5.40; recessive: OR, 2.15; 95% CI, 1.06-4.38; dominant: OR, 1.60; 95% CI, 1.07-2.38). Combined analysis indicated that IL-1β-511C/T polymorphism was also associated with increased risk of cervical cancer (TT vs CC: OR, 1.56; 95% CI, 1.22-1.99; CT vs CC: OR, 1.61; 95% CI, 1.31-1.99; dominant: OR, 1.60; 95% CI, 1.31-1.95). No significant association of IL-1β-31T/C and cervical cancer risk was detected. There was no evidence of publication bias.
CONCLUSIONS: This meta-analysis suggested that the IL-1RN and IL-1β-511C/T polymorphisms may contribute to genetic susceptibility of cervical cancer. More studies are needed to further evaluate the role of the IL-1β-31T/C polymorphism in the etiology of cancer.

Pehlivan M, Sahin HH, Ozdilli K, et al.
Gene polymorphisms and febrile neutropenia in acute leukemia--no association with IL-4, CCR-5, IL-1RA, but the MBL-2, ACE, and TLR-4 are associated with the disease in Turkish patients: a preliminary study.
Genet Test Mol Biomarkers. 2014; 18(7):474-81 [PubMed] Related Publications
AIMS: The aim of this study was to investigate the mannose-binding lectin 2 (MBL-2), interleukin (IL)-4, Toll-like receptor 4 (TLR-4), angiotensin converting enzyme (ACE), chemokine receptor 5 (CCR-5), and IL-1 receptor antagonist (RA) gene polymorphisms (GPs) in acute leukemias (ALs) and to evaluate their roles in febrile neutropenia (FN) resulting from chemotherapy.
METHODS: The study included 60 AL patients hospitalized between the period of July 2001 and August 2006. Polymorphisms for the genes ACE(I/D), CCR-5, IL-1RA, MBL-2, TLR-4, and IL-4 were typed by polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymerase. Genotype frequencies for these genes were compared in the patient and control groups. The relationships between the genotypes and the body distribution of infections, pathogens, the duration of neutropenia, and febrile episodes in AL patients were evaluated.
RESULTS: No significant differences in either the genotype distribution or the allelic frequencies of TLR-4, IL-4, CCR-5, IL-1RN GPs were observed between patients and healthy controls. The AB/BB genotype (53.3%) in the MBL-2 gene was found to be significantly higher in the AL patients compared with control groups. There were correlations between the presence of MBL-2, TLR-4, and ACE polymorphisms and clinical parameters due to FN. Overall, bacteremia was more common in MBL BB and ACE DD. Gram-positive bacteremia was more common in ACE for ID versus DD genotype. Gram-negative bacteremia was more common for both the MBL-2 AB/BB genotype and TLR-4 AG genotype. Median durations of febrile episodes were significantly shorter in ACE DD and MBL AB/BB.
CONCLUSION: Although TLR-4, ACE, and MBL-2 GPs have been extensively investigated in different clinical pictures, this is the first study to evaluate the role of these polymorphisms in the genetic etiopathogenesis of FN in patients with ALs. As a conclusion, TLR-4, ACE, and MBL-2 genes might play roles in the genetic etiopathogenesis of FN in patients with ALs.

Chiurillo MA
Role of gene polymorphisms in gastric cancer and its precursor lesions: current knowledge and perspectives in Latin American countries.
World J Gastroenterol. 2014; 20(16):4503-15 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Latin America shows one of the highest incidence rates of gastric cancer in the world, with variations in mortality rates among nations or even within countries belonging to this region. Gastric cancer is the result of a multifactorial complex process, for which a multistep model of carcinogenesis is currently accepted. Additionally to the infection with Helicobacter pylori, that plays a major role, environmental factors as well as genetic susceptibility factors are significant players at different stages in the gastric cancer process. The differences in population origin, demographic structure, socio-economic development, and the impact of globalization lifestyles experienced in Latin America in the last decades, all together offer opportunities for studying in this context the influence of genetic polymorphisms in the susceptibility to gastric cancer. The aim of this article is to discuss current trends on gastric cancer in Latin American countries and to review the available published information about studies of association of gene polymorphisms involved in gastric cancer susceptibility from this region of the world. A total of 40 genes or genomic regions and 69 genetic variants, 58% representing markers involved in inflammatory response, have been used in a number of studies in which predominates a low number of individuals (cases and controls) included. Polymorphisms of IL-1B (-511 C/T, 14 studies; -31 T/C, 10 studies) and IL-1RN (variable number of tandem repeats, 17 studies) are the most represented ones in the reviewed studies. Other genetic variants recently evaluated in large meta-analyses and associated with gastric cancer risk were also analyzed in a few studies [e.g., prostate stem cell antigen (PSCA), CDH1, Survivin]. Further and better analysis centered in gene polymorphisms linked to other covariates, epidemiological studies and the information provided by meta-analyses and genome-wide association studies should help to improve our understanding of gastric cancer etiology in order to develop appropriate health programs in Latin America.

