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Sample records for interleukin-6 polymorphisms modify

  1. A common polymorphism near the interleukin-6 gene modifies the association between dietary fat intake and insulin sensitivity

    PubMed Central

    Cuda, Cristina; Garcia-Bailo, Bibiana; Karmali, Mohamed; El-Sohemy, Ahmed; Badawi, Alaa

    2012-01-01

    Background Increasing evidence suggests a role for inflammation in the development of type 2 diabetes. Elevated levels of inflammatory cytokines, including interleukin-6, have been associated with insulin resistance, and dietary lipids can increase cytokine production. The objective of this study was to determine whether a single nucleotide polymorphism near the IL6 gene (rs7801406) modifies the relationship between dietary fat and markers of insulin sensitivity. Methods Subjects were healthy men and women aged 20–29 years from the Toronto Nutrigenomics and Health Study. Dietary intake was estimated using a one-month semiquantitative food frequency questionnaire. Fasting blood samples were taken for genotyping and biomarker measurement. Results The single nucleotide polymorphism was not associated with any of the measures of insulin sensitivity. However, it modified the relationship between total dietary fat and the homeostasis model assessment of insulin resistance (P = 0.053 for interaction). Total fat intake was positively related to HOMA-IR in individuals homozygous for the G allele (β = 0.005 ± 0.002, P = 0.03), but not among heterozygotes. There was an inverse relationship between total fat intake and HOMA-IR in individuals who were homozygous for the A allele (β = −0.012 ± 0.006, P = 0.047). Conclusion These findings suggest that dietary fat influences insulin sensitivity differently depending on genotype. PMID:22334790

  2. A common polymorphism near the interleukin-6 gene modifies the association between dietary fat intake and insulin sensitivity.

    PubMed

    Cuda, Cristina; Garcia-Bailo, Bibiana; Karmali, Mohamed; El-Sohemy, Ahmed; Badawi, Alaa

    2012-01-01

    Increasing evidence suggests a role for inflammation in the development of type 2 diabetes. Elevated levels of inflammatory cytokines, including interleukin-6, have been associated with insulin resistance, and dietary lipids can increase cytokine production. The objective of this study was to determine whether a single nucleotide polymorphism near the IL6 gene (rs7801406) modifies the relationship between dietary fat and markers of insulin sensitivity. Subjects were healthy men and women aged 20-29 years from the Toronto Nutrigenomics and Health Study. Dietary intake was estimated using a one-month semiquantitative food frequency questionnaire. Fasting blood samples were taken for genotyping and biomarker measurement. The single nucleotide polymorphism was not associated with any of the measures of insulin sensitivity. However, it modified the relationship between total dietary fat and the homeostasis model assessment of insulin resistance (P = 0.053 for interaction). Total fat intake was positively related to HOMA-IR in individuals homozygous for the G allele (β = 0.005 ± 0.002, P = 0.03), but not among heterozygotes. There was an inverse relationship between total fat intake and HOMA-IR in individuals who were homozygous for the A allele (β = -0.012 ± 0.006, P = 0.047). These findings suggest that dietary fat influences insulin sensitivity differently depending on genotype.

  3. Interleukin-6 Receptor Polymorphism Is Prevalent in HIV-negative Castleman Disease and Is Associated with Increased Soluble Interleukin-6 Receptor Levels

    PubMed Central

    Stone, Katie; Woods, Emily; Szmania, Susann M.; Stephens, Owen W.; Garg, Tarun K.; Barlogie, Bart; Shaughnessy, John D.; Hall, Brett; Reddy, Manjula; Hoering, Antje; Hansen, Emily; van Rhee, Frits

    2013-01-01

    Multicentric Castleman Disease is largely driven by increased signaling in the pathway for the plasma cell growth factor interleukin-6. We hypothesized that interleukin-6/interleukin-6 receptor/gp130 polymorphisms contribute to increased interleukin-6 and/or other components of the interleukin-6 signaling pathway in HIV-negative Castleman Disease patients. The study group was composed of 58 patients and 50 healthy donors of a similar racial/ethnic profile. Of seven polymorphisms chosen for analysis, we observed an increased frequency between patients and controls of the minor allele of interleukin-6 receptor polymorphism rs4537545, which is in linkage disequilibrium with interleukin-6 receptor polymorphism rs2228145. Further, individuals possessing at least one copy of the minor allele of either polymorphism expressed higher levels of soluble interleukin-6 receptor. These elevated interleukin-6 receptor levels may contribute to increased interleukin-6 activity through the trans-signaling pathway. These data suggest that interleukin-6 receptor polymorphism may be a contributing factor in Castleman Disease, and further research is warranted. PMID:23372742

  4. Association of interleukin-6 gene polymorphism with angina pectoris.

    PubMed

    Amorim, Fernanda Gobbi; Campagnaro, Bianca Prandi; Tonini, Clarissa Loureiro; Norbim, Ana Paula Capua; Louro, Iuri Drummond; Vasquez, Elisardo Corral; Arruda, Jose Airton; Meyrelles, Silvana Santos

    2011-10-01

    In this study, we investigated the role of the -174G>C polymorphism of interleukin-6 (IL-6) as a predisposing factor to angina pectoris. Patients were separated into 2 groups: angina (N = 72) and nonangina (N = 71). There were no statistical differences between groups for all cardiovascular risk factors evaluated. The GG genotype frequency was 18% lower in the angina than in the non-angina group, whereas GC + CC was 18% higher in the angina group (P = .036). The frequency of G allele was 11% lower in the angina than in the nonangina group and C allele was 11% higher in the angina group (P = .043). Patients carrying the C allele showed a 2-fold increased risk for angina pectoris (P = .036). Our study demonstrates a high incidence of the -174G>C polymorphism of the IL-6 gene in patients with angina pectoris compared with those carrying the G allele, reinforcing the contribution of genetic factors to the symptoms of angina pectoris.

  5. Association of Gene Polymorphisms in Interleukin 6 in Infantile Bronchial Asthma.

    PubMed

    Babusikova, Eva; Jurecekova, Jana; Jesenak, Milos; Evinova, Andrea

    2017-07-01

    The genetic background of bronchial asthma is complex, and it is likely that multiple genes contribute to its development both directly and through gene-gene interactions. Cytokines contribute to different aspects of asthma, as they determine the type, severity and outcomes of asthma pathogenesis. Allergic asthmatics undergoing an asthmatic attack exhibit significantly higher levels of pro-inflammatory cytokines, such as interleukins and chemokines. In recent years, cytokines and their receptors have been shown to be highly polymorphic, and this prompted us to investigate interleukin 6 promoter polymorphisms at position -174G/C (rs1800795) and at -572G/C (rs1800796) in relation to asthma in children. Interleukin 6 promoter polymorphisms were analyzed in bronchial asthma patients and healthy children using polymerase chain reaction-restriction fragment length polymorphism analysis. We observed a significant association between polymorphism at -174G/C and bronchial asthma (OR=3.4, 95% CI: 2.045-5.638, P<.001). Higher associations between polymorphism at IL-6 -174G/C and bronchial asthma were observed in atopic patients (OR=4.1, 95% CI: 2.308-7.280, P<8.10(-7)). Interleukin 6 polymorphism is associated with bronchial asthma, particularly its atopic phenotype. Expression and secretion of interleukins in asthmatic patients may be affected by genetic polymorphisms, and could have a disease-modifying effect in the asthmatic airway and modify the therapeutic response. Copyright © 2016 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  6. Modifying Effect of a Common Polymorphism in the Interleukin-6 Promoter on the Relationship between Long-Term Exposure to Traffic-Related Particulate Matter and Heart Rate Variability

    PubMed Central

    Adam, Martin; Imboden, Medea; Boes, Eva; Schaffner, Emmanuel; Künzli, Nino; Phuleria, Harish Chandra; Kronenberg, Florian; Gaspoz, Jean-Michel; Carballo, David; Probst-Hensch, Nicole

    2014-01-01

    Background Exposure to particulate matter (PM) has been associated with an increase in many inflammatory markers, including interleukin 6 (IL6). Air pollution exposure has also been suggested to induce an imbalance in the autonomic nervous system (ANS), such as a decrease in heart rate variability (HRV). In this study we aimed to investigate the modifying effect of polymorphisms in a major proinflammatory marker gene, interleukin 6 (IL6), on the relationship between long-term exposure to traffic-related PM10 (TPM10) and HRV. Methods For this cross-sectional study we analysed 1552 participants of the SAPALDIA cohort aged 50 years and older. Included were persons with valid genotype data, who underwent ambulatory 24-hr electrocardiogram monitoring, and reported on medical history and lifestyle. Main effects of annual average TPM10 and IL6 gene variants (rs1800795; rs2069827; rs2069840; rs10242595) on HRV indices and their interaction with average annual exposure to TPM10 were tested, applying a multivariable mixed linear model. Results No overall association of TPM10 on HRV was found. Carriers of two proinflammatory G-alleles of the functional IL6 -174 G/C (rs1800795) polymorphism exhibited lower HRV. An inverse association between a 1 µg/m3 increment in yearly averaged TPM10 and HRV was restricted to GG genotypes at this locus with a standard deviation of normal-to-normal intervals (SDNN) (GG-carriers: −1.8%; 95% confidence interval −3.5 to 0.01; pinteraction(additive) = 0.028); and low frequency power (LF) (GG-carriers: −5.7%; 95%CI: −10.4 to −0.8; pinteraction(dominant) = 0.049). Conclusions Our results are consistent with the hypothesis that traffic-related air pollution decreases heart rate variability through inflammatory mechanisms. PMID:25133672

