Interleukin-10 Promoter Region Research Articles

Inhibitory effect of alpinetin on IL-6 expression by promoting cytosine methylation in CpG islands in the IL-6 promoter region.

BackgroundAlpinetin is a flavonoid which exerts antibacterial and anti‐inflammatory functions. In order to prove that the induced methylation is an important mechanism for alpinetin in regulating the expression of inflammatory factor Interleukin‐6 (IL‐6), we detected the dinucleotide methylation status of CpG islands in the IL‐6 promoter region and IL‐6 level after treatment of RAW246.7 murine macrophages with alpinetin.MethodsAfter RAW246.7 murine macrophages were treated with alpinetin, alpinetin + GW9662 (the peroxisome proliferator‐activated receptor (PPAR) antagonist), and alpinetin + DNA methyltransferase 3 alpha (DNMT3A) siRNA for 96 hr, CpG islands were analyzed using time‐of‐flight mass spectrophotometry (TOF‐MS) and bisulfite sequencing polymerase chain reaction (BSP). Dinucleotide methylation status of the CpG islands in the IL‐6 promoter region was analyzed by methylation‐specific Polymerase Chain Reaction (PCR). IL‐6 level was detected using the enzyme‐linked immunosorbent assay (ELISA) method. Pearson's correlation analysis was conducted to test for potential correlation between the methylation status of CpG islands in the IL‐6 promoter region and IL‐6 level in RAW 246.7 cells.ResultsAlpinetin promoted dinucleotide methylation status of two CpG islands in the IL‐6 promoter region stretching 500–2500 bp upstream of the transcriptional start site (TSS) (p < .05). This promoting effect was more significant for the CpG island stretching 500–1500 bp long. The methylation ratio of dinucleotide at this position was significantly inversely correlated with the level of IL‐6 (p < .05). PPAR antagonist GW9662 and interference of DNMT3A could reverse both the alpinetin‐induced methylation and inhibitory effects on IL‐6 expression.ConclusionAlpinetin could induce dinucleotide methylation status of CpG islands in the IL‐6 promoter region by activating methyltransferase, thus inhibiting IL‐6 expression in murine macrophages.

SIRT1 alleviates isoniazid-induced hepatocyte injury by reducing histone acetylation in the IL-6 promoter region

Silent information regulator 1 (SIRT1) is a type III histone deacetylase that is related to the inhibition of the inflammatory response. The aim of this study was to investigate the regulation of SIRT1 on isoniazid-induced hepatocyte injury and the possible mechanism of histone modification. We found that compared with the blank control group, expression of SIRT1 was decreased in the isoniazid group and that expression of NF-κB p65 was increased, leading to an increase of the expression of inflammatory cytokines Interleukin-6 (IL-6) and Tumour necrosis factor alpha (TNF-α). The level of histone H3K9 acetylation in the promoter region of IL-6 was increased as well. Addition of a SIRT1 agonist (SRT1720) alleviated the inflammatory reaction caused by isoniazid, while the use of a SIRT1 inhibitor (EX527) aggravated the inflammatory damage to cells. In conclusion, these findings indicated that during the period of isoniazid-induced hepatocyte injury, SIRT1 levels were decreased and inflammatory factor levels were increased. Activation of SIRT1 may reduce hepatocyte injury by reducing the level of histone H3K9 acetylation in the promoter region of the IL-6 gene.

Bioinformatics Analysis of SNPs in IL-6 Gene Promoter of Jinghai Yellow Chickens.

