IL-10 Gene Promoter Research Articles

Impact of IL-10 gene promoter -1082 (G/A) polymorphism in B cell chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia among western population. Many interesting reports suggest the role of IL-10 polymorphisms in CLL oncogenesis. This study aimed to study the relation between IL-10 (rs1800896)-1082 (G/A) gene polymorphism and the risk of development of B cell chronic lymphocytic leukemia and its impact on the patient outcome. IL-10 (rs1800896)-1082 (G/A) gene polymorphism was assessed in fifty patients with chronic lymphocytic leukemia as well as 50 age and sex-matched apparently healthy controls using polymerase chain reaction (PCR). The IL-10 (rs1800896) AG hetero, GG homo, AG + GG genotypes, and G allele showed significantly higher frequency (P > 0.001) in CLL cases when compared to control groups. The genotype AG + GG were significantly associated with advanced stages (P > 0.001), short time to first treatment (TFT) (P = 0.032), shorter progression free survival (PFS) (P = 0.044), and lower response to treatment (P = 0.003) as compared to wild genotype (AA wild). The IL-10 (rs1800896) genotypes (GG, AG) might have a role in the pathogenesis of CLL and have deleterious impact on the CLL patient’s outcome.

CpG methylation in the TGFB1 and IL-6 gene promoters serve as surrogate biomarkers for diagnosis of IBD in children

Abstract Crohn’s disease (CD) and ulcerative colitis (UC) are recurrent, chronic forms of inflammatory bowel diseases (IBD), the diagnosis of which can entail long delays. The delays can lead to disease presentation with complications and high morbidity. Therefore, better diagnostic markers for IBD are required. We investigated whether methylation marks in the TGFB1 and IL-6 gene promoters could be of diagnostic utility in IBD. To this end, we conducted a case-control study using peripheral blood DNA samples from 67 CD and 37 UC pediatric patients, and from 43 age-matched healthy controls. The patients were recruited from three pediatric gastroenterology clinics across Canada. The DNA samples were processed to identify methylation sites (CpG) across the promoter regions of the TGFB1 and IL-6 genes using the Sequenom technology. After implementing quality control measures, and initial non-parametric univariate (Man-Whitney U test) analyses, multivariate logistic regression analyses was carried out to identify models with the best fit (Akaike Information Criteria) and the greatest discriminatory capabilities (Area Under the Receiver Operating Curve). Logistic regression analysis showed that a model comprising 14 TGFB1 CpG sites had high discriminatory ability to separate CD from controls (AUC=0.94). Similarly, a logistic model comprising 9 CpG sites in the TGFB1 gene had near perfect ability to discriminate between UC and controls (AUC=0.99). A logistic model comprising three CpG sites in the TGFB1 gene had moderate ability (AUC=0.81) to discriminate between CD and UC. In conclusion, CpG methylation in the TGFB1 gene promoter has high discriminative power for identifying CD and UC, and could serve as an important diagnostic markers.

PD47-07 A GENETICALLY MODIFIED BCG THAT OVEREXPRESSES A STING AGONIST SHOWS ENHANCED ANTITUMOR EFFICACY MEDIATED BY AN M1 MACROPHAGE POLARIZATION WITH POTENTIATION OF TRAINED IMMUNITY

