IL-6-174 G/C and -572 C/G polymorphisms and risk of Alzheimer's disease

Associations between interleukin 6 (IL-6) polymorphisms and Alzheimer's disease (AD) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations for the relationship between IL-6-174 G/C and -572 C/G polymorphisms and risk for AD. Electronic searches for all publications in databases PubMed and EMBASE were conducted on the associations between IL-6 polymorphisms and risk for AD until January 2012. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using fixed and random effects models. Twenty-seven studies were included with a total of 19,135 individuals, involving 6,632 AD patients and 12,503 controls. For IL-6-174 G/C polymorphism, the combined results showed significant differences in recessive model (CC vs. CG+GG: OR?=?0.65, 95%CI?=?0.52-0.82). As regards IL-6-572 C/G polymorphism, significant associations were shown in dominant model (CG+GG vs. CC: OR=?0.73, 95% CI?=?0.62-0.86) and in additive model (GG vs. CC, OR=?0.66, 95% CI?=?0.46-0.96). In conclusion, genotype CC of IL-6-174 G/C and genotype GG plus GC of IL-6-572 C/G could decrease the risk of AD.     

Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans

Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mU.min(-1).kg(-1)), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance.     

连续肾脏替代治疗对脓毒症患者血清中TNF-alpha、IL-6 和IL-8 表达的影响

目的：探讨连续肾脏替代治疗（CRRT）对脓毒症患者血清中肿瘤坏死因子alpha（TNF-alpha）、白介素-6（IL-6）和白介素-8（IL-8）的 影响。方法：将我院2013 年1 月-2014 年6 月间收治的80 例脓毒症患者随机分为观察组与对照组各40 例,两组患者均给予脓毒 症常规治疗,观察组另给予CRRT 治疗。观察比较两组患者治疗前1 天,治疗后24 h,72 h空腹静脉血TNF-alpha、IL-6、IL-8 水平。结 果：观察组治愈率为85.0%（34/40）,明显高于对照组的55.0%（22/40）,差异有统计学意义（P<0.05）;治疗24h、72h 后两组患者 TNF-alpha、IL-6和IL-8 水平均明显下降,其中观察组下降更显著,差异均有统计学意义（P<0.05）。结论：CRRT 能有效降低脓毒症患 者血清中TNF-alpha、IL-6 和IL-8 水平,有助于对炎症反应的正向调节。     

IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha

IL-10 is an immunosuppressive cytokine in the immune system. It was in clinical trial as an anti-inflammatory therapy for inflammatory bowel disease and various autoimmune diseases such as psoriasis, rheumatoid arthritis, and multiple sclerosis. IL-19 belongs to the IL-10 family, which includes IL-10, IL-19, IL-20, IL-22, melanoma differentiation-associated gene (MDA-7, IL-24), and AK155 (IL-26). Despite a partial homology in their amino acid sequences, they are dissimilar in their biologic functions. Little is known about the biologic function and gene regulation of IL-19. To understand the gene regulation of human IL-19, we identified a human IL-19 genomic clone and analyzed its promoter region. Five fusion genes containing different regions upstream of exon 1 linked to a luciferase reporter gene were expressed in the canine kidney epithelial-like Madin-Darby canine kidney cells. A fusion gene containing 394 bp showed luciferase activity 7- to 8-fold higher than the negative control of the promoterless fusion gene. We also isolated a full-length mouse cDNA clone. Mouse IL-19 shared 71% amino acid identity with human IL-19. Treatment of monocytes with mouse IL-19 induced the production of IL-6 and TNF-alpha. It also induced mouse monocyte apoptosis and the production of reactive oxygen species. Taken together, our results indicate that mouse IL-19 may play some important roles in inflammatory responses because it up-regulates IL-6 and TNF-alpha and induces apoptosis.     