Oliveira A, Dinis-Oliveira RJ, Nogueira A, et al.
Interleukin-1β genotype and circulating levels in cancer patients: metastatic status and pain perception.
Clin Biochem. 2014; 47(13-14):1209-13 [PubMed] Related Publications
OBJECTIVES: Proinflammatory cytokines released during inflammation can cause hyperexcitability in pain transmission neurons, leading to hyperalgesia and allodynia. Polymorphisms in interleukin 1 (IL-1) family of genes (IL1A, IL1B) and in IL-1 receptor antagonist (IL-1Ra, coded by IL1RN) may therefore induce alterations in cytokine levels/effects and pain related response. Our purpose was to investigate the influence of polymorphisms in IL1A/B/RN on cytokine serum levels and its correlation with pain intensity, performance status, adverse effects, metastases and breakthrough pain in Caucasian cancer patients.
DESIGN AND METHODS: Serum IL-1α/β levels of 74 cancer patients were measured by competitive enzyme immunosorbent assay. All patients were also genotyped for the polymorphisms in IL1A (rs17561), IL1B (rs1143634) and IL1RN (rs419598) with Real-Time PCR. Results were then correlated to the appearance of bone or CNS metastases and several pain-related parameters.
RESULTS: IL-1β rs1143634 homozygous for T allele were associated with lower levels of IL1-β (p=0.032, Mann-Whitney test) and presented a trend for lower levels of pain (p=0.06, Fisher's Exact Test). Also, IL1-β levels were related with cancer onset status, since a four-fold increase probability of metastatic disease was observed in high IL-1β individuals (OR=4.074, p=0.010, Pearson χ(2) test). Among the female patients presenting metastatic disease and carriers of the TT genotype we observed a trend to lower levels of IL1-β (p=0.053, Pearson χ(2) test).
CONCLUSIONS: Our results indicate that genetic variation at IL1-β gene may influence serum levels of IL1-β, with proportional consequences in cancer-related pain.

Slattery ML, Herrick JS, Torres-Mejia G, et al.
Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: the Breast Cancer Health Disparities Study.
Carcinogenesis. 2014; 35(8):1750-9 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Interleukins (ILs) are key regulators of immune response. Genetic variation in IL genes may influence breast cancer risk and mortality given their role in cell growth, angiogenesis and regulation of inflammatory process. We examined 16 IL genes with breast cancer risk and mortality in an admixed population of Hispanic/Native American (NA) (2111 cases and 2597 controls) and non-Hispanic white (NHW) (1481 cases and 1585 controls) women. Adaptive Rank Truncated Product (ARTP) analysis was conducted to determine gene significance and lasso (least absolute shrinkage and selection operator) was used to identify potential gene by gene and gene by lifestyle interactions. The pathway was statistically significant for breast cancer risk overall (P ARTP = 0.0006), for women with low NA ancestry (P(ARTP) = 0.01), for premenopausal women (P(ARTP) = 0.02), for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors (P(ARTP) = 0.03) and ER-/PR- tumors (P(ARTP) = 0.02). Eight of the 16 genes evaluated were associated with breast cancer risk (IL1A, IL1B, IL1RN, IL2, IL2RA, IL4, IL6 and IL10); four genes were associated with breast cancer risk among women with low NA ancestry (IL1B, IL6, IL6R and IL10), two were associated with breast cancer risk among women with high NA ancestry (IL2 and IL2RA) and four genes were associated with premenopausal breast cancer risk (IL1A, IL1B, IL2 and IL3). IL4, IL6R, IL8 and IL17A were associated with breast cancer-specific mortality. We confirmed associations with several functional polymorphisms previously associated with breast cancer risk and provide support that their combined effect influences the carcinogenic process.

Durães C, Muñoz X, Bonet C, et al.
Genetic variants in the IL1A gene region contribute to intestinal-type gastric carcinoma susceptibility in European populations.
Int J Cancer. 2014; 135(6):1343-55 [PubMed] Related Publications
The most studied genetic susceptibility factors involved in gastric carcinoma (GC) risk are polymorphisms in the inflammation-linked genes interleukin 1 (IL1) B and IL1RN. Despite the evidence pointing to the IL1 region, definite functional variants reproducible across populations of different genetic background have not been discovered so far. A high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to identify haplotype tagSNPs. Eighty-seven SNPs were genotyped in a Portuguese case-control study (358 cases, 1,485 controls) for the discovery analysis. A replication study, including a subset of those tagSNPs (43), was performed in an independent analysis (EPIC-EurGast) containing individuals from 10 European countries (365 cases, 1284 controls). Single SNP and haplotype block associations were determined for GC overall and anatomopathological subtypes. The most robust association was observed for SNP rs17042407, 16Kb upstream of the IL1A gene. Although several other SNP associations were observed, only the inverse association of rs17042407 allele C with GC of the intestinal type was observed in both studies, retaining significance after multiple testing correction (p = 0.0042) in the combined analysis. The haplotype analysis of the IL1A LD block in the combined dataset revealed the association between a common haplotype carrying the rs17042407 variant and GC, particularly of the intestinal type (p = 3.1 × 10(-5) ) and non cardia localisation (p = 4.6 × 10(-3) ). These results confirm the association of IL1 gene variants with GC and reveal a novel SNP and haplotypes in the IL1A region associated with intestinal type GC in European populations.