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV (PD47)1 Apr 2020PD47-07 A GENETICALLY MODIFIED BCG THAT OVEREXPRESSES A STING AGONIST SHOWS ENHANCED ANTITUMOR EFFICACY MEDIATED BY AN M1 MACROPHAGE POLARIZATION WITH POTENTIATION OF TRAINED IMMUNITY Alok Singh*, Monali Praharaj, Kara Lombardo, Andres Matoso, Gregory Joice, Takahiro Yoshida, Max Kates, David McConkey, William Bishai, and Trinity J. Bivalacqua Alok Singh*Alok Singh* More articles by this author , Monali PraharajMonali Praharaj More articles by this author , Kara LombardoKara Lombardo More articles by this author , Andres MatosoAndres Matoso More articles by this author , Gregory JoiceGregory Joice More articles by this author , Takahiro YoshidaTakahiro Yoshida More articles by this author , Max KatesMax Kates More articles by this author , David McConkeyDavid McConkey More articles by this author , William BishaiWilliam Bishai More articles by this author , and Trinity J. BivalacquaTrinity J. Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000934.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Trained immunity (TI) involving metabolic and epigenetic reprogramming of monocytes/macrophages confers a heightened immune status, and BCG has been shown to be a potent inducer of TI. We hypothesized that a genetically engineered BCG overexpressing a STING agonist may be a stronger inducer of antitumor TI. Using a recombinant BCG strain (BCG-disA-OE) which releases high levels of the STING agonist c-di-AMP, we tested induction of TI phenotypes in NMIBC models in vitro and in vivo. METHODS: WT-BCG (Tice strain) and BCG-disA-OE were compared for their induction of cytokines and phagocytic capacity in primary human and murine macrophages using ELISA, flow-cytometry, and immunofluorescence. We also measured epigenetic changes in the promoter regions of key cytokines using ChIP-PCR in human PBMC-derived monocytes. Antitumor efficacy was tested in the rat MNU-carcinogen model of NMIBC following intravesical BCG instillation weekly x 6 using histochemical tumor grading and qRT-PCR of bladder tissue. RESULTS: Compared with BCG-WT, BCG-disA-OE strains showed increased IFN I, IL-6, TNF-α, MCP-1 and IL-12 levels in primary macrophages and bladder cancer cell lines We observed increased M1 polarization shift and higher phagocytic capacity in primary macrophages after infection with rBCG-disA-OE. The modified BCG also elicited more pronounced epigenetic changes (H3K4Me3) on the TNF-α and IL-6 gene promoters following monocyte training. Intravesical instillations of BCG-disA-OE in MNU-rats resulted into significantly lower tumor involvement index and a more a potent induction of Th1 cytokines compared to BCG-WT. CONCLUSIONS: BCG-disA-OE demonstrated superior antitumor efficacy in the rat NMIBC model. It also elicited greater levels of pro-inflammatory cytokine secretion, M1 macrophage polarization, and epigenetic reprogramming. These observations suggest that BCG-disA-OE elicits more potent trained immunity changes monocytic cell populations in the bladder, and that elevated trained immunity may correlate with treatment outcome. BCG-disA-OE shows promise as a novel intravesical immunotherapy for NMIBC. Source of Funding: Maryland Tedco, Willowcroft Foundation, and Cigarette Restitution Fund © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e928-e928 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alok Singh* More articles by this author Monali Praharaj More articles by this author Kara Lombardo More articles by this author Andres Matoso More articles by this author Gregory Joice More articles by this author Takahiro Yoshida More articles by this author Max Kates More articles by this author David McConkey More articles by this author William Bishai More articles by this author Trinity J. Bivalacqua More articles by this author Expand All Advertisement PDF downloadLoading ...

RELATIONSHIP BETWEEN INTERLEUKIN-6 GENE POLYMORPHISM AND HEART FAILURE IN PATIENTS WITH CORONARY ARTERY DISEASE AND OBESITY

The aim: To examine the association between polymorphisms of the IL-6 gene promoter and HF in patients with CAD and obesity. Material and methods: 222 patients with coronary artery disease and obesity were identified. Comparison group consisted of 115 patients with coronary artery disease with normal body weight. The groups were comparable in age and sex. The exclusion group consisted of patients with severe concomitant diseases of the respiratory and digestive organs, kidneys and people with cancer. One single nucleotide polymorphisms in the interleukin-6 promoter region was analyzed. Odds ratio (OR) and 95 % confident interval (95 % CI) were calculated. Results: The combined course of coronary artery disease and obesity was characterized by the detection of allele C in 62 patients (27.93 %), allele G - in 160 patients (72.07 %), and genotypes CC, CG and GG - at 24 (10.81 %), 67 (30.18 %) and 131 (59.01 %) patients respectively. The results showed that the -174G allele and GG genotype in patients with coronary artery disease and obesity were associated with heart failure (OR = 2.55, 95% CI = [1.72-3.79], χ2 = 22.8; p<0.05) and (OR = 11.95, 95% CI = [3.41-41.91], χ2 = 22.5; p<0.05), whereas allele C-174 was associated with a decrease in the risk of heart failure (OR = 0.39, 95% CI = [0.26-0.58 ], χ2 = 22.75, p<0.05). Conclusions: The obtained results testify that the -174G>C polymorphism in the interleukin-6 gene is significantly associated with increased risk of heart failure in patients with coronary artery disease and obesity.