The proinflammatory cytokine, interleukin-6 (IL-6), plays a critical role in many chronic inflammatory diseases, particularly inflammatory bowel disease. To investigate the regulation of IL-6 gene expression at the molecular level, genomic DNA sequencing of Jinghai yellow chickens (Gallus gallus) was performed to detect single-nucleotide polymorphisms (SNPs) in the region −2200 base pairs (bp) upstream to 500 bp downstream of IL-6. Transcription factor binding sites and CpG islands in the IL-6 promoter region were predicted using bioinformatics software. Twenty-eight SNP sites were identified in IL-6. Four of these 28 SNPs, three [−357 (G > A), −447 (C > G), and −663 (A > G)] in the 5′ regulatory region and one in the 3′ non-coding region [3177 (C > T)] are not labelled in GenBank. Bioinformatics analysis revealed 11 SNPs within the promoter region that altered putative transcription factor binding sites. Furthermore, the C-939G mutation in the promoter region may change the number of CpG islands, and SNPs in the 5′ regulatory region may influence IL-6 gene expression by altering transcription factor binding or CpG methylation status. Genetic diversity analysis revealed that the newly discovered A-663G site significantly deviated from Hardy-Weinberg equilibrium. These results provide a basis for further exploration of the promoter function of the IL-6 gene and the relationships of these SNPs to intestinal inflammation resistance in chickens.

Association between -174G>C polymorphism in the IL-6 promoter region and the risk of obesity: A meta-analysis.

Background:Many researchers have suggested that the -174G>C polymorphism in the interleukin-6 (IL-6) promoter region contributes to the risk of obesity; however, this hypothesis is still inconclusive. Therefore, we conducted a meta-analysis to combine the data from several studies to arrive at a conclusion regarding the association between -174G>C polymorphism and the risk of obesity.Methods:The PubMed and Embase databases were searched up to February 20, 2018. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a random-effects model. Subgroup analysis and sensitivity were also performed.Results:Ten eligible studies involving 7210 cases were performed to identify the association strength. The association strength was measured by the ORs and 95% CIs. By pooling the eligible studies, we found a significant association between the -174G>C polymorphism and obesity risk (C vs G: OR = 1.37; 95% CI, 1.08–1.74; Pheterogeneity < .01). Overall, individuals with the variant CC (OR = 1.58; 95% CI, 1.09–2.28; Pheterogeneity < 0.01) and GC/CC (OR = 1.61; 95% CI, 1.13–2.29; Pheterogeneity < .01) were associated with a significantly increased risk of obesity.Conclusion:The meta-analysis results suggested that the polymorphism -174G>C in the IL-6 promoter region was associated with a significantly increased risk of obesity.

Identification of Functional Genetic Polymorphisms at IL-10 Promoter Region and their Association with Risk of Ischemic Stroke in Chinese Han Population.

Pleiotropic cytokine interleukin-10 (IL-10) has been suggested as modifying risk for atherosclerosis. Promoter region genetic polymorphism of IL-10 gene is known to be associated with the level of IL-10 production. Through these effects, they might be involved with the ischemic stroke (IS). Our aim was to assess the nature of the functional polymorphisms in IL-10 promoter and any links with IS in Chinese Han population. The IL-10 -1082 G>A, -819 C>T and -592 C>A functional polymorphisms were determined by TaqMan SNP Genotyping assays in 1296 subjects (648 IS patients diagnosed by CTs or/and magnetic resonance imaging (MRI) and 648 normal healthy controls from Chinese Han Population). Multivariate logistic regression analysis was used to show the association between the IL-10 genotypes and the IS events. We found that the CC genotype of -819 C>T was more common in controls than IS subjects (P<0.05, corrected for multiple testing) in the Han population. CC carriage may be associated with the decreased risk of IS in the Han ethnic group (OR 0.65, 95% CI 0.43-0.97). In addition, the CC genotype in -592 C>A and GG genotype in -1082 G>A are all extremely low in Chinese Han cases and controls. The G allele frequency at the -1082 promoter region of IL-10 was rare in Chinese Han population which are diffierent from American/European populations.. IL-10 -819 C>T may be an independent protective factor for IS in the Chinese Han population.

Interleukin-10 rs1800871 (-819C/T) and ATA haplotype are associated with preeclampsia in a Tunisian population.