Wen YY, Pan XF, Loh M, et al.
Association of the IL-1B +3954 C/T polymorphism with the risk of gastric cancer in a population in Western China.
Eur J Cancer Prev. 2014; 23(1):35-42 [PubMed] Related Publications
With an estimate of 380 000 new cases each year, gastric cancer (GC) is one of the most frequently occurring cancers in China. Genes encoding proinflammatory and anti-inflammatory cytokines are good candidates for the study of susceptibility to GC. We tested the hypothesis that the polymorphisms of interleukin 1B (IL-1B) and IL-1RN contribute toward host susceptibility to GC. In a matched case-control design, we enrolled 308 pairs of GC and control participants between October 2010 and August 2011. We sequenced IL-1B +3954 C/T, IL-1RN -9876 G/A, -9739 A/G, and IL-1RN -9091 A/C using MALDI-TOF MS and collected demographic data as well as lifestyle factors using a questionnaire. GC patients reported statistically significantly greater proportions with family history of cancer (29.9 vs. 10.7%, P<0.01) and alcohol drinking (54.5 vs. 43.2%, P<0.01) than the controls. The proportion of irregular eaters was statistically higher among the patients than among the controls (66.7 vs. 24.4%, P<0.01). The IL-1B +3954 CT or the TT variant genotype was statistically significantly associated with a risk of GC [adjusted odds ratio (OR), 2.94; 95% confidence interval (CI), 1.06-8.15], whereas variants of IL-1RN -9876 G/A, IL-1RN -9739 A/G, and IL-1RN -9091 A/C were not associated (adjusted OR, 1.29, 95% CI, 0.77-2.16; adjusted OR, 1.25, 95% CI, 0.75-2.07; adjusted OR, 1.09, 95% CI, 0.71-1.67, respectively). Haplotypes established from the three polymorphisms of IL-1RN were not associated with a risk of GC. The IL-1B +3954 C/T polymorphism is associated with a risk of GC in our study. Lifestyle and environmental factors such as drinking, eating irregularly, and family history of cancer increase the risk.

Wang YQ, Li YM, Li X, et al.
Hypermethylation of TGF-β1 gene promoter in gastric cancer.
World J Gastroenterol. 2013; 19(33):5557-64 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
AIM: To examine transforming growth factor-β1 (TGF-β1) promoter methylation in gastric cancer and to determine if Helicobacter pylori (H. pylori) or interleukin (IL)-1β could induce TGF-β1 hypermethylation in vitro.
METHODS: We examined the frequency and extent of TGF-β1 promoter methylation using methylation-specific PCR in the gastric tissues from 47 gastric cancer patients and 39 non-gastric cancer subjects. H. pylori infection was confirmed by a positive result from either a serological test, histological analysis or C¹³ urea breath test. GES-1 and MKN-45 cells co-cultured with H. pylori or treated with IL-1β for 12, 24 and 48 h in vitro tested the effects of H. pylori or IL-1β on TGF-β1.
RESULTS: Twenty-four/forty-seven (51%) cases of gastric cancer (GC) tissues showed TGF-β1 promoter methylation, 15/47 (31.9%) cases of matched non-cancerous gastric mucosa tissues from the GC patients, and 11/39 (28%) case of the normal gastric mucosa tissues from non-GC subjects showed TGF-β1 promoter methylation (51% vs 28%, P < 0.05). Significantly higher levels of methylation of TGF-β1 were found in the tumor tissues than in non-tumor tissues from GC patients (0.24 ± 0.06 vs 0.17 ± 0.04, P < 0.05) and normal gastric tissues from non-GC subjects (0.24 ± 0.06 vs 0.15 ± 0.03, P < 0.05). TGF-β1 methylation was found in 48.3% of H. pylori-positive gastric mucosal tissues whereas only 23.1% of H. pylori-negative gastric mucosal tissues showed TGF-β1 methylation (48.3% vs 23.1%, P < 0.05). IL-1β appeared to induce a dose-dependent methylation of TGF-β1 and the strongest methylation was observed in GES-1 cells treated with 2.5 ng/mL of IL-1β for 48 h. Further studies showed that pre-treatment of GES-1 cells with 20 ng/mL IL-1RA for 1 h could partially abolish the effect of IL-1β on TGF-β1 methylation. Infection of GES-1 cells by H. pylori was not found to induce significant TGF-β1 promoter methylation.
CONCLUSION: Our data revealed that TGF-β1 promoter is methylated in GC patients. IL-1β may be an important mediator for H. pylori induced gene methylation during GC development.