Impact of IL-18 gene promoter polymorphisms on renal cell carcinoma occurrence and prognosis in Chinese Han population*

Abstract Objective Genetic polymorphisms in various inflammatory cytokines have been associated with the risk and growth or invasiveness of renal cell carcinoma (RCC). However, the molecular basis of RCC pathogenesis is unclear. The aim of this study was to explore a possible association between two IL-18 gene promoter polymorphisms, -137G/C and -607C/A, and RCC occurrence and prognosis in a Chinese Han population. Methods Chinese Han patients with RCC (n = 175) and age-matched healthy controls (n = 200) were analyzed by single nucleotide polymorphism genotyping during follow-up. Results IL-18-137G allele frequency was significantly higher in patients with lymph node metastasis (Odds ratio [OR], 3.52; 95% confidence interval [CI], 0.97-16.17; P = 0.045). The IL-18-607 CC genotype was associated with distant metastasis (OR, 2.81; 95% CI, 1.35-6.24; P = 0.025). The IL-18-137 G allele was correlated with more advanced tumor stage (OR, 1.83; 95% CI, 1.05-3.72; P = 0.026) and higher tumor grade (OR, 2.23; 95% CI, 0.78-4.12; P = 0.041). The IL-18-607 CC genotype frequency was significantly higher in patients with more advanced cancer stage (OR, 2.92; 95% CI, 1.80-6.87; P = 0.001) and higher tumor grade (OR, 2.21; 95% CI, 1.25-12.25; P = 0.035). The IL-18-607 allele was associated with more advanced cancer stage (OR, 2.47; 95% CI, 1.38-3.83; P = 0.002).Carriers of the GG genotype with the -137G/ C polymorphism had a 2.165-times higher risk of RCC progression than carriers of the GC genotype (Hazard ratio = 2.15, 95% CI, 1.270-3.687). Conclusion The IL-18-137 G allele was correlated with more advanced stage, higher tumor grade, and lymph node metastasis. IL-18 gene promoter polymorphism -137G/C may thus influence the prognosis of RCC patients.

THE EFFECT OF MUSCLE DAMAGE AND THE IL-6-174C/G POLYMORPHISM ON THE SERUM IL-6 LEVELS OF OLDER MEN

ABSTRACT Introduction Fast population aging is a global reality. Today’s major challenge is to promote the healthy aging of more and more people by acting on factors that can be modified, such as physical exercise. Regular exercise could contribute to the prevention of chronic diseases associated with aging. Research has been conducted on the physical training response of elderly individuals, but there is not yet any consensus on the influence of strength training or IL-6 polymorphism on levels of inflammatory markers such as IL-6 and muscle damage marker CK, particularly in healthy elderly male individuals. Objectives The aim of this study was to evaluate the relationship of IL-6 promoter -174 C/G gene polymorphism on systemic IL-6 responses and muscle damage after eccentric strength training in elderly men. Methods This is a prospective, high-quality study. Gene frequency of polymorphism of promoter gene IL6 G-174C was identified using the Hardy-Weinberg test in 28 older male volunteers. The relationships of each genotype with IL-6 and CK serum levels were analyzed. CK and IL-6 levels were determined at pre-training and 0h, 3h, 24h, and 48h post-training periods. Results Differences in baseline and post-training IL-6 levels of genotypic groups were observed for all time periods analyzed (p = 0.029). Eccentric exercise efficiently reduced post-intervention muscle damage, thus showing a statistical difference between the pre- and post-intervention time points ( p = &lt;0.0005). Conclusion Eccentric training influenced CK and IL-6 modulation independently of the polymorphism of the IL-6 promoter gene -174 C/G. Level of evidence II, Prospective comparative type.