Interleukin-10 (IL-10) is implicated in several aspects of pregnancy. As genetic predisposition can be involved in the development of preeclampsia, the association between IL-10's promoter region polymorphisms and this pathology has been investigated, although with conflicting results. To date, only a small cohort study (total n = 40) has evaluated this association in the African continent, and none have been conducted in Tunisia. Hence, we evaluated the association between these polymorphisms and the risk of preeclampsia in a large Tunisian cohort. 345 preeclampsia patients and 300 controls were genotyped for the IL-10 promoter region variants -1082A/G, -819C/T and -592A/C using real-time PCR. Differences in means were determined by Student's t-test, while intergroup significance was assessed by Pearson χ2 or 2-way ANOVA. Genotypes were tested for Hardy-Weinberg equilibrium (HWE) in the control and cases. Logistic regression analysis was performed in order to determine the odds ratios and 95% confidence intervals associated with the linkage disequilibrium risk. An increased frequency of the -819 T (minor) allele and the -819 T/T genotype was seen in preeclampsia cases. Also, three-locus haplotype (-1082AG/-819CT/-592AC) analysis identified the ATA haplotype as having a higher incidence in women with preeclampsia (OR = 1.48, 95% CI: 1.03-2.11) and this was confirmed by multivariate regression analysis (OR = 1.65, 95% CI: 1.13-2.43) after controlling for covariates. We suggest that the IL-10 -819 T/T variant and the ATA haplotype, which are associated with low production of IL 10, represent genetic risk factors for preeclampsia in Tunisian women.

Genetic variations of IL-10: Identification of novel variations and evaluation of the impact of the SNPs/haplotype in the promoter region with the progression of Oral Squamous Cell Carcinoma in Indian population

The correlation of interleukin 10 (IL-10) with the outbreak and progression of cancer has been well established as it contributes to tumor immune evasion. Convincing number of evidences has been accumulated to reflect the critical correlation between IL-10 polymorphism and tumorogenesis. Several polymorphic sites at promoter regions have been reported to be associated with cancer susceptibility. The purpose of this study was to examine the effect of modulated genotypes in the promoter region of IL-10 gene with life-style habits in oral squamous cell carcinoma (OSCC) in the Indian population. A total of 300 subjects (100 OSCC, 50 precancer and 150 healthy controls) were recruited in this study. The IL-10 promoter region was amplified in 14 overlapping fragments by PCR and further screened through the high throughput technique of denaturing high-performance liquid chromatography (dHPLC) followed by sequencing. We identified three novel variations at positions (−924, −1045 & −1066); we also found some known SNPs (−592C/A, −657G/A, −851G/A, −819C/T, −1082A/G). The identified novel variations were submitted to the NCBI Gene Bank (accession numbers KT153594, KT291742 and KT291743). We also noticed a significant association of polymorphisms (−592C/A, −819C/T and −1082A/G) individually as well as in combination (haplotypes) along with lifestyle habits for the risk of oral carcinoma (p<0.0001). We have reported three novel SNPs in the Indian population for the first time, and these SNPs may be associated with OSCC. Besides, we showed the first evidence of IL-10 haplotypes, i.e., CCG and CTG, may act as a biomarker for early detection of oral pre-cancerous/cancerous lesions or treatment management of oral carcinoma.

Interleukin-6 -572C/G polymorphism is associated with serum interleukin-6 levels and risk of idiopathic pulmonary arterial hypertension