  7. Haptoglobin gene polymorphisms and interleukin-6 and -8 levels in patients with sickle cell anemia

    PubMed Central

    Pierrot-Gallo, Bruna Spinella; Vicari, Perla; Matsuda, Sandra Satiko; Adegoke, Samuel Ademola; Mecabo, Grazielle; Figueiredo, Maria Stella

    2015-01-01

    Background Haptoglobin genotypes, and interleukin-6 and -8 participate in the pathophysiology of sickle cell anemia. The expression of cytokines is regulated by genetic mechanisms however the effect of haptoglobin polymorphisms on these cytokines is not fully understood. This study aimed to compare the frequency of haptoglobin genotypes and the interleukin-6 and -8 concentrations in sickle cell anemia patients and controls to investigate the association between haptoglobin genotypes and cytokine levels. Methods Sixty sickle cell anemia patients and 74 healthy individuals were analyzed. Haptoglobin genotypes were determined by multiplex polymerase chain reaction, and the interleukin-6 and -8 levels by enzyme linked immunosorbent assay. The association between haptoglobin genotypes and cytokines was investigated by statistical tests. Results Hp2-1 was the most common genotype in both the cases and controls while Hp1-1 was less frequent among sickle cell anemia patients. Interleukin-6 and -8 levels were higher in patients than controls (p-value <0.0001). There was no significant difference in interleukin-6 and -8 concentrations between the genotypes (p-value >0.05). A similar trend was observed among the controls. Conclusion Although, levels of interleukin-6 and -8 were higher in the sickle cell anemia patients, they appeared not to be related to the haptoglobin genotypes. Further investigations are necessary to identify factors responsible for increased secretion of the interleukin-6 and -8 pro-inflammatory cytokines in patients with sickle cell anemia. PMID:26408368

  8. Interleukin-6 polymorphisms are associated with obesity and hyperglycemia in Mexican adolescents.

    PubMed

    Ramírez-López, Guadalupe; Portilla-de Buen, Eliseo; Sánchez-Corona, José; Salmerón-Castro, Jorge; Mendoza-Carrera, Francisco

    2013-01-01

    Interleukin-6 is an inflammatory response mediator used as a metabolic marker of obesity. Polymorphisms IL6 -597C>A, -572G>C, and -174G>C modify the production of this protein. The associations between these haplotypes and obesity or metabolic markers have not been studied in adolescents, so an analysis of these associations was performed. The cross-sectional study included 745 apparently healthy 14- to 19-year-old adolescents. Obesity, serum glucose, insulin, triglycerides, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and high-sensitivity C-reactive protein (hs-CRP) were evaluated, and IL6 -597G>A, -572G>C and -174G>C polymorphisms determined. The associations were analyzed using multivariate logistic regression models. The allele frequencies were 0.15 for -597A and -174C and 0.30 for -572C. Genotypes were in Hardy-Weinberg equilibrium. IL-6(-597/-572/-174) haplotypes GGG, GCG, and AGC comprised 99.74% of the total haplotypes. The associations were significant between genotype GCG/GCG and hyperglycemia (OR = 2.86, 95% CI = 1.02-7.97); between GCG/GCG and high hs-CRP (OR = 6.17, 95% CI = 1.13-33.77); between AGC/AGC and obesity (OR = 4.42, 95% CI = 1.40-14.01); and between GGG/GCG and low HDL-C (OR = 1.53, 95% CI = 1.03-2.28). Genotypes of the IL6(-597/-572/-174) polymorphisms are associated with metabolic risk factors in Mexican adolescents. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  9. The interleukin-6 –174 G/C promoter polymorphism and arterial stiffness; the Rotterdam Study

    PubMed Central

    Sie, Mark PS; Mattace-Raso, Francesco US; Uitterlinden, André G; Arp, Pascal P; Hofman, Albert; Pols, Huibert AP; Hoeks, Arnold PG; Reneman, Robert S; Asmar, Roland; van Duijn, Cornelia M; Witteman, Jacqueline CM

    2008-01-01

    Arterial stiffness normally increases with age and has been established as a precursor of cardiovascular disease. Interleukin-6 is a pleiotropic inflammatory cytokine with an important role in the inflammatory cascade, such as up-regulation of C-reactive protein (CRP). The interleukin-6 –174-G/C promoter polymorphism appears to influence levels of inflammatory markers, which have been shown to be associated with arterial stiffness. We studied the association of this polymorphism with levels of interleukin-6 and CRP and with arterial stiffness. The study (n = 3849) was embedded in the Rotterdam Study, a prospective, population-based study. Analyses on the association between the –174-G/C polymorphism and pulse wave velocity, distensibility coefficient, and pulse pressure were performed using analyses of variance. Analyses on the levels of inflammatory markers and arterial stiffness were performed using linear regression analyses. Analyses were adjusted for age, sex, mean arterial pressure, heart rate, known cardiovascular risk factors, and atherosclerosis. We found pulse wave velocity to be 0.35 m/s higher for CC-homozygotes vs. wildtype GG-homozygotes (p = 0.018) with evidence for an allele-dose effect (p trend = 0.013), and a similar pattern for pulse pressure (p trend = 0.041). No apparent consistent association with the distensibility coefficient was found. CRP levels were associated with pulse wave velocity (p = 0.007). In conclusion, the interleukin-6 –174 G/C polymorphism is associated with increased arterial stiffness and pulse pressure. PMID:19066003

  10. Association of Interleukin-6 Gene Promoter Polymorphism with Coronary Artery Disease in Pakistani Families

    PubMed Central

    Satti, Humayoon Shafiq; Javed, Qamar

    2013-01-01

    Interleukin-6 (IL-6) is a well-known inflammatory cytokine and suggested to be involved in the development of coronary artery disease (CAD). IL-6 gene expression has been investigated with controversy in CAD patients. This study investigates the association of the IL-6 gene expression with CAD, the molecular basis for the regulation of interleukin-6 expression in a Pakistani population. Our data show that the serum IL-6 levels were increased in patients with CAD compared with healthy controls and that the IL-6 gene polymorphism at -174 was more prevalent in CAD cases. There was a statistically significant association between the IL-6 gene polymorphism and CAD, which may be associated with an increased risk for the disease. Moreover, circulating IL-6 and hs-CRP levels were significantly higher in patients with CC genotype (P < 0.0001 and P < 0.0001, resp.). In a binary logistic-regression model, an independent association was found between CAD and increased serum IL-6 and hs-CRP levels and -174G>C polymorphism. This is the first report on the IL-6 expression and the IL-6 gene polymorphism in patients with CAD from Pakistan, and hence it highlights a novel risk factor for the disease. PMID:24363620

  11. Association between Interleukin-6 Promoter Polymorphism (-174 G/C), Serum Interleukin-6 Levels and Mortality in Severe Septic Patients

    PubMed Central

    Lorente, Leonardo; Martín, María M.; Pérez-Cejas, Antonia; Barrios, Ysamar; Solé-Violán, Jordi; Ferreres, José; Labarta, Lorenzo; Díaz, César; Jiménez, Alejandro

    2016-01-01

    The association between interleukin (IL)-6 promoter polymorphism (-174 G/C), circulating IL-6 levels and mortality in septic patients has scarcely been addressed, and then only in studies of small sample size, and a direct association among them has not been previously reported. Therefore, the purpose of our study was to determine whether this association exists. An observational, prospective and multicenter study including severe septic patients was undertaken and serum IL-6 levels at severe sepsis diagnosis and IL-6 promoter polymorphism (-174 G/C) were determined. The end-point of the study was 30-day mortality. The study included 263 patients with the following genotypes of IL-6 promoter polymorphism (-174 G/C): 123 (46.8%) GG, 110 (41.8%) GC and 30 (11.4%) CC. CC homozygous patients showed lower sepsis-related organ failure assessment (SOFA) score, serum IL-6 levels and mortality at 30 days compared to those with other genotypes (GC or GG). On regression analysis, CC homozygous patients showed lower 30-day mortality than those with genotype GG (odds ratio = 0.21; 95% CI = 0.053−0.838; p = 0.03) or GC (hazard ratio = 0.28; 95% CI = 0.074−1.037; p = 0.06). The most important results of our study were that CC might be a favorable genotype in septic patients showing lower serum IL-6 levels and lower risk of death within 30 days. PMID:27834822

  12. Correlation between an interleukin-6 -572C/G polymorphism and chronic periodontitis.

    PubMed

    Jingjin, Liu; Zemin, Guan; Xin, Ma; Donghong, Wu; Jianhua, Geng; Jie, Yi; Yonggong, Wang

    2010-06-01

    Genetic polymorphisms in the interleukin-6 (IL-6) gene are associated with bone homeostasis and diseases characterized by bone loss. The aim of this study was to investigate the correlation between the IL-6-572C/G polymorphism and the risk of chronic periodontitis in a Chinese Han population. The IL-6-572C/G polymorphism was genotyped in 93 patients suffering from chronic periodontitis and 96 control subjects by polymerase chain reaction-restriction fragment length polymorphism. DNA was extracted from the peripheral blood of patients and control subjects and amplified using a polymerase chain reaction. IL-6 genotypes were identified using gel electrophoresis. The IL-6-572 GG genotype and the G allele were more frequent in chronic periodontitis patients than in control subjects (P<.05). When compared with the CC genotype, the odds ratio for chronic periodontitis was 1.88 (95% confidence interval, 1.04 to 3.40; P<.05) for the CG+GG genotype. The frequency of the -572CG+GG genotype was significantly different between the control group and the group with chronic periodontitis. Therefore, the IL-6-572C/G polymorphism may contribute to the susceptibility to chronic periodontitis in the Chinese Han population.