Xiao H, Chen L, Luo G, et al.
Effect of the cytokine levels in serum on osteosarcoma.
Tumour Biol. 2014; 35(2):1023-8 [PubMed] Related Publications
Osteosarcoma (OS) is the most common malignant bone tumor in patients under 20 years old. Studies have shown that cytokines play important roles in regulating immune responses in OS. In the current study, we investigated the effect of cytokines on OS by assessing serum cytokine profiles. Serum levels of 11 cytokines were measured by multiplex protein arrays in 58 patients with OS and 72 healthy controls. Results showed that serum levels of interleukin 1 receptor antagonist (IL-1Ra), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α) were significantly increased in patients than in controls (2.5-fold, 2.4-fold, 2.7-fold, and 2.1-fold, respectively). When comparing the expression of cytokines in OS patients with different clinical parameters, cases with osteoblastic subtype revealed increased level of IL-6 than patients with other subtypes (p < 0.05); cases with metastasis demonstrated significantly higher level of TNF-α than those without metastasis (p < 0.05), whereas OS patients whose tumor size were bigger than 8 cm presented elevated levels of IL-8 and TNF-α than those with small tumor size (p < 0.05 and p < 0.05, respectively). These data indicated that IL-1Ra, IL-6, IL-8, and TNF-α were associated with increased risk of OS, in which IL-8 and TNF-α may be further correlated with the progression of this disease.

Gong Z, Quan L, Yao S, et al.
Innate immunity pathways and breast cancer Risk in African American and European-American women in the Women's Circle of Health Study (WCHS).
PLoS One. 2013; 8(8):e72619 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g., inflammatory responses) have received little attention as potential mechanisms underlying this disparity. We evaluated distributions of selected genetic variants in innate immune pathways in AA and EA women, and examined their associations with breast cancer risk within the Women's Circle of Health Study (WCHS). In stage I of the study (864 AA and 650 EA women) we found that genotype frequencies for 35 of 42 tested SNPs (18 candidate genes) differed between AAs and EAs (corroborated by ancestry informative markers). Among premenopausal AA women, comparing variant allele carriers to non-carriers, reduced breast cancer risk was associated with CXCL5-rs425535 (OR=0.61, P=0.02), while among EA women, there were associations with TNFA-rs1799724 (OR =2.31, P =0.002) and CRP-rs1205 (OR=0.54, P=0.01). For postmenopausal women, IL1B-rs1143627 (OR=1.80, P=0.02) and IL1B-rs16944 (OR=1.85, P =0.02) were associated with risk among EA women, with significant associations for TNFA-rs1799724 limited to estrogen receptor (ER) positive cancers (OR=2.0, P =0.001). However, none of the SNPs retained significance after Bonferroni adjustment for multiple testing at the level of P0.0012 (0.05/42) except for TNFA-rs1799724 in ER positive cancers. In a stage II validation (1,365 AA and 1,307 EA women), we extended evaluations for four SNPs (CCL2-rs4586, CRP-rs1205, CXCL5-rs425535, and IL1RN-rs4251961), which yielded similar results. In summary, distributions of variants in genes involved in innate immune pathways were found to differ between AA and EA populations, and showed differential associations with breast cancer according to menopausal or ER status. These results suggest that immune adaptations suited to ancestral environments may differentially influence breast cancer risk among EA and AA women.

Tjomsland V, Bojmar L, Sandström P, et al.
IL-1α expression in pancreatic ductal adenocarcinoma affects the tumor cell migration and is regulated by the p38MAPK signaling pathway.
PLoS One. 2013; 8(8):e70874 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.

Marcos-Pinto R, Dinis-Ribeiro M, Carneiro F, et al.
First-degree relatives of early-onset gastric cancer patients show a high risk for gastric cancer: phenotype and genotype profile.
Virchows Arch. 2013; 463(3):391-9 [PubMed] Related Publications
First-degree relatives (FDR) of early-onset gastric cancer (EOGC) is presumed to be a population with a distinct molecular and phenotypic profile, regarding the prevalence of gastric premalignant conditions and the association with Helicobacter pylori infection and host proinflammatory gene polymorphisms. A case-control study was conducted with FDR of EOGC patients (n = 103) and age and gender matched controls (n = 101; ranging from spouses to neighbors and dyspeptics). Upper endoscopy was performed, Operative Link on Gastritis Assessment (OLGA) system used for staging and H. pylori (cagA and vacA) and host IL1B-511, IL1RN intron2 VNTR and IFNGR1-56 genotyping. Seventy percent of cases showed atrophy, while 19 % presented with high-stage gastritis (OLGA stage III or IV) (p < 0.001); gastric dysplasia was present in seven cases (vs none in controls) (p = 0.007). In cases, H. pylori was present in 82 % (vs 62 % in controls; p = 0.004) with vacA s1 and vacA m1 + strains significantly associated with the presence of atrophy; individuals homozygous for IL1B-511*T present a significantly higher risk for dysplasia. An increased global prevalence of IFNGR1-56*T/*T polymorphism (37 % in cases vs 24 % in controls; p = 0.03) was observed with no association with atrophic changes or dysplasia. All trends observed were kept when comparing FDR of EOGC with spouses, neighbors, or dyspeptic controls. We demonstrated that FDR of EOGC patients have an increased prevalence of high-risk OLGA stages and dysplasia that seem to be associated with high virulence H. pylori strains and pro-inflammatory host genotypes, including a possible population-specific risk marker. FDR of EOGC patients may merit specific management through endoscopic and histopathological adequate assessment of gastric mucosa and surveillance.