PM2.5 exposure and cold stress exacerbates asthma in mice by increasing histone acetylation in IL-4 gene promoter in CD4+ T cells

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined effects of PM2.5 exposure and cold stress (PMCS) on asthma, as well as the underlying mechanisms by using a murine model. After different exposures, the immune-pathological changes and redox states in groups were evaluated. Besides, the balance of TH1/TH2 cells and the acetylation levels of H3K9 and H3K14 in IL-4 gene promotor were detected. Our results showed that, compared with other exposures, PMCS led to an increased inflammation and redox levels in mice. It also significantly increased the percentage of TH2 T cells, which was correlated with hyperacetylation of H3K9 and H3K14 in IL-4 gene promoter in CD4+T cells. Furthermore, a significantly increased P300 and decreased HDAC1 were detected in CD4 + T cells in PMCS group. In conclusion, our findings demonstrated that PMCS exacerbated asthma in mice by increasing H3K9 and H3K14 acetylation in IL-4 gene promoter in CD4 + T cells, and P300 and HDAC1 might contribute to their combined effects.

IL-18 Gene Polymorphisms Impacts on Its Serum Levels in Prostate Cancer Iraqi Patients

Prostate cancer is one of the most common types of cancer in men. A total of 110 Iraqi Arab individuals were included in this study; 60 individuals of them had prostate cancer with increased levels of TPSA (patients group); their age range 52-90 years. They were referred for diagnosis and treatment to the National Al-Amal Hospital for oncology in Baghdad during the period from July 2017 to October 2017. While the other 50 apparently healthy subjects were the control group, their age range similar to patients group. Sera and blood samples were collected from all patients and controls than used to assess for the level of IL-18 and DNA extraction, respectively. The polymorphisms were analyzed using polymerase chain reaction-single specific primer (PCR-SSP), at the position -137 G\C (rs187238) in the promoter of IL18 gene. The genetic polymorphism of the IL18 gene promoter -137G/C (rs187238) was determined and presented with three genotypes (GG, GC, and CC) in prostate cancer patients and controls. Testing for Hardy-Weinberg (H-W) equilibrium revealed that Prostate cancer patients showed insignificant variation in the distribution of IL-18 -137 genotypes (P&gt; 0.05). While the control samples showed significant variation (p ≤0.05) between the observed and expected. Comparing patients with controls indicated that IL-18-137 alleles or genotypes showed no association with the risk of prostate cancer development in Iraqi Arab population or protection against them. Serum level of IL-18 was highly significant (P ≤ 0.001) increased in patients compared to control. The IL-18 serum levels differences in GG and GC genotypes was significant (p &lt;0.05) between patients and control. While there were no significant differences between the three IL-18 -137 genotypes inpatient or in controls.

Association between (-590C / T) polymorphism of the IL-4 gene promoter and allergic asthma: An algerian case control study

Association between (-590C / T) polymorphism of the IL-4 gene promoter and allergic asthma: An algerian case control study

Association of interleukin-10 promoter polymorphisms with serofast state after syphilis treatment

ObjectivesRecent studies suggested that upregulation of anti-inflammatory immune response during early syphilis may be associated with persistence of Treponema pallidum infection despite adequate treatment, resulting in a serofast state. The...

CSTP1 inhibits IL-6 expression through targeting Akt/FoxO3a signaling pathway in bladder cancer cells

CSTP1, a recently identified protein phosphotase, is frequently repressed in bladder cancers. Previous results showed that CSTP1 over-expression inhibited cell cycle progression and promoted apoptosis through dephosphorylating Akt kinase at Ser473 site in bladder cancer cells, but the mechanisms how CSTP1 exerted tumor suppressive activity remains unclear. In this study, we analyzed the gene expression profile changes that affected by CSTP1 overexpression by microarray, and reported that CSTP1 decreased IL-6 expression/secretion in bladder cancer cells and re-expression of IL-6 abrogated CSTP1's tumor suppressive activity. We also found that FoxO3a occupy IL-6 gene promoter and repressed IL mRNA transcription. Further results showed that decreased expression of IL-6 in CSTP1-overexpressing cells inactivated Stat3 transcriptional factor, which resulted in the down-regulation of cyclin D1, Bcl-xl expression. Spearman correlation analysis revealed that the mRNA level of CSTP1 correlated inversely with that of IL-6 in bladder cancer tissues. In conclusion, our studies revealed that protein phosphotase CSTP1 inhibited IL-6 expression through targeting Akt/FoxO3a signaling pathway and IL-6 inactivated Stat3 was necessary for CSTP1's tumor suppressive function.