Association of TNF-alpha,IL-6 and IL-1beta gene polymorphisms with polycystic ovary syndrome: a meta-analysis

Background

Several studies on the association of TNF-alpha (−308 G/A), IL-6 (−174 G/C) and IL-1beta (−511 C/T) polymorphisms with polycystic ovary syndrome (PCOS) risk have reported conflicting results. The aim of the present study was to assess these associations by meta-analysis.

Results

A total of 14 eligible articles (1665 cases/1687 controls) were included in this meta-analysis. The results suggested that there was no obvious association between the TNF-alpha (−308 G/A) polymorphism and PCOS in the overall population or subgroup analysis by ethnicity, Hardy–Weinberg equilibrium (HWE) in controls, genotyping method, PCOS diagnosis criteria, and study sample size. Also, no obvious association was found between the TNF-alpha (−308 G/A) polymorphism and obesity in patients with PCOS (body mass index [BMI] ≥ 25 kg/m² vs. BMI < 25 kg/m²). Regarding the IL-6 (−174 G/C) polymorphism, also no association was found in the overall population in heterozygote comparison, dominant model, and recessive model. Even though an allelic model (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.41–0.96) and a homozygote comparison (OR = 0.52, 95% CI = 0.30–0.93) showed that the IL-6 (−174 G/C) polymorphism was marginally associated with PCOS. Further subgroup analysis suggested that the effect size was not significant among HWE in controls (sample size ≤ 200) and genotyping method of pyrosequencing under all genetic models. Similarly, there was no association between the IL-1beta (−511 C/T) polymorphism and PCOS in the overall population or subgroup analysis under all genetic models. Furthermore, no significant association was found between the IL-1beta (−511 C/T) polymorphism and several clinical and biochemical parameters in patients with PCOS.

Conclusions

The results of this meta-analysis suggest that the TNF-alpha (−308 G/A), IL-6 (−174 G/C), and IL-1beta (−511 C/T) polymorphisms may not be associated with PCOS risk. However, further case–control studies with larger sample sizes are needed to confirm our results.

Electronic supplementary material

The online version of this article (doi:10.1186/s12863-015-0165-4) contains supplementary material, which is available to authorized users.     

IL-6 -174G/C polymorphism and IL-6 serum levels in patients with liver cirrhosis and hepatocellular carcinoma

Recently, a link between high levels of circulating IL-6 and hepatocellular carcinoma (HCC) has been proposed. In addition, single nucleotide polymorphisms (SNPs) in the promoter region of the IL-6 gene have been reported to be related to several inflammatory-related conditions, including cancer. The purpose of this article is: (1) to evaluate the frequencies of SNPs in the IL-6 promoter region at position -174 and IL-6 serum levels in a group of patients with HCC and underlying liver cirrhosis (LC), and compare them with a group of LC patients without HCC; (2) to determine whether a possible correlation exists between the allelic variations, IL-6 serum levels, and the risk of developing HCC. The study included 105 HCC and 95 LC patients. Genomic DNA was isolated using commercially available kits. DNA samples were typed for relevant SNPs of the IL-6 promoter region (-174?G>C, G allele being associated with higher levels of the cytokine). The Restriction Fragment Length Polymorphism (RFLP-PCR) method was used to type the SNPs. IL-6 serum levels were determined using an ultrasensitive commercially available ELISA kit. IL-6 serum levels were higher in G/G compared to C/C genotypes only in HCC (z=2; p=0.04) and G/G versus G/C (z=1.8; p<0.03). IL-6 serum levels in G carriers (G/G+G/C) were higher in HCC 4.8 (0.2-17.5) versus LC patients 2.2 (0.07-11.5) (z=2.8; p=0.004). There was no difference for genotype C/C. IL-6 serum levels in HCC correlated with G carriers (G/G+G/C) (ρ=0.25, p=0.05). A positive correlation was also found between sIL-6 levels and some parameters of liver function both in LC and in HCC patients.     