Interleukin 6 (IL-6) is a multifunctional proinflammatory cytokine that is elevated in patients with pulmonary arterial hypertension (PAH). Single nucleotide polymorphisms in the promoter region of IL-6 have been reported to transcriptional regulate the expression of IL-6. The aim of the present study is to investigate the roles of two common polymorphisms (-572C/G [rs1800796] and -6331T/C [rs10499563]) of IL-6 in idiopathic PAH (IPAH). A total of 338 IPAH patients and 352 age- and gender-matched healthy controls were enrolled. Genotyping of the two polymorphisms was performed by polymerase chain reaction and direct sequencing. Serum IL-6 levels were determined by ELISA assay. The frequencies of -572C/G genotypes CC, CG, and GG were found to be 63.6%, 32.3%, and 4.1% in IPAH patients group and 51.7%, 39.5%, and 8.8% in the controls, respectively. Compared with the individuals carrying the common genotype CC, the individuals carrying the GG genotype had a decreased risk of IPAH (adjusted odds ratio, 0.40; 95% confidence interval, 0.20–0.77; P = .006). The CG genotype and G allele carriers (CG/GG genotypes) were also observed to be associated with decreased risks of IPAH. Moreover, we found that individuals harboring -572GG or GC genotype showed significantly lower IL-6 levels than those harboring the -572CC genotype. No association between -6331T/C polymorphism and risk of IPAH or IL-6 levels was found. These results suggest that IL-6 promoter polymorphism -572C/G, but not -6331T/C, is associated with serum IL-6 levels and risk of IPAH.

Correlation between polymorphism (-1082) of interleukin-10 and the injury of development cancer of skin

OBJECTIVE: Skin cancer is the most common in Brazil especially in Santa Catarina. Interleukin-10 (IL-10) is an immunosuppressive cytokine that can allow the escape of cancer cells of the immune system, thereby polymorphisms in the IL-10 gene have been implicated in susceptibility and the development of malignancies. This study aimed to analyze the frequencies of the alleles and genotypic at position -1082 of the promoter region of IL-10 and its association with skin carcinomas. METHODS: This was a case-control study which analyzed 90 samples, and the test group of 49 skin tissue carcinoma and the control group by 41 scrapings oral mucosa of healthy individuals. The ARMS-PCR was used to identify the polymorphism. RESULTS: The allelic frequency for the control group was 70% for the A allele and 30% for G; in the test group gave 44% to 56% allele A and allele G Genotype frequency observed in the control group was AA (42%), AG (56%) and GG (25), while in group test was AA (24%), AG (39%) and GG (37%). There was a statistical difference between groups for both the allelic frequency, as for genotype (p <0.05). CONCLUSION: There was a higher prevalence of the G allele and genotype AG and GG in the test group compared to the control group, a factor that could be an adjuvant in the development of skin carcinomas. This result demonstrates the importance of developing immune response in the malignant transformation process.

Associations of IL-10 genetic polymorphisms with the risk of urologic cancer: a meta-analysis based on 18,415 subjects.

BackgroundInterleukin-10 (IL-10) is a powerful modulator of anti-tumor immune responses. The IL-10 promoter region polymorphisms are known to regulate IL-10 production, and thus are thought to be implicated in tumorigenesis. Recently, the roles of these polymorphisms in urologic cancer have been extensively studied, with conflicting results. Therefore, we conducted the present meta-analysis to better elucidate the correlations between IL-10 polymorphisms and urologic cancer risk.MethodsEligible articles were searched in PubMed, Medline, Embase, Scopus and CNKI up to May 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between IL-10 polymorphisms and the risk of urologic cancer.ResultsA total of 22 case–control studies including 8572 patients and 9843 controls were analyzed. The overall meta-analysis results showed that IL-10 −592C>A polymorphism was significantly associated with urologic cancer in CA versus AA (P = 0.04, OR 0.87, 95% CI 0.76–0.99) and AA versus CC+CA (P = 0.03, OR 1.15, 95% CI 1.02–1.31). Subgroup analyses by cancer types suggested there were significant associations between all the three investigated IL-10 polymorphisms and bladder cancer. However, subgroup analyses by ethnicity only detected a weak association between IL-10 −819C>T and Asian population.ConclusionsOur findings suggests that IL-10 −592C>A polymorphism may implicate with urologic cancer risk. Besides, promoter region polymorphisms of IL-10 may serve as potential biological markers, especially for bladder cancer. Furthermore, IL-10 −819C>T polymorphism may contribute to urologic cancer susceptibility in Asians while all the three studied variants of IL-10 did not relate to Caucasian urologic cancer predisposition.