Inhibition of TNFα-induced interleukin-6 gene expression by barley (Hordeum vulgare) ethanol extract in BV-2 microglia.

Inflammation in the central nervous system is closely associated with pathological neurodegenerative diseases as well as psychiatric disorders. Prolonged activation of microglia can produce many inflammatory mediators, which may result in pathological neurotoxic side effects. Interleukin (IL)-6 serves as a hallmark of the injured brain. Whole grains are known to contain many bioactive components. However, little information is available about anti-neuroinflammatory effects of grains in the CNS. This study aims to investigate the effect of Hordeum vulgare ethanol extract (HVE) on the suppression of IL-6 expression in BV2 microglia. Inhibitory effects of HVE on IL-6 expression were analyzed by immunoblot anaysis, immunofluoresce microscopic analysis, reverse transcription-polymerase chain reaction, and luciferase promoter reporter assay. HVE inhibited TNFα-induced phosphorylation of IKKα/β, IκB, and p65/RelA NF-κB. TNFα-induced IL-6 mRNA expression and promoter activity were reduced by HVE. Point mutation of NF-κB-binding site within the IL-6 gene promoter abolished TNFα-induced reporter activity, whereas exogenous expression of p65 NF-κB enhanced IL-6 promoter activity. NF-κB-binding site within the IL-6 promoter region is a HVE target element involved in the inhibition of TNFα-induced IL-6 gene transcription. HVE inhibits TNFα-induced IL-6 expression via suppression of NF-κB signaling in BV2 microglial cells.

Association of common IL-10 promoter gene variants with the susceptibility to head and neck cancer in Tunisia

Background/aimWe investigated the association of three IL-10 promoter single-nucleotide polymorphisms and altered IL-10 plasma levels with the risk of head and neck cancer (HNC). Materials and methodsStudy subjects comprised 194 HNC patients [137 nasopharyngeal cancer (NPC) and 57 laryngeal cancer (LC)], and 263 healthy controls. Genotyping of rs1800896 (-1082A>G), rs1800871 (-819C>T), and rs1800872 (-592A>C) IL-10 variants was performed by real-time PCR; IL-10 levels were measured by enzyme amplified immuno sensitivity assay (EAISA). Results Carriage of rs1800896 A/A genotype was more frequent in the HNC and NPC cases, but was less frequent in the controls than the LC patients. Significant differences in IL-10 levels were observed between the rs1800896A/G genotype-carrying NPC patients and the controls. Positive association with NPC and LC was observed for rs1800871C/C, and carriage of rs1800872A/A genotype, and A allele were associated with higher risk of HNC and NPC, but not LC. GT rs1800896-rs1800871 haplotype was more frequent among the HNC and NPC patients than the controls in contrast to GC haplotype, which has a protective effect. Positive association was found between TA haplotype and LC. ConclusionOur results demonstrate that IL-10-1082, IL-10-819, and IL-10-592 variants, and haplotypes GC and GT constitute biomarkers for early detection of HNC, especially NPC subtype. IL-10 -819T/C and TA haplotype may be used as biomarkers for early detection of LC.

GSK3\u03b2 inhibition attenuates LPS-induced IL-6 expression in porcine adipocytes

IL-6 is not only a proinflammatory cytokine associated with inflammatory responses but also a regulator on the energy and glucose metabolism in adipose tissue. Glycogen synthase kinase 3β (GSK3β) has fundamental roles in the regulation of pro- and anti-inflammatory cytokines production. However, the regulatory role for GSK3β in the pig inflammatory response in adipocytes remains unknown. We show here that SB216763 and LPS increased the phosphorylation of GSK3β (Ser9), and decreased the phosphorylation of GS (Ser641) in adipocytes. The activity of porcine GSK3β was inhibited by SB216763, an inhibitor of GSK3β, attenuated the production of IL-6 in LPS-stimulated adipocytes. Additionally, the essential core region of the pig IL-6 promoter located at −191 bp to −59 bp, and an NF-κBp65 element in this region was responsible for IL-6 promoter activity. The transcription activity of NF-κBp65 was activated by LPS stimulation, and the GSK3β inhibition repressed LPS-induced luciferase activity of the IL-6 promoter. Furthermore, LPS increased p65 binding to the NF-κB site, and GSK3β inhibition had no effect on the association of NF-κBp65 with IL-6 gene promoter after LPS treatment. These results demonstrate that GSK3β has important regulatory roles in the LPS-induced inflammatory response of IL-6 production in pig adipocytes.