  13. Ethnic Variation in Interleukin-6 –174 (G/C) Polymorphism in the Malaysian Population

    PubMed Central

    Gan, G-G; Subramaniam, R; Lian, L-H; Nadarajan, VS

    2013-01-01

    Interleukin-6 (IL-6) is one of the cytokines that has been well studied and implicated in many diseases including cancers. The frequency of the IL-6 –174 (G/C) polymorphism had been proven to differ in various populations. Malaysia is a country with three major ethnic populations, Malays, Chinese and Indians. In this study, we proposed to determine the G or C allele frequency of the IL-6 –174 polymorphism in these three populations. A total of 348 blood samples were available for analysis. The median age for the subjects was 31 years. There were a total of 245 males and 103 females. A total of 86 Malays (25.0%), 122 Chinese (33.0%) and 140 Indians (40.0%) were genotyped. The result showed a significant difference in the G or C allele frequency of the –174 polymorphism. The total frequencies for the G and C alleles were 91.0 and 9.0%, respectively. In the Malays, the allele frequency of the C allele was 4.0% compared with 19.0% in the Indians. The C allele was not detected in the Chinese population. This finding is the first reported on the Malaysian population and may be important in determining risk of diseases associated with the IL-6 polymorphism in these three populations. PMID:24778564

  14. Interleukin-6 gene -174G/C polymorphism and bronchial asthma risk: a meta-analysis

    PubMed Central

    Li, Fangwei; Xie, Xinming; Li, Shaojun; Ke, Rui; Zhu, Bo; Yang, Lan; Li, Manxiang

    2015-01-01

    The Interleukin-6 (IL-6) genetic polymorphism is associated with bronchial asthma, a number of studies have been conducted to investigate the association between IL-6 gene -174G/C polymorphism and bronchial asthma risk. However, the results are inconclusive. This meta-analysis aims to investigate whether -174G/C polymorphism is a potential risk factor for bronchial asthma. We searched Web of Science, PubMed, Google Scholar, China National Knowledge Infrastructure (CNKI) and Wanfang Database from inception through December 1st, 2014. Meta-analysis was performed using the STATA 12.0. Overall, a significantly reduced risk for asthma was found in IL-6 -174 CC genotype (CC vs. GG: OR = 0. 51, 95% CI = 0.27-0.96, P = 0.038). Furthermore, analysis by ethnicity indicated that there was a markedly reduced risk for asthma in IL-6 -174 CC genotype in Caucasian (CC vs. GG: OR = 0.51, 95% CI = 0.27-0.96, P = 0.038). Analysis by age indicated that there was a significantly reduced risk for asthma in IL-6 -174 CC genotype in adults (CC vs. GG: OR = 0.47, 95% CI = 0.23-0.97, P = 0.042). In conclusion, the current meta-analysis indicates that IL-6 -174 CC genotype may be a protective factor against asthma in Caucasian and adults. PMID:26550171

  15. Interleukin-6 and Interleukin-10 Gene Promoter Polymorphisms and Risk of Endemic Burkitt Lymphoma

    PubMed Central

    Oduor, Cliff I.; Chelimo, Kiprotich; Ouma, Collins; Mulama, David H.; Foley, Joslyn; Vulule, John; Bailey, Jeffrey A.; Moormann, Ann M.

    2014-01-01

    Overexpression of interleukin-6 (IL-6) and IL-10 in endemic Burkitt lymphoma (eBL) may facilitate tumorigenesis by providing a permissive cytokine milieu. Promoter polymorphisms influence interindividual differences in cytokine production. We hypothesized that children genetically predisposed for elevated cytokine levels may be more susceptible to eBL. Using case-control samples from western Kenya consisting of 117 eBL cases and 88 ethnically matched healthy controls, we tested for the association between eBL risk and IL-10 (rs1800896, rs1800871, and rs1800872) and IL-6 (rs1800795) promoter single nucleotide polymorphisms (SNPs) as well as IL-10 promoter haplotypes. In addition, the association between these variants and Epstein Barr Virus (EBV) load was examined. Results showed that selected IL-10 and IL-6 promoter SNPs and IL-10 promoter haplotypes were not associated with risk eBL or EBV levels in EBV-seropositive children. Findings from this study reveal that common variants within the IL-10 and IL-6 promoters do not independently increase eBL risk in this vulnerable population. PMID:25071000

  16. Genetic variations in interleukin-6 polymorphism and the association with susceptibility and overall survival of osteosarcoma.

    PubMed

    Qi, Yunlong; Zhao, Chengbin; Li, Hongxi; Zhang, Benning; Tada, Kazuhiro; Abe, Hiroyuki; Tada, Midori

    2016-07-01

    Interleukin-6 (IL-6), a central proinflammatory cytokine, may be involved in both development and progression of many human malignancies. Therefore, we aimed to evaluate any associations of IL-6 gene polymorphisms with susceptibility and overall survival of osteosarcoma in a Chinese population. A total of 412 subjects, including 206 patients with osteosarcoma and 206 healthy controls, were recruited and were assessed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in this study. Significant differences of genotype distribution were observed between osteosarcoma cases and controls at the IL-6 -174 G/C genotypes. Compared with the homozygote GG, the heterozygous GC genotype was associated with significantly increased risk for osteosarcoma (odds ratio [OR] = 1.58, 95 % confidence interval [CI] = 1.13-3.05, p = 0.028); the CC genotype was associated with increased risk for osteosarcoma (OR = 1.57, 95 % CI = 1.21-3.26, p = 0.022). Moreover, the genotype CC of IL-6 -174 G/C carried a higher risk of osteosarcoma metastasis and later Enneking stages, compared with the GG genotype. The IL-6 -174 G/C genotype was associated with risk for development and metastasis of osteosarcoma in Chinese Han population.

  17. Association between interleukin-6 polymorphisms and periodontitis in Indian non-smokers.

    PubMed

    Franch-Chillida, Fernando; Nibali, Luigi; Madden, Isobel; Donos, Nikos; Brett, Peter

    2010-02-01

    Genetic polymorphisms (SNPs) in the interleukin-6 (IL-6) gene have been associated with the presence of periodontitis. The aim of this study was to investigate the association between five SNPs in the IL-6 promoter region and the periodontal status of a rural Indian population. Two hundred and fifty-one systemically healthy volunteers were clinically assessed by a single calibrated examiner and divided into: healthy individuals and periodontitis patients based on the European Workshop on Periodontitis definitions and on a recently suggested definition, which takes into account age and clinical attachment levels. Their genomic DNA was analysed blindly using real-time polymerase chain reaction to study IL-6 variants. The association between genetic factors and the presence of periodontitis was assessed by logistic regression. The IL-6-174 GG genotype was associated with periodontitis in non-smokers and older subjects (>45 years old). No statistically significant associations were detected between IL-6 haplotypes and periodontal status, after adjusting for confounders. The IL-6-174 polymorphism showed some evidence of an association with the periodontal status in non-smokers and older subjects in this rural Indian population. This association might be mediated by the effect of IL-6 on inflammatory responses.

  18. Interleukin-6 promoter polymorphism (-174 G/C) in Indian patients with chronic periodontitis.

    PubMed

    Kalburgi, Nagaraj B; Bhatia, Aman; Bilichodmath, Shivaprasad; Patil, Sudhir R; Mangalekar, Sachin B; Bhat, Kishore

    2010-09-01

    Recent studies have focused on genetic polymorphism of the interleukin-6 (IL-6) gene, which has led to a better understanding of the intricate interactions between host response, microorganisms, and genetics. Genotype prevalence appears to vary by the race and ethnicity of the population studied. We used a polymerase chain reaction technique to determine the prevalence of single nucleotide polymorphism in IL-6 at position -174 G>C in a population of 30 South Indians. Blood samples were collected from 15 chronic periodontitis patients and 15 healthy controls. The results showed that the G/G genotype was significantly more frequent in the chronic periodontitis group and that the C/C genotype was significantly more frequent in the control group (P = 0.0069 for both). The G allele was more frequent in chronic periodontitis patients (76.67%), whereas the C allele was more frequent in the control group (73.33%). Among chronic periodontitis patients, the odds ratio for having the G allele, as compared with the controls, was 9.04. In this population, the presence of the G/G genotype of IL-6 (-174) might increase susceptibility to chronic periodontitis, whereas the C/C genotype may have a protective effect.

  19. Association among interleukin-6 gene polymorphisms, type 2 diabetes mellitus, and chronic periodontitis: a pilot study.