Circulating IL-6, IL-10, and TNF-alpha and IL-10/IL-6 and IL-10/TNF-alpha ratio profiles of polyparasitized individuals in rural and urban areas of gabon

Malaria, blood-borne filarial worms and intestinal parasites are all endemic in Gabon. This geographical co-distribution leads to polyparasitism and, consequently, the possibility of immune-mediated interactions among different parasite species. Intestinal protozoa and helminths could modulate antimalarial immunity, for example, thereby potentially increasing or reducing susceptibility to malaria. The aim of the study was to compare the cytokine levels and cytokine ratios according to parasitic profiles of the population to determine the potential role of co-endemic parasites in the malaria susceptibility of populations. Blood and stool samples were collected during cross-sectional surveys in five provinces of Gabon. Parasitological diagnosis was performed to detect plasmodial parasites, Loa loa, Mansonella perstans, intestinal helminths (STHs) and protozoan parasites. Nested PCR was used to detect submicroscopic plasmodial infection in individuals with negative blood smears. A cytometric bead array was used to quantify interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in the plasma of subjects with different parasitological profiles. Median IL-6 and IL-10 levels and the median IL-10/TNF-α ratio were all significantly higher among individuals with Plasmodium (P.) falciparum infection than among other participants (p<0.0001). The median TNF-α level and IL-10/IL-6 ratio were higher in subjects with STHs (p = 0.09) and P. falciparum-intestinal protozoa co-infection (p = 0.04), respectively. IL-6 (r = -0.37; P<0.01) and IL-10 (r = -0.37; P<0.01) levels and the IL-10/TNF-α ratio (r = -0.36; P<0.01) correlated negatively with age. Among children under five years old, the IL-10/TNF-α and IL-10/IL-6 ratios were higher in those with intestinal protozoan infections than in uninfected children. The IL-10/TNF-α ratio was also higher in children aged 5–15 years and in adults harbouring blood-borne filariae than in their control counterparts, whereas the IL-10/IL-6 ratio was lower in those aged 5–15 years with filariae and intestinal parasites but higher in adults with intestinal parasitic infections. Asymptomatic malaria is associated with a strong polarization towards a regulatory immune response, presenting high circulating levels of IL-10. P. falciparum/intestinal protozoa co-infections were associated with an enhanced IL-10 response. Immunity against malaria could differ according to age and carriage of other parasites. Helminths and intestinal protozoa can play a role in the high susceptibility to malaria currently observed in some areas of Gabon, but further investigations are necessary.     

The involvement of IL-10, IL-6, IFN-gamma, TNF-alpha and TGF-beta gene polymorphisms among Turkish lung cancer patients

Several genes encoding different cytokines may play crucial roles in host susceptibility to lung cancer, since cytokine production capacity varies among individuals and depends on cytokine gene polymorphisms. The association between cytokine gene polymorphisms with primary lung carcinoma was investigated. DNA samples were obtained from a Turkish population of 44 patients with primary lung cancer, and 59 healthy control subjects. All genotyping (IFN-gamma, TGF-beta1, TNF-alpha, IL-6 and IL-10) experiments were performed using sequence-specific primers (SSP)-PCR. When compared to the healthy controls, the frequencies of high/intermediate producing genotypes of IL-10 and low producing genotype of TNF-alpha were significantly more common in the patient group. It is noteworthy that lung cancer patients with the TGF-beta T/T genotype in codon 10 had statistically longer survival compared to those having the C/C genotype (Kaplan-Meier survival function test, log rank significance = 0.014). These results suggest that IL-10, TNF-alpha and TGF-beta1 gene polymorphisms may affect host susceptibility to lung cancer and the outcome of the patients.     