Association of IL-8 gene promoter -251 A/T and IL-18 gene promoter -137 G/C polymorphisms with head and neck cancer risk: a comprehensive meta-analysis.

PurposeNo consensus exists on the impact of polymorphisms in cytokines (such as interleukin IL-8 and IL-18) on cancer risk; moreover, there is very little evidence regarding head and neck cancer (HNC).MethodsThus, a meta-analysis including 22 studies with 4731 cases and 8736 controls was conducted to evaluate this association. The summary odds ratio (OR) and corresponding 95% confidence intervals (CIs) for C-X-C motif chemokine ligand 8 (CXCL8, which encodes IL-8) and IL-18 polymorphisms and HNC risk were estimated.ResultsThe results showed a significantly increased risk of HNC susceptibility for IL18 −137 G/C in five genetic models, but, interestingly, no significant association was found for the CXCL8 −251 A/T polymorphism. When stratified by cancer type, an increased risk of nasopharyngeal cancer was found for both −137 G/C and −251A/T. When the studies were stratified by ethnicity and genotyping method, there were significant associations between Asian populations and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) studies for −137 G/C, and African populations for −251 A/T in some genetic models. A positive association was also found between the population-based groups in some models for −137 G/C; conversely, significantly decreased risk was found among the −251 A/T hospital-based group. Meta-regression was also conducted. The publication year, control source, and cancer type contributed to CXCL8 −251 A/T heterogeneity; however, no factors were found that contributed to IL-18 −137 G/C heterogeneity. Marginal significance was found in the recessive model for IL-18 −137 G/C by Egger’s test, whereas no publication bias was detected for CXCL8 −251 A/T.ConclusionsThe results indicate that the IL-18 −137 G/C polymorphism is associated with HNC risk, especially nasopharyngeal cancer, in Asian populations and, when using PCR-RFLP, CXCL8 −251 A/T polymorphisms play a complex role in HNC development.

A study of association between regulatory polymorphism in the IL-10 gene promoter region and acute viral hepatitis, and acute liver failure.

The level of inflammatory cytokine Interleukin (IL)-10 is increased in patients infected with hepatitis-related acute liver failure (ALF), and this was thought to be because of the regulatory polymorphism in the IL-10 gene promoter region. The present study was designed to analyze the possible association between IL-10 gene promoter polymorphism and acute viral hepatitis (AVH), and ALF. An attempt was made to quantify IL-10 levels at admission, during the hospital stay, and at the final outcome to study its relationship with liver injury among patients with AVH, ALF, and controls. The study included 40 patients each with ALF and AVH. IL-10 gene promoter polymorphism was detected by the PCR-RFLP method. Quantification of IL-10 was done using commercially available ELISA kits. The individuals with -592 AC, -819 TC, -1082 AA genotypes were found to have a significantly higher risk of ALF whereas those with -592 AA and - 819 CC polymorphism were found to be less susceptible. Individuals with - 819 CC were found to be more susceptible to AVH while those with -592 AA and -819 TT were less susceptible as compared to controls. Mean serum IL-10 at admission was significantly elevated in patients with ALF (38.4±11.3 pg/mL) as compared to patients with AVH (16.7±5.4pg/mL) and control population (8.3±3.6 pg/mL, p < 0.05). Regulatory polymorphism in the IL-10 gene promoter has a possible and significant association with severity and outcome in patients with AVH and ALF. Raised levels of IL-10 could be predictive of prognosis in patients with ALF.