    PubMed

    Kavitha, Loganathan; Vijayshree Priyadharshini, Jayaseelan; Sivapathasundharam, Balasundaram

    2017-08-01

    The purpose of this pilot study was to determine the association between single nucleotide polymorphisms (-174 G>C) in the interleukin-6 (IL-6) gene with chronic periodontitis (CP) and type 2 diabetes mellitus (T2DM) in south Indian population. Genomic DNA was obtained from the white blood cells of 30 patients with T2DM, 30 patients with CP, 30 patients with T2DM with CP, and 30 controls. DNA was amplified using polymerase chain reaction with specific primers flanking the locus -174 of the IL-6 gene and further genotyped using the restriction fragment length polymorphism method. The genotype distribution and allele frequencies between the study groups were determined using χ(2) -test. The relative risk was estimated with a 95% confidence interval. The CP group (26.7%) displayed a greater percentage of GC genotype (P = 0.026) when compared to the control group (3.3%). A statistically-significant difference in the allele frequencies was found between the control and CP group with the C-allele frequency being greater (0.13) in the CP group than normal controls (0.02). The GC genotype was found to be the risk genotype and the C allele was found to be the risk allele for the development of CP. © 2016 John Wiley & Sons Australia, Ltd.

  20. Interleukin-6 Gene Promoter Polymorphisms and Cardiovascular Risk Factors. A family study

    PubMed Central

    Guzmán-Guzmán, Iris Paola; Muñoz-Valle, José Francisco; Flores-Alfaro, Eugenia; Salgado-Goytia, Lorenzo; Salgado-Bernabé, Aralia Berenice; Parra-Rojas, Isela

    2010-01-01

    Interleukin-6 (IL-6) is a cytokine involved in inflammatory process, as well as in glucose and lipid metabolism. Several studies of the biological relevance of IL-6 gene polymorphisms have indicated a relationship with cardiovascular disease. The aim of this study was to assess whether the –174 G/C and –572 G/C of IL-6 gene polymorphisms are associated with cardiovascular risk factors in Mexican families. Ninety members of 30 Mexican families, in which an index case (proband) had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical and hematological parameters. High sensitivity C- reactive protein levels were measurement for nephelometric analysis. Screening for both polymorphisms studied was performed by PCR-RFLP. In the parents, both polymorphisms were in Hardy-Weinberg's equilibrium. The genotypes –174 GC/CC were associated with T2D (OR = 1.23, IC95% 1.01–1.5) and highest levels of hsCRP (p = 0.02), whereas genotype –572 GG was associated with T2D (OR = 1.24, IC95% 1.04–1.47) with an inflammatory state determined by the increase in the leukocyte count (OR = 1.24, IC95% 1.02–1.51). The genotypes –174 GC/CC and –572 GG may confer susceptibility for the development of subclinical inflammation and type 2 diabetes in Mexican families. PMID:20164544

  1. Interleukin-6 g.-174G>C promoter polymorphism is associated with obesity in the EPIC-Potsdam Study.

    PubMed

    Klipstein-Grobusch, Kerstin; Möhlig, Matthias; Spranger, Joachim; Hoffmann, Kurt; Rodrigues, Fabio U S; Sharma, Arya M; Klaus, Susanne; Pfeiffer, Andreas F H; Boeing, Heiner

    2006-01-01

    Homozygosity for the interleukin-6 (IL-6) g.-174G>C promoter polymorphism has recently been associated with indices of overweight. Homozygous subjects were observed to have reduced energy expenditure, suggesting that lower IL-6 gene transcription, caused by the IL-6 g.-174G>C promoter polymorphism, may be associated with obesity. The aim of this study was to investigate the association of this polymorphism with long-term weight gain. For 334 normal weight (20 < BMI < or = 25 kg/m2) and 334 obese (BMI > 30 kg/m2) subjects matched by age and sex originating from the population-based EPIC-Potsdam Study, recalled weight change from age 25 to study enrollment was determined, the IL-6 g.-174G>C promoter polymorphism was defined, and plasma concentrations of IL-6 and C-reactive protein were measured. The IL-6 g.-174G>C promoter polymorphism was significantly associated with obesity (chi2 = 7,34, p = 0.026). Odds ratios for subjects with GC and CC genotypes for obesity were 1.19 (95% CI: 0.84 to 1.68; p = 0.323) and 1.91 (95% CI: 1.19 to 3.08; p = 0.007), respectively. Recalled weight change from age 25 years to study enrollment differed significantly according to genotype (p = 0.044) and was most pronounced in subjects with the CC genotype, suggesting that the IL-6 g.-174G>C promoter polymorphism is a susceptibility or modifying locus for common obesity and weight gain.

  2. Correlation of interleukin-6-174 GC and interleukin-6-572 GC gene polymorphisms with periodontal disease in an Iranian population

    PubMed Central

    Salman, Bahareh Nazemi; Vahabi, Surena; Biglari, Alireza; Salavitabar, Simindokht; Doabsari, Maryam Hassani

    2016-01-01

    Background: Periodontal disease has a multifactorial etiology. A combination of microbial agents and environmental, habitual, systemic, and genetic risk factors is responsible for the development of periodontal disease. Host immune response causes the destruction of tooth-supporting structure and eventual tooth loss. This study aimed to assess the correlation of interleukin 6 (IL-6) -174-GC and IL-6-572-GC gene polymorphisms with periodontal disease in an Iranian population. Materials and Methods: This case–control analytical study was conducted on 129 subjects presenting to the laboratory of Taleghani Hospital. Subjects underwent clinical and periodontal examinations and divided into five groups of healthy, gingivitis and mild, moderate and severe periodontitis. Blood samples (2 ml) were obtained. Genomic DNA was extracted manually using the salting-out method. IL-6 sequence amplification was performed using polymerase chain reaction with three thermal protocols. Digested products were analyzed by electrophoresis through 2% agarose gel using Gel Red staining. Data were analyzed using Chi-square, Kruskal–Wallis, and Mann–Whitney tests, and P < 0.05 was considered significant. Results: The frequency of GG polymorphism at IL-6-174 and IL-6-572 genomic regions was 51.2% and 71.3%, respectively. The frequency of IL-6-572-GG polymorphism was significantly greater than that of IL-6-572-GC polymorphism (P < 0.001). Comparison of the mean and maximum pocket depth and clinical attachment level, as well as bleeding on probing percentage, revealed significant differences between the healthy controls and periodontitis patients (P < 0.001). The frequency percentages of GC and GG polymorphisms were almost equal in the healthy, gingivitis, and periodontitis groups. In other words, the frequency of the two polymorphisms was not significantly different between the health and disease states (P = 0.065 for IL-6-572 and P = 0.63 for IL-6-174). Conclusion: This study found no

  3. Association Between Interleukin-6 Gene Polymorphisms and Bone Mineral Density: A Meta-Analysis

    PubMed Central

    Wang, Zhao; Yang, Yonghong; He, Minjuan; Wang, Ran; Ma, Juming; Zhang, Yimin; Zhao, Lingyun

    2013-01-01

    Background: Many studies have examined the association between interleukin-6 (IL-6) gene polymorphisms and bone mineral density (BMD). However, the results remain conflicting. To assess the relationship more precisely, a meta-analysis was performed. Methods: The PubMed, Embase, Chinese BioMedical Literature (CBM), Wanfang, and China National Knowledge Infrastructure (CNKI) database were searched for relevant articles published up to March 2013. Weighted mean difference (WMD) and 95% confidence interval (95% CI) were calculated using a fixed-effects or random-effects model. Results: A total of 16 articles with 11,957 subjects were investigated in this meta-analysis. Overall, −634C/G polymorphism was significantly associated with BMD at the femoral neck (WMD, −0.016 g/cm2; 95% CI, −0.028 to −0.003 g/cm2), lumbar spine (WMD, −0.049 g/cm2; 95% CI, −0.069 to −0.030 g/cm2), and whole body (WMD, −0.023 g/cm2; 95% CI, −0.037 to −0.009 g/cm2) for GG versus CC+CG. In subgroup analyses stratified by ethnicity, individuals carrying −634GG genotype had a significantly lower mean BMD at any skeletal site examined, compared with individuals with −634CC or −634CG genotype in Asian populations. For −174G/C polymorphism, the BMD differences between CC+CG and GG genotype were 0.004 g/cm2 at the distal radius (95% CI, 0.004 to 0.005 g/cm2), 0.011 g/cm2 at the trochanter (95% CI, 0.002 to 0.020 g/cm2), and 0.017 g/cm2 at the Ward's triangle (95% CI, 0.003 to 0.032 g/cm2). No significant publication bias was observed in either the −634C/G or −174G/C polymorphism. Conclusions: This suggests that there are modest effects of the −634C/G and −174G/C polymorphisms on BMD. Large-scale and well-designed studies are required to further investigate gene–gene and gene–environment interactions on IL-6 polymorphisms and BMD in various populations. PMID:24053561

  4. Association between the interleukin-6 genetic polymorphism 174 G/C and thrombosis disorder risk

    PubMed Central

    Ren, Honggang; Zhang, Yue; Yao, Yonghua; Guo, Tao; Wang, Huafang; Mei, Heng; Hu, Yu