Interleukin-6 gene polymorphism -174G/C influences plasma lipid levels in women

Elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6) have been associated with cardiovascular risk factors. The objective of this study was to investigate potential associations between the promoter polymorphism IL-6 -174G/C and the following indices of metabolism: BMI, waist-to-hip ratio, and plasma levels of IL-6, cholesterol, low-density lipoprotein, triglycerides, high-density lipoprotein, leptin, and C-reactive protein in 252 42-year-old women and 245 51-year-old men. Subgroups were also studied 5 years later. The CC genotype of the IL-6 polymorphism was associated with lower levels of cholesterol and low-density lipoprotein (p < 0.001) in women. This finding was replicated in the follow-up, when a significant association between the CC genotype and low triglycerides was also observed. The association between the C allele and lipid pattern found in women was not found in men, where on the contrary, C carriers tended to display elevated triglycerides. IL-6 genotype was not associated with IL-6 plasma levels in either sample. The results suggest different effects of the IL-6 polymorphism on metabolic indices in women and men. None of the associations between IL-6 genotype and lipid pattern seemed to result from an effect of the polymorphism on IL-6 plasma levels.     

糖皮质激素对大叶性肺炎患儿血清TNF-alpha、IL-6、IL-8水平的影响

目的：探究糖皮质激素对大叶性肺炎患儿血清TNF-alpha、IL-6、IL-8 水平的影响。方法：选取2014 年3 月至2014 年8月我院收 治的大叶性肺炎患儿60 例,并将其随机分为对照组和实验组。对照组30 例,给抗炎、退热、镇咳、平喘等临床常规治疗;实验组30 例,在与对照组相同治疗的基础上加用糖皮质激素联合治疗。治疗结束后,比较两组患儿治疗前后血清TNF-alpha、IL-6、IL-8 水平的 变化。结果：治疗前,两组患儿的血清TNF-alpha、IL-6、IL-8 水平比较均无统计学差异(P 均>0.05);治疗后,两组患儿的血清TNF- alpha、 IL-6、IL-8 水平均较治疗前显著降低(P 均<0.05),且实验组患儿的血清TNF-alpha、IL-6、IL-8 水平均显著低于对照组,差异均有统计 学意义(P 均<0.05)。结论：糖皮质激素辅助治疗可降低大叶性肺炎患儿血清TNF-alpha、IL-6、IL-8 的水平,这可能是其治疗儿童大叶 性肺炎的药理学作用之一。     

胆囊切除术后患者IL-6、IL-10 及TNF-alpha水平的变化及意义

目的：探讨胆囊摘除术后患者IL-6,IL-10 以及TNF-alpha水平变化。方法：选取我院收治的行胆囊切除术患者120 例,根据手术 方式的不同随机分为实验组60 例,为腹腔镜胆囊切除术患者,对照组60 例,为常规开腹切除术患者。观察并比较术前、术后第1 天、第2 天、第3 天患者的IL-6,IL-10、TNF-alpha水平以及术后患者的疲劳情况。结果：①手术后,两组患者较手术前IL-6 均有所升 高,且对照组较实验组升高明显,差异有统计学意义(P＜0.05);两组患者较手术前IL-10 均有所降低,且对照组较实验组降低明 显,差异有统计学意义(P＜0.05)。②手术后,两组与手术前相比较TNF-alpha水平明显升高,与实验组相比较,对照组升高明显,差异 有统计学意义(P＜0.05)。③手术后,两组的疲劳情况相比较,实验组明显低于对照组,差异有统计学意义(P＜0.05)。结论：胆囊切除 术后患者IL-6,IL-10,以及TNF-alpha均有所升高,说明应激反应正在发生,进而出现术后疲劳。     

TNF-alpha and IL-8: serum levels and gene polymorphisms (-308G>A and -251A>T) are associated with classical biomarkers and medical history in children with sickle cell anemia