Murakami Y, Watari K, Shibata T, et al.
N-myc downstream-regulated gene 1 promotes tumor inflammatory angiogenesis through JNK activation and autocrine loop of interleukin-1α by human gastric cancer cells.
J Biol Chem. 2013; 288(35):25025-37 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
The expression of N-myc downstream-regulated gene 1 (NDRG1) was significantly correlated with tumor angiogenesis and malignant progression together with poor prognosis in gastric cancer. However, the underlying mechanism for the role of NDRG1 in the malignant progression of gastric cancer remains unknown. Here we examined whether and how NDRG1 could modulate tumor angiogenesis by human gastric cancer cells. We established NU/Cap12 and NU/Cap32 cells overexpressing NDRG1 in NUGC-3 cells, which show lower tumor angiogenesis in vivo. Compared with parental NU/Mock3, NU/Cap12, and NU/Cap32 cells: 1) induced higher tumor angiogenesis than NU/Mock3 cells accompanied by infiltration of tumor-associated macrophages in mouse dorsal air sac assay and Matrigel plug assay; 2) showed much higher expression of CXC chemokines, MMP-1, and the potent angiogenic factor VEGF-A; 3) increased the expression of the representative inflammatory cytokine, IL-1α; 4) augmented JNK phosphorylation and nuclear expression of activator protein 1 (AP-1). Further analysis demonstrated that knockdown of AP-1 (Jun and/or Fos) resulted in down-regulation of the expression of VEGF-A, CXC chemokines, and MMP-1, and also suppressed expression of IL-1α in NDRG1-overexpressing cell lines. Treatment with IL-1 receptor antagonist (IL-1ra) resulted in down-regulation of JNK and c-Jun phosphorylation, and the expression of VEGF-A, CXC chemokines, and MMP-1 in NU/Cap12 and NU/Cap32 cells. Finally, administration of IL-1ra suppressed both tumor angiogenesis and infiltration of macrophages by NU/Cap12 in vivo. Together, activation of JNK/AP-1 thus seems to promote tumor angiogenesis in relationship to NDRG1-induced inflammatory stimuli by gastric cancer cells.

Yang DR, Ding XF, Luo J, et al.
Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer.
J Biol Chem. 2013; 288(23):16476-83 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.

da Costa DM, Neves-Filho EH, Alves MK, Rabenhorst SH
Interleukin polymorphisms and differential methylation status in gastric cancer: an association with Helicobacter pylori infection.
Epigenomics. 2013; 5(2):167-75 [PubMed] Related Publications
AIM: Interleukin polymorphisms and Helicobacter pylori infection are believed to play critical roles in DNA methylation, a process frequently associated with carcinogenesis. The aim of this study was to determine the associations between interleukin polymorphisms and methylation status of three genes related to gastric cancer. Furthermore, the influence of the H. pylori strains was evaluated.
MATERIALS & METHODS: 75 gastric tumor samples had the DNA extracted for interleukin polymorphisms genotyping by PCR-RFLP, promoter methylation by MS-PCR and detection and subtyping of H. pylori by PCR.
RESULTS: In the cardia tumors, methylation in the COX-2 promoter was associated with IL1RN*2 (p = 0.015), and the associated genotypes IL1B511T + IL1RN*2 seem to be important in the methylation of COX-2 (p = 0.013), especially in the presence of cagA(+) (p = 0.026) and vacAs1 (p = 0.025) H. pylori strains. The associated genotypes IL6 CC+TNF GG seem to be involved in the unmethylation of CDKN2A (p = 0.046), along with H. pylori cagA(+) infection.
CONCLUSION: DNA methylation in gastric cancer seems to be influenced by the presence of interleukin polymorphisms and by the H. pylori cagA/vacAs1m1 strains.

Sousa H, Breda E, Santos AM, et al.
IL-1RN VNTR polymorphism as a susceptibility marker for nasopharyngeal carcinoma in Portugal.
Arch Oral Biol. 2013; 58(8):1040-6 [PubMed] Related Publications
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare malignancy in Western countries that is widely associated with the infection by Epstein-Barr virus (EBV). Several studies have showed that a common allele (allele 2) of the 86-bp variable number of tandem repeats (VNTR) polymorphism within intron 2 of the interleukin 1 receptor antagonist (IL-1RN) gene is associated with several disorders, including viral-associated cancers.
METHODS: We have developed a hospital-based case-control study to characterise the role of the IL-1RN 86-bp VNTR polymorphism in the development of NPC with 112 patients with the disease and 433 healthy individuals from the northern region of Portugal. IL-1RN genotypes were combined according to the number of repeats: allele 2 (A2), the short allele that corresponds to two repeats, and L, the long allele that corresponds to three or more repeats.
RESULTS: Our study revealed that 31.2% of NPC patients were IL-1RN A2*A2, compared with 9.7% observed in the control group. The statistical analysis revealed that IL-1RN*A2 homozygosity for the A2 allele was associated with a fourfold increased risk for NPC development (p<0.001). Additionally, cumulative hazard analysis revealed that estimated median age of onset of NPC is significantly (p<0.001) different for A2*A2 homozygous versus non-A2*A2 (57.0 vs. 74.0, respectively).
CONCLUSIONS: This is the first study to evaluate the role of the IL-1RN VNTR in NPC development in Portugal. Our study indicates IL-1RN*A2 homozygosity as a significant risk marker in our population and that it should be further investigated for the potential role in the definition of a susceptibility profile for NPC onset.