    2016-01-01

    Abstract Studies investigating the association between interleukin-6 (IL-6) gene-174 G/C polymorphism (rs1800795) and thrombosis disorder risk reported conflicting results. The aim of our study was to assess the association between the IL-6 gene 174 G/C polymorphisms and the risk of thrombosis disorders. Thirty four case–control studies in 29 articles with 29,865 individuals were incorporated in this meta-analysis by searching the public databases including Medline, Embase, and ISI Web of Science databases as of June 1st, 2015. The odds ratio (OR) and 95% confidence interval (95%CI) were used to assess the strength of the association. By pooling all studies, there was marginal association between and the risk of thrombotic disorders (1.09[0.97–1.22]), arterial thrombotic disorders (1.08[0.95–1.23]), and myocardial infarction (MI, 1.14[0.99–1.32]) under dominant genetic effect (C carriers vs GG). In subgroup analyses stratified by ethnicity, study scale, thrombotic category, and country, the results indicated that IL-6 gene-174 G/C polymorphism was significantly associated with increased risk of thrombotic disorders given the conditional such as Asians, large sample-sized, MI, population-based, and Indian studies (C carriers vs GG: 1.39 [1.13–1.72] and C allele vs G allele: 1.36 [1.18–1.56] for Asian; C carriers vs GG: 1.15 [1.01–1.31] and C allele vs G allele: 1.12 [1.01–1.23] for large sample-sized studies; C allele vs G allele: 1.10 [1.03–1.18] for population-based studies; and C carriers vs GG: 1.40 [1.19–1.65] for Indian studies). We did not observe significant association between IL-6-174 G/C and the risk of Caucasians, small sample-sized studies, stroke and venous studies, and other country studies. This meta-analysis suggests that IL-6 gene-174 G/C polymorphism may be marginally associated with risk of thrombotic disorders, arterial disorders, MI especially for Asian, Indian, population-based, and large sample-sized studies

  5. Association between interleukin-6 polymorphisms and urinary system cancer risk: evidence from a meta-analysis

    PubMed Central

    Zhang, Kaiping; Zhang, Li; Zhou, Jun; Hao, Zongyao; Fan, Song; Yang, Cheng; Liang, Chaozhao

    2016-01-01

    Background Interleukin-6 (IL-6) is a multifunctional proinflammatory cytokine involved in cancer initiation and progression. Numerous studies have investigated the associations between IL-6 polymorphisms (IL-6 −174G>C, −592G>C, −597G>A) and risk of urinary system cancers, including prostate cancer, bladder cancer, and renal cell cancer. However, conclusions from these studies were controversial. Thus, we conducted the current meta-analysis to obtain the comprehensive profile regarding the association between IL-6 polymorphisms and urinary system cancer risk. Methods According to inclusion and exclusion criteria, the associations of IL-6 polymorphisms with urinary system cancer were searched from database and analyzed using STATA 12.0 statistical software. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. Results A total of 20 previous publications consisting of 15,033 cases and 17,655 controls were involved in this meta-analysis. Significant association was observed in overall population regarding IL-6 −592G>C polymorphisms (G vs C: OR =0.1.30, 95% CI =1.13−2.52; GG vs CC: OR =1.81, 95% CI =1.31−2.52; GG vs GC + CC: OR =1.33, 95% CI =1.02−1.75; GG + GC vs CC: OR =1.41, 95% CI =1.09−1.83). In the stratified analyses by ethnicity, the significant associations were found among Asian (GG vs CC: OR =1.89, 95% CI =1.34−2.66; GG + GC vs CC: OR =1.43, 95% CI =1.09−1.87) and Black population (GC vs CC: OR =0.20, 95% CI =0.05−0.82) rather than Caucasian men. Likewise, there were noticeable associations in almost all the other subanalyses such as cancer types, control sources, genotyped methods, and sample sizes. However, no significant associations were identified between any of IL-6 −174G>C polymorphisms with urinary system cancer, except for Asian population (G vs C: OR =0.81, 95% CI =0.70−0.95; GG vs CC: OR =0.51, 95% CI =0.35−0.74; GC vs CC: OR =0.49, 95% CI =0.33−0.72; GG + GC vs CC

  6. Association between interleukin-6 polymorphisms and urinary system cancer risk: evidence from a meta-analysis.

    PubMed

    Zhang, Kaiping; Zhang, Li; Zhou, Jun; Hao, Zongyao; Fan, Song; Yang, Cheng; Liang, Chaozhao

    2016-01-01

    Interleukin-6 (IL-6) is a multifunctional proinflammatory cytokine involved in cancer initiation and progression. Numerous studies have investigated the associations between IL-6 polymorphisms (IL-6 -174G>C, -592G>C, -597G>A) and risk of urinary system cancers, including prostate cancer, bladder cancer, and renal cell cancer. However, conclusions from these studies were controversial. Thus, we conducted the current meta-analysis to obtain the comprehensive profile regarding the association between IL-6 polymorphisms and urinary system cancer risk. According to inclusion and exclusion criteria, the associations of IL-6 polymorphisms with urinary system cancer were searched from database and analyzed using STATA 12.0 statistical software. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. A total of 20 previous publications consisting of 15,033 cases and 17,655 controls were involved in this meta-analysis. Significant association was observed in overall population regarding IL-6 -592G>C polymorphisms (G vs C: OR =0.1.30, 95% CI =1.13-2.52; GG vs CC: OR =1.81, 95% CI =1.31-2.52; GG vs GC + CC: OR =1.33, 95% CI =1.02-1.75; GG + GC vs CC: OR =1.41, 95% CI =1.09-1.83). In the stratified analyses by ethnicity, the significant associations were found among Asian (GG vs CC: OR =1.89, 95% CI =1.34-2.66; GG + GC vs CC: OR =1.43, 95% CI =1.09-1.87) and Black population (GC vs CC: OR =0.20, 95% CI =0.05-0.82) rather than Caucasian men. Likewise, there were noticeable associations in almost all the other subanalyses such as cancer types, control sources, genotyped methods, and sample sizes. However, no significant associations were identified between any of IL-6 -174G>C polymorphisms with urinary system cancer, except for Asian population (G vs C: OR =0.81, 95% CI =0.70-0.95; GG vs CC: OR =0.51, 95% CI =0.35-0.74; GC vs CC: OR =0.49, 95% CI =0.33-0.72; GG + GC vs CC: OR =0.50, 95% CI =0.35-0.72; respectively). In addition

  7. Impact of interleukin-6 promoter polymorphism and serum interleukin-6 level on the acute inflammation and neovascularization stages of patients with Eales’ disease

    PubMed Central

    Sen, Aditi; Paine, Suman Kalyan; Chowdhury, Imran Hussain; Mukherjee, Amrita; Choudhuri, Subhadip; Saha, Avijit; Mandal, Lakshmi Kanta

    2011-01-01

    Purpose To evaluate the role of interleukin-6 (IL-6) in the inflammatory and proliferative stages of Eales’ disease (ED) and to determine the influence of IL-6–174G/C polymorphism in the IL-6 and IL-6-regulated protein expression, as well as the development of ED. Methods One hundred and twenty-one patients diagnosed with ED, 223 matched healthy controls, and 16 control patients with macular holes were recruited from the eastern Indian population. Serum and vitreous levels of IL-6 and vascular endothelial growth factors (VEGF) were measured by enzyme-linked immunosorbent assay. Serum levels of high-sensitivity C-reactive protein (hsCRP) were measured by enzyme immunoassay. Subjects were genotyped for the IL-6–174G/C polymorphism (rs1800795) by a custom TaqMan single-nucleotide polymorphism (SNP) Genotyping Assays system. Results Serum IL-6 (p<0.0001), hsCRP (p<0.0001), and VEGF (p=0.0031) levels were significantly higher in the inflammatory stage of ED than in healthy controls. Serum IL-6 also significantly correlated with hsCRP (Spearman’s correlation coefficient; r=0.4992, p=0.0009), but not with VEGF in this stage in ED patients. At the proliferative stage of ED, significantly higher levels of vitreous IL-6 (p=<0.0001) and VEGF (p=<0.0001) were found compared with the vitreous of patients with macular holes. A significant correlation was observed between vitreous IL-6 and VEGF in ED patients (Spearman’s correlation coefficient; r=0.5834, p=0.0087). A statistically significant association was found between the −174GG genotype (p=0.006) and occurrence of ED. Mean serum and vitreous concentrations of IL-6 were also higher in the subjects with the GG genotype than in those with the GC or CC genotype in this population. Conclusions IL-6 expression, regulated by the allelic distribution of −174 loci and the enhanced level of IL-6, modulates CRP and VEGF concentration depending respectively on the acute inflammatory stimulation at the initial stage and

  8. Polymorphisms of the interleukin-6 gene promoter and abdominal aortic aneurysm.

    PubMed

    Smallwood, L; Allcock, R; van Bockxmeer, F; Warrington, N; Palmer, L J; Iacopetta, B; Norman, P E

    2008-01-01

    Elevated levels of circulating interleukin-6 (IL-6) have been reported in patients with abdominal aortic aneurysms (AAAs). Although this implicates inflammation as a cause of AAAs, there is also evidence that the aneurysmal aorta may secrete IL-6 into the circulation as a result of aortic proteolysis. Genetic association studies are one means of trying to clarify the role of specific mediators in the causal pathway. The aim of the present study was to examine the association between variants of the IL-6 gene and AAAs. An association study involving 677 men with screen-detected AAAs and 656 age-matched controls was performed. Three variants in the IL-6 promoter region were analysed: IL-6-174G>C (rs1800795), IL-6-572G>C (rs1800796) and IL-6-597G>A (rs1800797). Univariate regression of SNP genotype on AAA as a binary outcome was initially performed under a range of genetic models (additive, dominant and recessive). This was followed by multivariate analyses, testing the same models but including risk factors known to be associated with AAAs. All analyses and haplotype estimation were performed under a generalized linear model framework. IL-6-572G>C polymorphism (frequency 1.5% in cases) was identified as an independent risk factor for AAA with an odds ratio (OR) of 6.00 (95%CI: 1.22, 29.41) when applied to the recessive model. No association was seen in the additive or dominant models. In a multivariate analysis using the most common haplotype (h.111, frequency 48.7%) as a reference, h.211 (frequency 4.4%) was an independent risk factor for AAA (OR 1.56, 95%CI: 1.02, 2.39). The IL-6 572G>C polymorphism (and h.211 haplotype) is associated with AAA, however it is too rare to be an important cause of most AAAs. This does not support the concept that the elevated level of IL-6 reported in patients with AAAs is a primary cause of the aneurysmal process.