Sickle cell anemia (SCA) is a disorder characterized by a heterogeneous clinical outcome. In the present study, we investigated the associations between Tumor Necrosis Factor-alpha (TNF-alpha) −308G>A and Interleukin 8 (IL-8) −251A>T gene polymorphisms, medical history and classical biomarkers in children with steady-state SCA. In total, 210 SCA patients aged 2–21 years and 200 healthy controls were studied. Gene polymorphisms, beta^S-globin haplotypes and a 3.7-kb deletion in alpha2-thalassemia (α₂-thal^{3.7 kb}) were investigated by PCR/RFLP analysis, and cytokine levels were determined by ELISA. Splenomegaly (p = .032) was more prevalent among children younger than 5 years of age. The A allele of the TNF-alpha −308G>A gene polymorphism and the presence of α₂-thal^{3.7 kb} were associated with an increase risk of splenic sequestration events (p = .001; p = .046), while the T allele of the IL-8 −251A>T gene polymorphism was considered to be a protective factor for splenomegaly events (p = .032). Moreover, the A allele of the TNF-alpha −308G>A gene polymorphism was associated with high TNF-alpha levels (p = .021), and the hemoglobin F and hemoglobin S haplotypes were correlated with serum levels of IL-8. The logistic regression analysis showed significant effects of the TNF-alpha and IL-8 gene polymorphisms, beta^S-globin gene haplotypes and α₂-thal^{3.7 kb} on the occurrence of splenic sequestration events. Our study emphasizes that the identification of new genetic and immunological biomarkers and their associations with classical markers is an important strategy to elucidate the underlying causes of different SCA phenotypes and their effects on patient outcome.     

Association of the IL-6 -174G/C gene polymorphism with knee osteoarthritis in a Thai population

Osteoarthritis is a chronic progressive degenerative joint disease characterized by age-related regressive change in articular cartilage. A single nucleotide polymorphism has been described at position -174 of the interleukin-6 (IL-6) promoter region, leading to three possible genotypes, GG, GC, and CC. We investigated a possible association of the IL-6 -174G/C gene polymorphism with knee osteoarthritis in a Thai population. Genotype distributions and allelic frequencies of the IL-6 -174G/C polymorphism were investigated in 115 knee osteoarthritis patients and 100 healthy controls. Genotyping was performed using PCR-RFLP. The genotype distribution of IL-6 was 79 GG, 36 GC, 0 CC in knee osteoarthritis patients and 88 GG, 12 GC, 0 CC in controls. The frequency of the GC genotype in subjects with knee osteoarthritis was higher than in controls (P< 0.001). Logistic regression analysis showed that the GC genotype was independently associated with increased risk of knee osteoarthritis (odds ratio = 3.3, 95% confidence interval = 1.6-6.9, P = 0.001). These findings suggest that the -174G/C polymorphism of the IL-6 gene promoter plays a role in the pathogenesis of knee osteoarthritis.     

Interleukin-6 -174 promoter polymorphism does not influence IL-6 production after LPS and IL-1 beta stimulation in human umbilical cord vein endothelial cells

The IL-6 is a typical pleiotropic cytokine, which regulates T cell response, B cell differentiation and immunoglobulin production. Endothelial cells can produce large amounts of IL-6. SNP at position -174 (G/C) in the IL-6 promoter region was found to be associated with a series of complex diseases. In this study we analyzed whether IL-6 -174 G/C polymorphism has any effect on IL-6 production of in vitro cultured HUVECs. Thirty-three fresh umbilical cords were recruited from healthy pregnancies. The endothelial cells isolated from human umbilical cords were genotyped for IL-6 -174 SNP. C allele frequency was 0.379. The IL-6 production of each primary HUVEC line was measured after IL-1beta or LPS treatment by ELISA. Serial dilutions of the stimulating agents were applied and maximum amount of produced IL-6 (R(max)) and stimulator concentrations at half-maximal IL-6 response (MR(50)) were calculated for each of the cell lines. IL-6 production was not associated with IL-6 -174 SNP genotypes or with presence of C allele. Our results showed that IL-6 production of HUVEC after proinflammatory stimulation was not influenced by IL-6 -174 SNP. Further functional studies are required to compare differences and similarities in IL-6 -174 SNP dependent expression of IL-6 among various cell types.     