Association of interleukin-10 polymorphisms with risk factors of Alzheimer’s disease and other dementias (SADEM study)

Some studies have reported a genetic association between single nucleotide polymorphisms (SNPs) in the promoter region of Interleukin (IL) 10 and Alzheimer's disease (AD), with conflicting results. To further investigate the proposed association and to clarify the role of cytokines as a potential cause for AD susceptibility, we analyzed genotypes, allele distributions and haplotypes of IL-10 promoter polymorphisms −1082 (rs1800896) and −819 (rs1800871) in a Mexican population: 986 normal controls and 221 cases divided as follows: 122 with Alzheimer disease (AD), 67 with (VaD) and 32 with mixed dementia (AD/VaD). Patients with dementia showed increased frequency of “ATA, CTG, and CTA” haplotypes when compared to controls. We identified two risk haplotypes: ATA (OR=3.56, 95%CI=2.84–4.45, p<0.0001), and CTA (OR=1.90, 95%CI=1.38–2.62, p<0.0001), and four protection haplotypes: ATG (OR=0.60, 95%CI=0.45–0.82, p=0.0012), CTG (OR=0.38, 95%CI=0.23–0.62, p<0.0001), ACG (OR=0.01, 95%CI=0.002–1.13, p<0.0001), and CCG (OR=0.02, 95%CI=0.004–0.203, p<0.0001). In summary, this is the first study in Mexican population that considers the analysis of IL-10 in patients with AD, VaD and AD/VaD. Our results showed the relevance of the role that IL-10 plays in the pathological mechanisms that result in the development of dementia. In addition, in our study, it was possible to distinguish two protective and two risk haplotypes for the development of dementia.

The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages.

Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.

Association of interleukin-6 gene polymorphism with coronary artery disease: an updated systematic review and cumulative meta-analysis.

Interleukin-6 (IL-6) is an important mediator of atherosclerotic disease and is also associated with coronary artery disease (CAD). The growing evidences suggest that polymorphisms in the IL-6 promoter region influence the progression of CAD. This study was performed to update the systematic results of association of IL-6 gene polymorphisms with CAD. PubMed, Embase, and China Biology Medicine were searched systematically for English and Chinese articles published up to October 31, 2014. Data were extracted using standardized forms. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. Subgroup analyses were made on ethnicity. A total of 42 studies including 15,145 cases and 21,496 controls were combined in this meta-analysis. IL-6 gene -174G/C polymorphism was associated with an increased risk of CAD (for C allele versus G allele: OR = 1.11, 95 % CI 1.02-1.20; for C/C versus G/G: OR = 1.21, 95 % CI 1.03-1.42; for C/C + C/G versus G/G: OR = 1.14, 95 % CI 1.03-1.27). In the subgroup analyses based on ethnicity, a significant association was found between -174 G/C polymorphism and CAD in Caucasians (for C allele versus G allele: OR = 1.12, 95 % CI 1.03-1.22; for C/C versus G/G: OR = 1.21, 95 % CI 1.02-1.42; for C/C + C/G versus G/G: OR = 1.16, 95 % CI 1.05-1.29). In order to reduce heterogeneity, we removed the outlier studies by a Galbraith plot analysis. As a result, the pooled ORs demonstrated no association of -174G/C polymorphism and CAD (C allele versus G allele: OR = 1.02, 95 % CI 0.97-1.06, p = 0.48; C/C versus G/G: OR = 0.1.03, 95 % CI 0.94-1.13, p = 0.48; C/G + C/C versus G/G: OR = 1.03, 95 % CI 0.96-1.09, p = 0.41; C/C versus C/G + G/G: OR = 1.02, 95 % CI 0.94-1.10, p = 0.70, respectively). The polymorphism of -572 G/C was not associated with CAD significantly (for C allele versus G allele: OR = 0.86, 95 % CI 0.74-1.01; C/C versus G/G: OR = 0.99, 95 % CI 0.43-2.27; C/G + C/C versus G/G: OR = 0.96, 95 % CI 0.80-1.15, respectively). In addition, subgroup analyses showed an association between -572 G/C polymorphism and CAD risk among Chinese (C allele versus G allele: OR = 0.64, 95 % CI 0.48-0.85; C/C versus G/G: OR = 0.38, 95 % CI 0.18-0.81; C/G + C/C versus G/G: OR = 0.47, 95 % CI 0.22-1.00; C/C versus C/G + G/G: OR = 0.58, 95 % CI 0.42-0.81). The C allele of -174G/C polymorphism may associate with increased sensibility to CAD among Caucasians in overall analysis. Nevertheless, the effect is interfered by heterogeneity across the included studies. The C allele of -572G/C polymorphism may decrease the risk of CAD in Chinese.