Xia YH, Yao L, Zhang ZX
Correlation between IL-1β, IL-1Ra gene polymorphism and occurrence of polycystic ovary syndrome infertility.
Asian Pac J Trop Med. 2013; 6(3):232-6 [PubMed] Related Publications
OBJECTIVE: To explore the relationship between IL-1β, IL-1Ra gene polymorphism and the occurrence of polycystic ovary syndrome (PCOS) infertility.
METHODS: A total of 59 PCOS infertility cases visiting the reproductive center of our hospital from Mar. 2010 to Mar. 2012 and 56 healthy women were selected. ELISA method was used for the detection of IL-1β, IL-1Ra levels, and the levels of serum supersensitivity C reaction protein (US-CRP), insulin (FINS), follicule-stimulating hormone (FSH) and fasting blood-glucose (FBG) were detected. PCR analysis technology was adopted to detect the gene polymorphism of the 511 site of IL-1β and the second introne of IL-1Ra.
RESULTS: The levels of IL-1β, IL-1Ra, US-CRP, FINS and FBG in blood serum of patients in PCOS group were significantly higher than those in control group (P<0.05 or P<0.01). The level of FSH in PCOS group was significantly lower than that in control group (P<0.05). The genotypic frequency of T/T, the 511 site of IL-1β in PCOS group was 42.37%, significantly higher than 12.50% in control group (P<0.01). The frequency of T allele was also significantly higher than that in control group (P<0.01). The genotypic frequency of I/V, the second introne of IL-1Ra in PCOS group was 20.34%, signiciantly higher than 3.57% in control group (P<0.05). The frequency of V allele in PCOS group was significantly higher than that in control group (P<0.05).
CONCLUSIONS: T allele of the 511 site of IL-1β gene and V allele of the second introne of IL-1Ra gene might be the genetic basis of the rising of IL-1β, IL-1Ra and US-CRP levels in blood serum of PCOS patients, and are associated with the infertility occurrence of PCOS patients.

Burada F, Dumitrescu T, Nicoli R, et al.
IL-1RN +2018T>C polymorphism is correlated with colorectal cancer.
Mol Biol Rep. 2013; 40(4):2851-7 [PubMed] Related Publications
Epidemiological and experimental evidence indicates chronic inflammation as a risk factor for colorectal cancer. We investigated whether IL-1B -511C>T (rs16944), IL-1B +3954C>T (rs1143634) and IL1-RN +2018T>C (rs419598) cytokine polymorphisms are correlated with colorectal cancer. Blood samples were obtained from 377 Romanian subjects: 144 patients with sporadic colorectal cancer and 233 healthy controls. Polymorphisms were analyzed by allelic discrimination TaqMan PCR assays with specific probes. The results of our study showed that IL-1RN +2018T>C polymorphism is associated with colorectal cancer. We found that there was a significant difference in the frequency of CC genotype between patients with colorectal cancer and the control group (OR 2.42, 95 % CI: 1.06-5.53, p = 0,034) when TT genotype was used as reference. Furthermore, in a stratified analysis, a positive association was found only for IL-1RN +2018CC genotype, that was limited to early I and II stages (OR 2.72, 95 % CI: 1.05-7.03, p = 0,033). We did not find any association between any of the IL-1B polymorphisms and colorectal cancer. In conclusion this study found that IL-1RN +2018T>C polymorphism is associated with colorectal cancer, mainly for localized disease.