  9. Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys

    PubMed Central

    Murakami, Ikuo; Ishikawa, Yuichi; Suzuki, Tomoki; Sumida, Shun-ichiro; Ibaragi, Shigeru; Kasai, Hayato; Horai, Naoto; Drolet, Daniel W.; Gupta, Shashi; Janjic, Nebojsa

    2016-01-01

    Interleukin-6 (IL-6) is a potent mediator of inflammatory and immune responses, and a validated target for therapeutic intervention of inflammatory diseases. Previous studies have shown that SL1026, a slow off-rate modified aptamer (SOMAmer) antagonist of IL-6, neutralizes IL-6 signaling in vitro. In the present study, we show that SL1026 delays the onset and reduces the severity of rheumatoid symptoms in a collagen-induced arthritis model in cynomolgus monkeys. SL1026 (1 and 10 mg/kg), administered q.i.d., delayed the progression of arthritis and the concomitant increase in serum IL-6 levels compared to the untreated control group. Furthermore, SL1026 inhibited IL-6-induced STAT3 phosphorylation ex vivo in T lymphocytes from human blood and IL-6-induced C-reactive protein and serum amyloid A production in human primary hepatocytes. Importantly, SOMAmer treatment did not elicit an immune response, as evidenced by the absence of anti-SOMAmer antibodies in plasma of treated monkeys. These results demonstrate that SOMAmer antagonists of IL-6 may be attractive agents for the treatment of IL-6-mediated diseases, including rheumatoid arthritis. PMID:26579954

  10. Influence of interleukin-6 and G174C polymorphism in IL-6 gene on obesity and energy balance

    PubMed Central

    2010-01-01

    Obesity is a multifactor disease with a very complicated etiology. Genetic factors play an important role in the development of primary obesity. They may be responsible for up to 40% of causes leading to obesity. There are a great number of genes affecting food intake and energy expenditure. Serious consequences accompanying obesity, e.g., type 2 diabetes and lipid abnormalities may be caused by increased level of proinflammatory cytokines, such as IL-1, IL-6, and TNF. It is possible that polymorphisms located in cytokine genes affect the level of protein expression. It is known that IL-6 plays a role in lipid metabolism and energy expenditure. The polymorphism found in point 174 (G174C) of a promoter region of IL-6 gene affects the level of interleukin-6 expression and, consequently, may lead to obesity and correlated conditions. PMID:21147639

  11. Influence of interleukin-6 and G174C polymorphism in IL-6 gene on obesity and energy balance.

    PubMed

    Popko, Katarzyna; Gorska, E; Demkow, U

    2010-11-04

    Obesity is a multifactor disease with a very complicated etiology. Genetic factors play an important role in the development of primary obesity. They may be responsible for up to 40% of causes leading to obesity. There are a great number of genes affecting food intake and energy expenditure. Serious consequences accompanying obesity, e.g., type 2 diabetes and lipid abnormalities may be caused by increased level of proinflammatory cytokines, such as IL-1, IL-6, and TNF. It is possible that polymorphisms located in cytokine genes affect the level of protein expression. It is known that IL-6 plays a role in lipid metabolism and energy expenditure. The polymorphism found in point 174 (G174C) of a promoter region of IL-6 gene affects the level of interleukin-6 expression and, consequently, may lead to obesity and correlated conditions.

  12. Interleukin-1β and interleukin-6 gene polymorphisms are associated with manifestations of sickle cell anemia.

    PubMed

    Vicari, Perla; Adegoke, Samuel A; Mazzotti, Diego Robles; Cançado, Rodolfo Delfini; Nogutti, Maria Aparecida Eiko; Figueiredo, Maria Stella

    2015-03-01

    Sickle cell anemia (SCA), a disorder characterized by both acute and chronic inflammation, exhibits substantial phenotypic variability. Interleukin-1 beta (IL-1β) and IL-6 are important in acute and chronic diseases, and their single nucleotide polymorphisms (SNPs) have been considered as predictors of prognosis in several inflammatory conditions. This study aims at exploring possible association of IL-1β and IL-6 SNPs as potential genetic modifiers and or predictors of SCA clinical and laboratory phenotypes. This cross-sectional study involved 107 SCA patients and 110 age, sex and ethnicity-matched healthy individuals. The SNPs were identified by PCR-RFLP for IL-1β (-511C>T and +3954C>T) and IL-6 (-597G>A and -174G>C) genes. Associations between these SNPs and the clinical and laboratory profiles of patients with SCA were then determined. Allelic and genotypic frequencies of IL-1β and IL-6 SNPs between patients with SCA and controls were similar and followed HWE. IL-1β +3954C>T SNP was associated with increased risk of osteonecrosis, elevated pulmonary arterial pressure and lower absolute reticulocyte count, while IL-6 -597G>A was associated with higher likelihood of retinopathy and leg ulcer. These data indicate that IL-1β and IL-6 gene SNPs are associated with SCA complications among Brazilian patients and may act as genetic predictors of SCA clinical heterogeneity.

  13. Genetic polymorphism of interleukin-6 influences susceptibility to HBV-related hepatocellular carcinoma in a male Chinese Han population.

    PubMed

    Tang, Shengli; Yuan, Yufeng; He, Yueming; Pan, Dingyu; Zhang, Yongxi; Liu, Yuanyuan; Liu, Quanyan; Zhang, Zhonglin; Liu, Zhisu

    2014-04-01

    As a multifunctional cytokine, interleukin-6 (IL-6) plays a key role in chronic inflammation as well as tumor growth and progression of hepatitis B virus (HBV) infection. Recent studies have implicated that single nucleotide polymorphism (SNP) -572C>G (rs1800796) located within the promoter region of IL-6 gene was associated with susceptibility to several diseases. Here, a case-control study was undertaken to investigate the association between this polymorphism and HBV-related hepatocellular carcinoma (HCC) susceptibility in a Chinese Han population. A total of 900 patients with chronic HBV infection, including 505 HBV-related HCC patients and 395 HBV infected patients without HCC were enrolled, and rs1800796 polymorphism was genotyped by the TaqMan method and DNA sequencing technology. The results indicated no significant association between rs1800796 polymorphism and the risk of HBV-related HCC in all subjects; however, a significant difference was identified in male subjects. Under the dominant model, male subjects with the G allele (CG/GG) have higher susceptibility to HBV-related HCC than those with CC genotype after adjusting confounding factors (P=0.012, odds ratio [OR] 1.68, 95% confidence interval [95% CI] 1.15-2.42). Our results suggested that rs1800796 polymorphism of IL-6 gene was associated with susceptibility to HBV-related HCC in a male Chinese Han population.

  14. -174G/C polymorphism in the interleukin-6 promoter is differently associated with prostate cancer incidence depending on race

    PubMed Central

    Mandal, S.; Abebe, F.; Chaudhary, J.