Single nucleotide polymorphism at -1087 locus of interleukin-10 gene promoter is associated with severe chronic periodontitis in nonsmoking patients.

Objective:Single nucleotide polymorphisms (SNPs) in the promoter region of interleukin (IL)-10 gene, which codes for the anti-inflammatory cytokine IL-10, have been associated with its level of production in chronic periodontitis. The prevalence of promoter SNP genotypes is known in other populations with chronic periodontitis, while its association in the Indian population is not known. Hence, the present study was designed to investigate the prevalence of IL-10 promoter polymorphism in a racially defined group of Indians with severe chronic periodontitis as the Indian population is known to be genetically diverse.Materials and Methods:Genomic deoxyribonucleic acid was extracted from 46 nonsmoking patients with severe chronic periodontitis and 45 subjects with healthy periodontium. A SNP locus at −1087 of IL-10 was chosen, as this locus has been frequently associated with chronic periodontitis in other population. Genotyping was carried out using allele-specific polymerase chain reaction (AS-PCR), and the frequencies of genotype were analyzed between the groups.Results:The distribution of genotype and allele frequencies showed significant differences between the study groups. The prevalence of genotype AA alleles at −1087 locus of IL-10 was significantly higher in severe chronic periodontitis patients compared to the healthy controls (P = 0.05).Conclusion:The study has identified a positive association between the occurrence of AA allele at −1087 locus of IL-10 gene and severe chronic periodontitis in nonsmoking patients.

Epigenetic Modulation of Microglial Inflammatory Gene Loci in Helminth-Induced Immune Suppression: Implications for Immune Regulation in Neurocysticercosis.

In neurocysticercosis, parasite-induced immune suppressive effects are thought to play an important role in enabling site-specific inhibition of inflammatory responses to infections. It is axiomatic that microglia-mediated (M1 proinflammatory) response causes central nervous system inflammation; however, the mechanisms by which helminth parasites modulate microglia activation remain poorly understood. Here, we show that microglia display a diminished expression of M1-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide synthase 2 (NOS2) in murine neurocysticercosis. Microglia also exhibited a lack of myeloid cell maturation marker major histocompatibility complex (MHC)-II in these parasite-infected brains. Treatment of microglia with helminth soluble/secreted factors (HSFs) in vitro did not induce expression of M1-inflammatory signature molecule NOS2 as well as MHC-II in primary microglia. However, HSF treatment completely inhibited lipopolysaccharide-induced increase in expression of MHC-II, NOS2 and nitric oxide production in these cells. As epigenetic modulation of chromatin states that regulates recruitment of RNA polymerase II (Pol-II) is a key regulatory step in determining gene expression and functional outcome, we next evaluated whether HSF induced modulation of these phenomenon in microglia in vitro. Indeed, HSF downregulated Pol-II recruitment to the promoter region of TNF-α, IL-6, NOS2, MHC-II, and transcription factor CIITA (a regulator of MHC-II expression), by itself. Moreover, HSF suppressed the lipopolysaccharide-induced increase in Pol-II recruitment as well. In addition, HSF exposure reduced the positive histone marks H3K4Me3 and H3K9/14Ac at the promoter of TNF-α, IL-6, NOS2, MHC-II, and CIITA. These studies provide a novel mechanistic insight into helminth-mediated immune suppression in microglia via modulation of epigenetic processes.