Association of Interleukin-6 Genetic Polymorphisms and Environment Factors Interactions with Coronary Artery Disease in a Chinese Han Population

ABSTRACTObjectives: To investigate the influence of IL-6 single nucleotide polymorphisms (SNPs), additional gene-gene and gene-environment interactions on coronary artery disease (CAD) risk. Methods: A total of 751 participants (429 CAD patients and 322 controls) were recruited in this study. Logistic regression analysis was conducted to evaluate the association of IL-6 SNPs with CAD risk and generalized multifactor dimensionality reduction (GMDR) was performed to investigate the best interaction combinations for gene-gene and gene-environment interactions. Results: CAD risk is significantly higher in carriers of C allele of the rs1800795 polymorphism than those with GG genotype (CC + CG versus GG, adjusted OR (95%CI) = 2.07 (1.56–2.86), p < 0.001). GMDR analysis revealed rs1800795 was significantly interacted with tobacco smoking and alcohol drinking in two-locus model (p < 0.0010). Current smokers with CC or CG of rs1800795 genotype have the highest CAD risk, OR (95%CI) = 3.22 (2.45–3.94) and current drinkers with CC or CG of rs1800795 genotype have the highest CAD risk, OR (95%CI) = 3.17 (2.20–4.24). Conclusion: The C allele of rs1800795 within IL-6 gene promoter, rs1800795-tobacco smoking and rs1800795-alcohol drinking interaction were all associated with increased CAD risk.

Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression

BackgroundDiabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors. MethodsWe screened nine genetic variations in three cytokine genes (TNF-α, IL-6 and IL-β) in 1326 unrelated subjects comprising of healthy controls (n = 464), type 2 diabetics with nephropathy (DN, n = 448) and type 2 diabetes without nephropathy (T2D, n = 414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR). ResultsIndividual SNP analysis showed highest association of IL-1β rs16944-TT genotype (OR = 3.51, 95%CI = 2.36–5.21, P = 0.001) and TNF-α rs1800629-AA genotype (OR = 2.75, 95% CI = 1.64–4.59, P = 0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR = 4.25, 95%CI = 3.3–14.20, P = 0.0016) and GACGACCTT (OR = 21.3, 95%CI = 15.1–28.33, P = 0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-α expression was increased by more than four-folds (n-fold = 4.43 ± 1.11) in DN. TNF-α, IL-6 and IL-1β transcript levels were significantly modulated by promoter region SNPs. ConclusionsThe present study implicates a strong association between cytokine TNF-α, IL-6 and IL-1β gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis.

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii, which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1β (IL-1β) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls (P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients (P = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT (P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1β gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT (P = 0.0494). The IL-10, IFN-γ, and IL-1β polymorphisms influence the development of OT in the Colombian population.

Inhibition of SOX9 Promotes Inflammatory and Immune Responses of Dental Pulp

IntroductionThe process of pulpitis is characterized by extracellular matrix imbalance and inflammatory cell infiltration. As an essential transcription factor, sex-determining region Y-box 9 (SOX9) is significantly inhibited by tumor necrosis factor alpha in inflammatory joint diseases. The aim of this study was to explore the role of SOX9 in extracellular matrix balance, cytokine expression, and the immune response in dental pulp. MethodsThe expression of SOX9 in normal and inflamed pulp tissue/human dental pulp cells (HDPCs) was detected by immunohistochemistry, Western blot, and quantitative polymerase chain reaction (qPCR). SOX9 small interfering RNA was used to knock down SOX9 expression of dental cells in vitro; extracellular matrix imbalance was analyzed by qPCR, Western blot, and gelatin/collagen zymography, and the secretion of cytokines was scanned by antibody arrays. The immune response of THP-1 was investigated by cell migration assay, cell attachment assay, phagocytosis assay, and enzyme-linked immunosorbent assay. The interaction of SOX9 with target genes was explored by chromatin immunoprecipitation (ChIP). ResultsSOX9 was strongly expressed in normal dental pulp tissue and HDPCs and reduced in inflamed pulp. SOX9 knockdown could inhibit the production of type I collagen, stimulate the enzymatic activities of MMP2 and MMP13, and regulate the production of interleukin (IL) 8 of HDPCs. SOX9 knockdown also effectively suppressed the differentiation and functional activities of THP-1. ChIP showed that the binding of the SOX9 protein with matrix metalloproteinase (MMP)-1, MMP-13, and IL-8 gene promoters was reduced after being treated with recombinant human tumor necrosis factor alpha. ConclusionsSOX9 was inhibited in inflamed dental pulp and may participate in the regulation of extracellular matrix balance, the inflammatory process, and the immune response.