    2014-01-01

    Interleukin-6 (IL-6), a pro-inflammatory cytokine, is involved in prostate cancer progression, including androgen independence. Serum IL-6 levels also correlate with prostate tumor burden, prostate-specific antigen levels and metastasis. Since circulating cytokine levels vary considerably inter-individually, such variation could be linked to genetic factors, including genetic polymorphism. The -174G>C/rs1800795 polymorphism in the IL-6 promoter is functionally relevant in terms of transcriptional regulation and disease association. We investigated a possible association of the -174G/C polymorphism with prostate cancer. Since significant racial disparities exist in prostate cancer incidence, we also investigated this association between the -174G/C polymorphism and prostate cancer in Caucasians and African-Americans, separately. Direct sequencing of the PCR amplicon from genomic DNA was used for genotyping rs1800795 in all subjects [age-matched controls (N = 140) and prostate cancer patients (N = 164)]. Sample size and power was calculated using the PGA software. We found the GG genotype to be associated with increased risk of prostate cancer in Caucasian subjects, whereas the CC genotype was associated with increased risk in the African-American sample set. Such a dimorphic genotypic association with cancer and race is unique and suggests a complex gene-gene and gene-environment interaction. PMID:24446297

  15. Genetic association of interleukin-6 polymorphism (-174 G/C) with chronic liver diseases and hepatocellular carcinoma

    PubMed Central

    Giannitrapani, Lydia; Soresi, Maurizio; Balasus, Daniele; Licata, Anna; Montalto, Giuseppe

    2013-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine which is expressed in many inflammatory cells in response to different types of stimuli, regulating a number of biological processes. The IL-6 gene is polymorphic in both the 5’ and 3’ flanking regions and more than 150 single nucleotide polymorphisms have been identified so far. Genetic polymorphisms of IL-6 may affect the outcomes of several diseases, where the presence of high levels of circulating IL-6 have been correlated to the stage and/or the progression of the disease itself. The -174 G/C polymorphism is a frequent polymorphism, that is located in the upstream regulatory region of the IL-6 gene and affects IL-6 production. However, the data in the literature on the genetic association between the -174 G/C polymorphism and some specific liver diseases characterized by different etiologies are still controversial. In particular, most of the studies are quite unanimous in describing a correlation between the presence of the high-producer genotype and a worse evolution of the chronic liver disease. This is valid for patients with hepatitis C virus (HCV)-related chronic hepatitis and liver cirrhosis and hepatocellular carcinoma (HCC) whatever the etiology. Studies in hepatitis B virus-related chronic liver diseases are not conclusive, while specific populations like non alcoholic fatty liver disease/non-alcoholic steatohepatitis, autoimmune and human immunodeficiency virus/HCV co-infected patients show a higher prevalence of the low-producer genotype, probably due to the complexity of these clinical pictures. In this direction, a systematic revision of these data should shed more light on the role of this polymorphism in chronic liver diseases and HCC. PMID:23674845

  16. Interleukin-6 c.-174G>C Polymorphism and Periodontitis in a Brazilian Population.

    PubMed

    Gabriela Teixeira, Fernanda; Mendonça, Samir Andrade; Menezes Oliveira, Kamilla; Barbosa Dos Santos, Djanilson; Miranda Marques, Lucas; Mendonça Amorim, Maise; de Souza Gestinari, Raquel

    2014-01-01

    Aim. Periodontitis is an inflammatory disease that affects the teeth supporting structures, triggered by periodontal pathogens, and is influenced by environmental and genetic factors. Genes encoding molecules related to the immune response, such as cytokine, are the main candidates for polymorphisms analysis and may be possibly associated with this pathology. A G/C promoter polymorphism on the IL6 gene has been shown to affect basal IL-6 levels. The aim of this study was to investigate the association between the IL6 c.-174G>C polymorphism and periodontitis in individuals from Vitória da Conquista, Bahia, Brazil. Material and Methods. Three hundred and thirty individuals (134 cases, 196 controls) were genotyped for the IL6 c.-174G>C by MS-PCR technique. Concentrations of salivary IL-6 were determined by ELISA method. Results. The IL6 c.-174G>C polymorphism was associated with periodontitis when comparing the distribution of genotypes between patients with periodontitis and control subjects. The GC genotype appeared as a protective factor for periodontitis. Results showed increased levels of salivary IL-6 in periodontitis patients. Nevertheless, there was no relationship between the concentrations of IL-6 and genotypes when comparing the case and control groups. Conclusions. Our data indicate an association between IL6 c.-174G>C polymorphism and periodontitis and showed that IL-6 may be considered an important marker for periodontitis.

  17. Interleukin-6 c.-174G>C Polymorphism and Periodontitis in a Brazilian Population

    PubMed Central

    Gabriela Teixeira, Fernanda; Mendonça, Samir Andrade; Menezes Oliveira, Kamilla; Barbosa dos Santos, Djanilson; Miranda Marques, Lucas; Mendonça Amorim, Maise; de Souza Gestinari, Raquel

    2014-01-01

    Aim. Periodontitis is an inflammatory disease that affects the teeth supporting structures, triggered by periodontal pathogens, and is influenced by environmental and genetic factors. Genes encoding molecules related to the immune response, such as cytokine, are the main candidates for polymorphisms analysis and may be possibly associated with this pathology. A G/C promoter polymorphism on the IL6 gene has been shown to affect basal IL-6 levels. The aim of this study was to investigate the association between the IL6 c.-174G>C polymorphism and periodontitis in individuals from Vitória da Conquista, Bahia, Brazil. Material and Methods. Three hundred and thirty individuals (134 cases, 196 controls) were genotyped for the IL6 c.-174G>C by MS-PCR technique. Concentrations of salivary IL-6 were determined by ELISA method. Results. The IL6 c.-174G>C polymorphism was associated with periodontitis when comparing the distribution of genotypes between patients with periodontitis and control subjects. The GC genotype appeared as a protective factor for periodontitis. Results showed increased levels of salivary IL-6 in periodontitis patients. Nevertheless, there was no relationship between the concentrations of IL-6 and genotypes when comparing the case and control groups. Conclusions. Our data indicate an association between IL6 c.-174G>C polymorphism and periodontitis and showed that IL-6 may be considered an important marker for periodontitis. PMID:25548674

  18. Coronary heart disease and chronic periodontitis: is polymorphism of interleukin-6 gene the common risk factor in a Chinese population?

    PubMed

    Fan, W H; Liu, D L; Xiao, L M; Xie, C J; Sun, S Y; Zhang, J C

    2011-04-01

    Coronary heart disease (CHD) and chronic periodontitis (CP) both are multifactorial chronic diseases and related to inflammation. Interleukin-6 (IL-6) plays an important role in the pathogenesis of inflammatory diseases. The purpose of the study was to investigate the association among IL-6 gene polymorphisms, CP and CHD susceptibility in a Chinese population.   The investigation was conducted as a case-control study involving 505 individuals: 113 patients with CHD and CP, 84 patients with CHD, 178 patients with CP and 130 control individuals. The polymorphisms of IL-6 gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Relationships between the distributions of the genotypes and risk factors were also assessed.   Mutations at the loci -174 G/C, -597 G/A of IL-6 were rare in a Chinese population. No significant difference for IL-6-572C/G polymorphism was detected among moderate CP group, severe CP group and control (P = 0.312 and 0.481), significant differences were found between CHD groups and non-CHD groups (P ≤ 0.001). After adjustment for CHD risk factors, the G allele resulted in an increased risk (OR = 1.676-1.856), the GG/CG genotype was nearly two times higher risk compared to CC genotype (OR = 2.010-2.136).   IL-6-572C/G polymorphism did not correlate with CP susceptibility, but might be a potential risk factor for CHD in a Chinese population. © 2010 John Wiley & Sons A/S.

  19. Clinical response to non-surgical periodontal treatment in patients with interleukin-6 and interleukin-10 polymorphisms

    PubMed Central

    Doufexi, Aikaterini-Ellisavet; Kouvatsi, Anastasia

    2017-01-01

    Background Genetic polymorphisms are commonly associated with altered transcriptional activity and possibly make individuals more susceptible to periodontal disease development, increased disease severity and poor treatment outcome. The study aimed to determine the effect of Interleukin-6 (IL-6) -572 G/C (rs1800796) and IL-10 -592 C/A (rs1800872) polymorphisms on the outcomes of non-surgical periodontal therapy in a Caucasian population. Material and Methods Sixty-eight patients with chronic periodontal disease were grouped according to their genotype: IL-6, IL-10, IL-6 and IL-10 susceptible (SCP) and non-susceptible (NSCP). All individuals were clinically evaluated at the first visit, and blood sample were collected from patients after checking the inclusion and exclusion criteria of the study. All patients received non-surgical periodontal therapy from a single-blinded periodontist. Clinical periodontal measurements were repeated 45 days after therapy. Results This population mean aged 47.63 years included 52.2% females and 58.2% non-smokers. Following DNA separation and genotyping, 65.7% of patients were homozygous carriers of the IL-6 - 572G; 49.3% were carriers of the IL-10 -592A- allele (AA and CA genotypes); and 35.8% carried SCP genotypes for both polymorphisms. The clinical parameters after therapy were not associated with the genotype status. The multiple logistic regression analysis did not show any statistically significant association between the genotypes and the variables tested. Conclusions Within the limitations of this longitudinal study, it can be suggested that IL-6 -572 G/C and IL-10 -592 C/A polymorphisms as well as their combination do not influence the outcome of nonsurgical periodontal therapy in Caucasian patients diagnosed with chronic periodontal disease. Key words:Gene polymorphism, genetics, interleukins, periodontal disease, treatment outcome. PMID:28624837

  20. Polymorphisms in interleukin-6 and interleukin-10 may be associated with risk of preeclampsia.

    PubMed

    Fan, D M; Wang, Y; Liu, X L; Zhang, A; Xu, Q

    2017-02-23

    Preeclampsia is a common condition unique to pregnant women. Previous studies have suggested that several cytokines may contribute to defective placental invasion and endothelial damage in this condition. We investigated the influence of four single nucleotide polymorphisms (SNPs) in the promoters of IL-6 (-572G/C, -597G/A, and -174G/C) and IL-10 (-592A/C) on susceptibility to preeclampsia in a Chinese population. This study included 142 newly diagnosed preeclampsia patients and 260 controls recruited from Qingdao Women and Children's Hospital between January 2013 and May 2015. Genotyping of IL-6 and IL-10 SNPs was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Logistic regression analysis was then performed to determine the association between these variants and preeclampsia risk. Our findings indicated that compared to the AA genotype, the CC and AC+CC genotypes of IL-10 -592A/C correlate with elevated risk of developing preeclampsia, with adjusted odds ratios (and 95% confidence intervals) of 2.45 (1.26-4.72) and 1.71 (1.09-2.68), respectively. However, the IL-6 -572G/C, -597G/A, and -174G/C polymorphisms were not found to play a critical role in susceptibility to this disorder. In conclusion, the IL-10 -592A/C genetic variant was observed to be associated with preeclampsia risk in pregnant women.