Polymorphisms of IL-10 affect the severity and prognosis of myelodysplastic syndrome.

Polymorphisms of the interleukin-10 (IL-10) gene, which alter the production of IL-10, have been implicated in many cancers. We investigated the association between gene polymorphisms of the promoter region of IL-10 (-1082 G/A, IL-10-819 C/T, and -592 C/A) and the risk to develop myelodysplastic syndrome (MDS) and clinical features of MDS. Genomic DNA was extracted from 119 patients with MDS or chronic myelomonocytic leukemia and 202 healthy controls. Genotypes were determined by PCR-restriction fragment length polymorphism. There were no statistically significant differences in the genotype, allele, and haplotype frequencies of IL-10 -1082 G/A, IL-10-819 C/T, and -592 C/A between the patients with MDS and the control group. However, the IL-10 -592 CC genotype group (IL-10 high producer type) was associated with lower hemoglobin level (7.85 ± 2.02 g/dL vs. 9.37 ± 2.25 g/dL, P = 0.027) and poorer prognosis as compared to the IL-10 -592 non-CC genotype group (median survival time 50.2 m vs. not reached, p = 0.026). In addition, the IL-10 high producer haplotype group (GCC/ACC or ACC/ACC) was also associated with lower hemoglobin level and shorter survival time. Our findings indicate that IL-10 gene polymorphisms may not contribute to susceptibility to MDS, but they may be associated with the severity and prognosis of MDS.

Association of interleukin-10 promoter region polymorphisms with risk factors of Atherosclerosis.

Atherosclerosis is considered as an inflammatory disease, and carotid artery intima-media thickness (IMT) and carotid plaque are generally used as intermediated phenotype of atherosclerosis. The aim of this study was to investigate whether carotid IMT and plaque are associated with promoter region polymorphisms of interleukin 10 (IL-10) gene. We recruited 135 subjects from a rural area of south-eastern part of South Korea. Three polymorphisms in the promoter region of IL-10 (-1082 A/G, -819 T/C and -592 A/C) were genotyped by pyrosequencing. Carotid IMT was measured at common carotid arteries, and carotid bulbs and cardiovascular risk factors such as cholesterol, blood pressure, uric acid and homocysteine were measured using blood samples. Subjects with the minor allele (C) of -819 T/C or the minor allele (C) of -592 A/C showed lower values in carotid IMT than those with major allele homozygote of each polymorphism (P = 0.018 and P = 0.031, respectively). Subjects with carotid plaque were significantly older and showed higher values in carotid IMT, uric acid and homocysteine than those without plaque (P < 0.01, respectively). In conclusion, the promoter region polymorphisms of IL-10 gene associate with carotid IMT and plaque. Further studies with larger samples are needed to provide stronger evidence to justify anti-atheromatous properties of IL-10.

A critical role of the transcription factor fli-1 in murine lupus development by regulation of interleukin-6 expression.

The Fli-1 transcription factor is implicated in the pathogenesis of systemic lupus erythematosus (SLE), both in humans and in animal models. Dysregulation of interleukin-6 (IL-6) is also associated with SLE. The purpose of this study was to investigate whether Fli-1 directly regulates the expression of IL-6. Sera were collected from wild-type and Fli-1-heterozygous (Fli-1(+/-) ) MRL/lpr mice, and the concentration of IL-6 was measured by enzyme-linked immunosorbent assay (ELISA). Expression of IL-6 in the kidney was measured by real-time polymerase chain reaction analysis. T cells were isolated from wild-type and Fli-1(+/-) MRL/lpr mice and stimulated with CD3/CD28 beads, and the concentration of IL-6 in the supernatants was measured by ELISA. MS1 endothelial cells were transfected with Fli-1 and control small interfering RNA, and the production of IL-6 was compared after lipopolysaccharide stimulation. A chromatin immunoprecipitation (ChIP) assay was performed to determine whether Fli-1 binds to the IL-6 promoter region. Transient transfections with the NIH3T3 cell line were performed to examine whether Fli-1 regulates the expression of IL-6. Fli-1(+/-) MRL/lpr mice had significantly decreased IL-6 levels in sera and reduced expression of IL-6 in kidneys as compared to their wild-type littermates. T cells isolated from Fli-1(+/-) MRL/lpr mice produced less IL-6 than did those from wild-type mice. Inhibiting the expression of Fli-1 in endothelial cells resulted in reduced production of IL-6. The ChIP assay revealed direct binding of Fli-1 to 3 regions within the IL-6 promoter. Fli-1 activated transcription from the IL-6 promoter in a dose-dependent manner. The direct regulation of IL-6 expression by Fli-1 represents one possible mechanism for the protective effect of decreased Fli-1 expression in lupus.