Byrne LS, Peng J, Sarkar S, Chang SL
Interleukin-1 beta-induced up-regulation of opioid receptors in the untreated and morphine-desensitized U87 MG human astrocytoma cells.
J Neuroinflammation. 2012; 9:252 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Interleukin-1beta (IL-1β) is a pro-inflammatory cytokine that can be produced in the central nervous system during inflammatory conditions. We have previously shown that IL-1β expression is altered in the rat brain during a morphine tolerant state, indicating that this cytokine may serve as a convergent point between the immune challenge and opiate mediated biological pathways. We hypothesized that IL-1β up-regulates opioid receptors in human astrocytes in both untreated and morphine-desensitized states.
METHODS: To test this hypothesis, we compared the basal expression of the mu (MOR), delta (DOR), and kappa (KOR) opioid receptors in the human U87 MG astrocytic cell line to SH-SY5Y neuronal and HL-60 immune cells using absolute quantitative real time RT-PCR (AQ-rt-RT-PCR). To demonstrate that IL-1β induced up-regulation of the MOR, DOR and KOR, U87 MG cells (2 x 105 cells/well) were treated with IL-1β (20 ng/mL or 40 ng/mL), followed by co-treatment with interleukin-1 receptor antagonist protein (IL-1RAP) (400 ng/mL or 400 ng/mL). The above experiment was repeated in the cells desensitized with morphine, where U87 MG cells were pre-treated with 100 nM morphine. The functionality of the MOR in U87 MG cells was then demonstrated using morphine inhibition of forksolin-induced intracellular cAMP, as determined by radioimmunoassay.
RESULTS: U87 MG cells treated with IL-1β for 12 h showed a significant up-regulation of MOR and KOR. DOR expression was also elevated, although not significantly. Treatment with IL-1β also showed a significant up-regulation of the MOR in U87 MG cells desensitized with morphine. Co-treatment with IL-1β and interleukin-1 receptor antagonist protein (IL-1RAP) resulted in a significant decrease in IL-1β-mediated MOR up-regulation.
CONCLUSION: Our results indicate that the pro-inflammatory cytokine, IL-1β, affects opiate-dependent pathways by up-regulating the expression of the MOR in both untreated and morphine-desensitized U87 MG.

de Oliveira JG, Rossi AF, Nizato DM, et al.
Profiles of gene polymorphisms in cytokines and Toll-like receptors with higher risk for gastric cancer.
Dig Dis Sci. 2013; 58(4):978-88 [PubMed] Related Publications
BACKGROUND: Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk.
AIMS: The purpose of this study was to investigate the combined effect of the pro- and anti-inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample.
METHODS: We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL-1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR-RFLP.
RESULTS: Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A-857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis, with an OR increased 2.95-fold to 50.4-fold, highlighting the combinations IL-1RN2/TNF-A-857T/IL-8-845C, IL-1RN2/IL-8-845C/TLR2del, IL-1RN2/IL-10-592A/TLR4 + 896G, IL-10-592A/TLR2del/TLR4 + 896G, and IL-1RN2/TNFA-857T/IL8-845C/TLR2del.
CONCLUSIONS: Our findings evidenced that the combined effect of polymorphisms in genes involved in the inflammatory process may potentiate the risk of gastric cancer, thus emphasizing the importance of evaluating multiple polymorphisms together.

Sousa H, Santos AM, Catarino R, et al.
IL-1RN VNTR polymorphism and genetic susceptibility to cervical cancer in Portugal.
Mol Biol Rep. 2012; 39(12):10837-42 [PubMed] Related Publications
Human Papillomavirus infection is considered as the main etiological factor of cervical cancer (ICC), although, the role of host genetic factors in ICC susceptibility has been increasing. Immunological response is crucial for the prevention of viral associated diseases. Interleukin 1 receptor antagonist (IL-1RN) is considered to be an important regulator of host immunity and several studies have shown a potential role of a 86 bp VNTR polymorphism within intron 2 of the IL-1RN gene in host immune response variability. We investigated the role of this polymorphism in cervical cancer development in Portugal with a case-control study developed with peripheral blood samples from 196 healthy women and 340 women with cervical lesions from the Northern Region of Portugal. We observed that IL-1RN Allele 2 homozygosis was significantly higher in cases than in controls. In fact, IL-1RN A2*A2 homozygous revealed to be associated with an increased risk of HSIL + ICC (OR = 1.90; 95 % IC 1.13-3.21; p = 0.015). Furthermore, we also observed that median age of onset of HSIL + ICC was significantly different (46.0 vs 52.0) in IL-1RN A2*A2 homozygous comparing to non-A2*A2 (p = 0.028). Our results indicated that IL-1RN A2 allele is associated with an increased susceptibility to cervical cancer development, probably by increasing predisposition to shorter immune responses.

Zhang Y, Liu C, Peng H, et al.
IL1 receptor antagonist gene IL1-RN variable number of tandem repeats polymorphism and cancer risk: a literature review and meta-analysis.
PLoS One. 2012; 7(9):e46017 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
IL1 receptor antagonist (IL1RA) and IL1beta (IL1β), members of the pro-inflammatory cytokine interleukin-1 (IL1) family, play a potential role against infection and in the pathogenesis of cancers. The variable number of tandem repeats (VNTR) polymorphism in the second intron of the IL1 receptor antagonist gene (IL1-RN) and a polymorphism in exon 5 of IL1B (IL1B+3954C>T, rs1143634) have been suggested in predisposition to cancer risk. However, studies have shown inconsistent results. To validate any association, a meta-analysis was performed with 14,854 cases and 19,337 controls from 71 published case-control studies for IL1-RN VNTR and 33 eligible studies contained 7,847 cases and 8917 controls for IL1B +3954. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from comparisons to assess the strength of the association. There was significant association between the IL1-RN VNTR polymorphism and the risk of cancer for any overall comparison. Furthermore, cancer type stratification analysis revealed that there were significantly increased risks of gastric cancer, bladder cancer and other cancer groups. Infection status analysis indicated that the H. pylori or HBV/HCV infection and IL1-RN VNTR genotypes were independent factors for developing gastric or hepatocellular cancers. In addition, a borderline significant association was observed between IL1B+3954 polymorphism and the increased cancer risk. Although some modest bias could not be eliminated, this meta-analysis suggested that the IL1-RN VNTR polymorphisms may contribute to genetic susceptibility to gastric cancer. More studies are needed to further evaluate the role of the IL1B+3954 polymorphism in the etiology of cancer.