血液灌流联合血液透析对维持性血液透析患者IL-6、TNF-alpha、hs-CRP及 Hcy等指标水平的影响

目的：研究血液灌流联合血液透析对接受维持性血液透析（MHD）的患者白介素-6（IL-6）、肿瘤坏死因子（TNF-alpha）、超敏C 反应蛋白（hs-CRP）及同型半胱氨酸（Hcy）等指标水平的影响。方法：选择2010年5 月至2013 年5 月在我院接受MHD的终末期 肾病112 例作为研究对象。根据数字法随机分成观察组及对照组,每组均含56 例患者。对照组行常规血液透析治疗,观察组行血 液灌流及血液透析的联合治疗。治疗12 周后对比分析两组治疗前后的各项炎性因子与营养学指标,及生活质量指数（QOL）评 分。结果：治疗后观察组的hs-CRP、IL-6 及TNF-alpha与Hcy水平均显著低于对照组,差异均有统计学意义（均P＜0.05）。治疗后观察 组的血清Hb、TP及Alb 与TRF水平均显著高于对照组,差异均有统计学意义（均P＜0.05）。两组治疗后的QOL评分较治疗前均 显著上升,但观察组的上升幅度显著大于对照组,差异均有统计学意义（均P＜0.05）。结论：血液灌流与血液透析联合治疗接受 MHD的患者,可有效改善患者机体的微炎症及营养状况,提升患者的生活质量,效果明显,值得临床推荐。     

Association of resistin polymorphisms with resistin levels and lipid profile in children

Previous research has found a correlation between resistin and lipid level variations. Polymorphisms in the resistin gene (RETN) could be involved in this relationship, but the results of the different studies are contradictory. The aim of this study was to examine the association between resistin and lipid levels, and to determine whether resistin polymorphisms are associated with resistin levels and lipid profile in prepubertal children and adolescents. The single nucleotide polymorphisms (SNPs) rs1862513 and rs10401670 were analyzed in 442 randomly selected 6- to 8-year-old children and 827 children aged 12–16 years. Anthropometric data were recorded. Lipid profile was determined using standard methods. Serum resistin levels were measured using a multiplexed bead immunoassay. Resistin polymorphisms were determined by TaqMan^® allelic discrimination assays. A relationship was found between serum levels of resistin and the SNP rs10401670 in 6- to 8-year-old boys. SNP rs10401670 was also related to TC and LDL-cholesterol in 12- to 16-year-old boys and to HDL-C in 12- to 16-year-old girls. SNP rs1862513 was not related to any of the studied variables. Serum resistin levels were significantly and negatively associated with ApoAI levels in 12- to 16-year-old girls. A SNP in the 3′UTR region of RETN (rs10401670) is associated with resistin levels and lipid profile in children, showing different associations depending on age and gender.     

Correlation of VEGF genetic polymorphisms and lipid profile to aortic calcification

Background

Aortic calcification is developed due to accumulation of a large amount of calcium in the aorta of the heart and it is the leading cause of aortic valve replacement and third leading cause of cardiovascular disease. The purpose of this study was to investigate the relation between aortic calcification and VEGF SNPs (− 2578C>A, − 1154G>A and + 936C>T) and to evaluate the association of these SNPs with biochemical parameter in relation to aortic calcification.

Methods

Aortic calcification was diagnosed by examining the posteroanterior chest X-rays by a radiologist and graded into four groups. The real-time polymerase chain reaction with melting curve analysis in LightCycler was used to genotype the VEGF SNPs.

Results

Among the VEGF SNPs, a significant genetic difference was found only between the aortic calcification and control group with VEGF SNP − 2578C>A but haplotypes T–A–A of (+ 936/− 1154/− 2578) were significantly different in control and aortic calcification and could enhance the aortic calcification development. By regression analysis, it was found that age, hypertension, diabetes, dyslipidemia, and hyperhomocysteinemia were found significantly different with the different genotypes of VEGF SNPs which may induce aortic calcification development.

Conclusion

Age, hypertension, diabetes, dyslipidemia, and hyperhomocysteinemia were established as aggravating factors for the aortic calcification in association with different VEGF genotypes.