The -1082A>G polymorphism in promoter region of interleukin-10 and risk of digestive cancer: a meta-analysis.

The -1082A>G polymorphism is located in promoter region of interleukin-10 (IL-10) and it could affect the production of IL-10. Numerous studies have investigated the association between IL-10 -1082A>G and risk of digestive cancer. However, the conclusion is still inconsistent. Here, we have performed a meta-analysis and systematic review to determine the association between the IL-10 -1082A>G and susceptibility to digestive cancer. In this meta-analysis, we identified 40 eligible studies, involving 7195 patients of digestive cancer and 11755 controls. By pooling all eligible studies, we found the variant -1082G allele significantly increased risk of digestive cancer (G vs. A: OR = 1.181, 95% CI: 1.057–1.319). Further stratified analysis was performed to evaluate the influence of cancer types, ethnicities, study design, sample size and Hardy–Weinberg equilibrium. Stratified analysis suggested that, the -1082A>G polymorphism was only associated with increased risk for gastric cancer (G vs. A: OR = 1.281, 95% CI: 1.102–1.488) and in Asian population (G vs. A: OR = 1.399, 95% CI: 1.188–1.646). No significant publication bias was detected. Based on 40 studies and 18950 participants, we found the variant IL-10 -1082G allele significantly increased susceptibility to digestive cancer, especially for gastric cancer and in Asian population.

Response to the dipeptidyl peptidase-4 inhibitors in Japanese patients with type 2 diabetes might be associated with a diplotype of two single nucleotide polymorphisms on the interleukin-6 promoter region under a certain level of physical activity.

Aims/IntroductionMuscle-derived interleukin-6 (IL-6) has been reported to promote glucagon-like peptide-1 (GLP-1) secretion, and we explored the association of single nucleotide polymorphisms (SNPs) in the human IL-6 promoter region with the responsiveness to dipeptidyl peptidase-4 inhibitors (DPP-4Is), drugs that increase circulating GLP-1.Materials and MethodsThe present observational study enrolled Japanese patients with type 2 diabetes who took a DPP-4I over 3 months, and most of the clinical information was collected retrospectively. We defined non-responders as those having less than a 0.2% decrease of the glycated hemoglobin level at 3 or 4 months after starting DPP-4I treatment. Physical activity was retrospectively estimated by the Japanese short version of International Physical Activity Questionnaire.ResultsWe studied 316 patients whose physical activity corresponding to the season of the DPP-4I administration was estimated. The non-responder rate was 29.7%. We analyzed rs1800796 and rs2097677, both are suggested to be functional in Japanese. Multivariate analysis for all patients showed that the adjusted odds ratio for the non-responder risk of the diplotype rs1800796 G/*–rs2097677 A/* against C/C-G/G (OR_G*A*) was 0.445 (P = 0.068). When patients were stratified by the International Physical Activity Questionnaire into low (n = 149) and moderate/high (n = 167) activity groups, however, OR_G*A* in each group was 1.58 (P = 0.615) and 0.153 (P = 0.003), respectively.ConclusionsThe diplotype rs1800796 G/*–rs2097677 A/* might contribute to responsiveness to DPP-4Is in Japanese patients with type 2 diabetes under a certain level of physical activity. However, further investigation is warranted to confirm this.