García-González MA, Nicolás-Pérez D, Lanas A, et al.
Prognostic role of host cyclooxygenase and cytokine genotypes in a Caucasian cohort of patients with gastric adenocarcinoma.
PLoS One. 2012; 7(9):e46179 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Genetic factors influencing the prognosis of gastric adenocarcinoma (GAC) are not well known. Given the relevance of cytokines and other pro-inflammatory mediators in cancer progression and invasiveness, we aimed to assess the prognostic role of several functional cytokine and cyclooxygenase gene polymorphisms in patients with GAC.
METHODOLOGY: Genomic DNA from 380 Spanish Caucasian patients with primary GAC was genotyped for 23 polymorphisms in pro-inflammatory (IL1B, TNFA, LTA, IL6, IL12p40), anti-inflammatory (IL4, IL1RN, IL10, TGFB1) cytokine, and cyclooxygenase (PTGS1 and PTGS2) genes by PCR, RFLP and TaqMan assays. Clinical and histological information was collected prospectively. Survival curves were estimated by the Kaplan-Meier method and compared using the log rank test. Outcome was determined by analysis of Cox proportional hazards, adjusting for confounding factors.
RESULTS: The median follow-up period and median overall survival (OS) time were 9.9 months (range 0.4-120.3) and 10.9 months (95% CI: 8.9-14.1), respectively. Multivariate analysis identified tumor stages III (HR, 3.23; 95% CI:2-5.22) and IV (HR, 5.5; 95% CI: 3.51-8.63) as independent factors associated with a significantly reduced OS, whereas surgical treatment (HR: 0.44; 95%CI: 0.3-0.6) was related to a better prognosis of the disease. Concerning genetic factors, none of the 23 polymorphisms evaluated in the current study did influence survival. Moreover, no gene-environment interactions on GAC prognosis were observed.
CONCLUSIONS: Our results show that, in our population, the panel of selected pro- and anti-inflammatory cytokine, and cyclooxygenase gene polymorphisms are not relevant in determining the prognosis of gastric adenocarcinoma.

Zapata-Tarrés M, Arredondo-García JL, Rivera-Luna R, et al.
Interleukin-1 receptor antagonist gene polymorphism increases susceptibility to septic shock in children with acute lymphoblastic leukemia.
Pediatr Infect Dis J. 2013; 32(2):136-9 [PubMed] Related Publications
BACKGROUND: Interleukin-1 receptor antagonist polymorphism (ILRN) 2 (ILRN*2) has been associated with a poor outcome in septic patients because of an elevated production of anti-inflammatory cytokines. In >70% of patients, morbidity and mortality in childhood acute lymphoblastic leukemia is caused by infections. The aim of this study was to determine the association between this polymorphism and the frequency of septic shock from the time of diagnosis until completion of treatment.
METHODS: This cohort study was conducted in 57 consecutive children with acute lymphoblastic leukemia. At the end of follow-up, children were stratified according to their IL1RN polymorphism (ILRN*1/ILRN*2), evaluating the impact of genotype on the severity of febrile neutropenic events during their treatment.
RESULTS: Overall survival was 80% at 55 months after treatment. The average number of febrile neutropenic events in this cohort was 2.82 per patient. Genotype distribution was 50.9% for homozygote IL-1RN*1, 38.6% for heterozygote ILRN*1/ILRN*2 and 10.5% for homozygote IL-1RN*2. The risk of presenting septic shock for homozygote IL1RN*2/IL1RN*2 and heterozygote ILRN*1/ILRN*2 patients was significantly greater (odds ratio, 45; P = 0.001) adjusted for age, gender, risk of leukemia and presence of pathogenic bacteria. Genotype IL-1RN*2 is associated with the risk of development of septic shock in children with acute lymphoblastic leukemia. Further research in larger population-based studies is needed to replicate these findings.
CONCLUSIONS: This information would allow us to identify more predictive factors in this group of acute lymphoblastic leukemia patients in whom this information is lacking to establish an earlier and more aggressive approach.

Dluzniewski PJ, Wang MH, Zheng SL, et al.
Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.
Cancer Epidemiol Biomarkers Prev. 2012; 21(10):1774-82 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer.
METHODS: We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI).
RESULTS: The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00-3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48-0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence.
CONCLUSION: Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors.
IMPACT: This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis.

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