  1. Association Between Interleukin-6 -572 C>G and -174 G>C Polymorphisms and Hypertension

    PubMed Central

    Ma, He; Sun, Guixiang; Wang, Wei; Zhou, Yunti; Liu, Dang; Tong, Yue; Lu, Zhaojun

    2016-01-01

    Abstract Whether hypertension is associated with −572 C>G or −174 G>C polymorphism in interleukin (IL)-6 genes still remains hazy and ambiguous. We conducted a meta-analysis to offer a more reliable and clearer evaluation about the association. Electronic literature databases including PubMed, Web of Science, EMBASE, Google Scholar, Chinese National Knowledge Infrastructure and Wanfang database were searched. The study included the following: evaluating associations between −572 C>G or −174 G>C polymorphism in IL-6 gene and hypertension; case-control design; essential information must be offered; precise diagnostic criteria of hypertension; and no language restriction. Patients who met the diagnostic criteria and controls without a history of hypertension were included. Interventions were not available. A quality assessment was conducted using Newcastle-Ottawa scale. Combined odds ratios with 95% confidence intervals were calculated in 5 genetic models. Sources of heterogeneity were explored by subgroup analysis, meta-regression, and Galbraith plots. Finally, test for publication bias was performed to prove the stabilization. Fifteen studies were finally included. Eleven articles were judged high-quality reports. Overall, the −572 C>G polymorphism was proved to be significantly associated with hypertension in 4 genetic models. Subgroup analysis based on ethnicity revealed significant associations in Asian population in recessive model and homozygote comparison. The association in Europeans and Mid-East required further confirmation. No significant association was observed between the −174 G>C polymorphism and hypertension under all of the genetic models. The limitations of the study were the following: restrictive number of eligible studies limited the extrapolation range in subgroup analysis; gene–environment factors could not be described due to lack of data; some relevant studies could not be included because of various reasons. Current researches

  2. Lack of association between a functional polymorphism (rs1800796) in the interleukin-6 gene promoter and lung cancer

    PubMed Central

    2014-01-01

    Background A number of studies have examined the association between interleukin-6 (IL-6) rs1800796 polymorphism and risk of lung cancer but revealed inconsistent results. The aim of this study was to clarify the association between IL-6 rs1800796 polymorphism and risk of lung cancer. Methods Literature databases including PubMed, Embase and CNKI were searched up to January 2014. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) under co-dominant model, dominant model and recessive model were estimated using random-effects model. Results A total of seven studies, including 2691 lung cancer cases and 3067 controls, were included in the meta-analysis. The results suggested that IL-6 rs1800796 polymorphism was not associated with risk of lung cancer under homogeneous co-dominant model (OR = 1.06, 95%CI = 0.73-1.54), heterogeneous co-dominant model (OR = 1.24, 95%CI = 0.96-1.60), dominant model (OR = 1.23, 95%CI = 0.95-1.58) and recessive model (OR = 0.96, 95%CI = 0.70-1.32). The association was still not significant in either never-smokers (OR = 1.19, 95%CI = 0.95-1.48) or ever-smokers (OR = 1.73, 95%CI = 0.89-3.36). Conclusion The present meta-analysis suggested that there was no association between IL-6 rs1800796 polymorphism and lung cancer, which was independent of smoking status. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1060061508127855 PMID:24984610

  3. The Interleukin-6 Gene Promoter Polymorphism -174 and Atherosclerotic Events in Overweight Transplanted Patients

    PubMed Central

    Bamoulid, Jamal; Courivaud, Cécile; Deschamps, Marina; Gaugler, Béatrice; Tiberghien, Pierre; Chalopin, Jean-Marc; Saas, Philippe; Ducloux, Didier

    2011-01-01

    Chronic inflammation plays a pivotal role in atherosclerosis. We hypothesized that combining overweight and a greater genetic capacity to produce IL-6 predicted by IL-6 gene promoter polymorphism at position -174 (G→C) may allow to identify individuals exhibiting higher IL-6 and C-reactive protein (CRP) concentrations with a higher risk of atherosclerotic events (AE). The occurrence of AE was analyzed with respect to body mass index, IL-6 gene promoter polymorphism at position -174 (G→C), and other relevant risk factors, retrospectively, in 217 renal transplant recipients and, prospectively, in 132. Circulating IL-6 concentrations were closely related to BMI (r = 0.55, P = .0005). In overweight patients, serum IL-6 concentration was found to be significantly lower in C carriers than in GG patients (4.2 [1.0–5.1] versus 7.3 pg/mL [4.4–100]; P = .025). The incidence of AE was higher in overweight GG patients (29.5% versus 10.1%; P = .0003). In multivariate analysis, overweight-GG had an increased risk to develop AE (HR 2.96 [95% CI 1.09–8.04], P = .034 in the retrospective cohort, and HR 2.99 [95% CI 0.92–9.33], P = .069 in the prospective cohort). All these data are consistent with a role for both genetic and environmental determinants of inflammation (white adipose tissue mass) in the development of AE in renal transplanted patients. PMID:21766010

  4. Common Polymorphism in Interleukin 6 Influences Survival of Women with Ovarian and Peritoneal Carcinoma.

    PubMed Central

    Garg, Ruchi; Wollan, Melissa; Galic, Vijaya; Garcia, Rochelle; Goff, Barbara A.; Gray, Heidi J.; Swisher, Elizabeth

    2007-01-01

    Objectives The IL6 -174 promoter polymorphism impacts serum cytokine levels through transcriptional regulation. The objective of our study was to determine if -174 IL6 genotype influences survival in ovarian cancer. Methods The IL6 -174 polymorphism was assessed by direct DNA sequencing in lymphocyte DNA from 160 women with invasive ovarian, or peritoneal cancer patients. IL6 levels were measured in ascites and plasma in a subset of cases using colorimetric sandwich ELISA procedure. Overall survival was calculated according to the method of Kaplan and Meier. Cox regression analysis was used to evaluate the significance of individual variables in multivariate analysis. Chi-square or Fishers Exact was used to assess the significance of contingency tables. Results The IL6 -174 genotype frequencies of CC (19%), CG (50%), and GG (31%) were in Hardy-Weinberg equilibrium and were similar to published frequencies in Caucasian controls. There were no associations with IL6 -174 genotype and age, stage or optimal cytoreduction. Stage had a significant impact on survival (p=0.003). The IL6 -174 GG genotype was significantly associated with longer overall survival (median 131 months) compared to CC or CG (median 28 months, p=0.0007). In cox regression analysis using the covariates genotype (p=0.006) and stage (p=0.02), both were independently significant. Furthermore, there was no association found between IL6 levels in ascites or plasma, and genotype, stage, or overall survival. Conclusions The IL6 -174 GG genotype has a strong, independent, and favorable impact on survival for women with ovarian, and peritoneal carcinoma. PMID:17023036

  5. Common polymorphism in interleukin 6 influences survival of women with ovarian and peritoneal carcinoma.

    PubMed

    Garg, Ruchi; Wollan, Melissa; Galic, Vijaya; Garcia, Rochelle; Goff, Barbara A; Gray, Heidi J; Swisher, Elizabeth

    2006-12-01

    The IL6 -174 promoter polymorphism impacts serum cytokine levels through transcriptional regulation. The objective of our study was to determine if -174 IL6 genotype influences survival in ovarian cancer. The IL6 -174 polymorphism was assessed by direct DNA sequencing in lymphocyte DNA from 160 women with invasive ovarian, or peritoneal cancers. IL6 levels were measured in ascites and plasma in a subset of cases using colorimetric sandwich ELISA procedure. Overall survival was calculated according to the method of Kaplan and Meier. Cox regression analysis was used to evaluate the significance of individual variables in multivariate analysis. Chi-square or Fishers Exact was used to assess the significance of contingency tables. The IL6 -174 genotype frequencies of CC (19%), CG (50%), and GG (31%) were in Hardy-Weinberg equilibrium and were similar to published frequencies in Caucasian controls. There were no associations with IL6 -174 genotype and age, stage or optimal cytoreduction. Stage had a significant impact on survival (p=0.003). The IL6 -174 GG genotype was significantly associated with longer overall survival (median 131 months) compared to CC or CG (median 28 months, p=0.0007). In cox regression analysis using the covariates genotype (p=0.006) and stage (p=0.02), both were independently significant. Furthermore, there was no association found between IL6 levels in ascites or plasma, and genotype, stage, or overall survival. The IL6 -174 GG genotype has a strong, independent, and favorable impact on survival for women with ovarian, and peritoneal carcinoma.

  6. Interleukin-6 Promoter Polymorphisms and Susceptibility to Atrial Fibrillation in Elderly Han Chinese Patients with Essential Hypertension

    PubMed Central

    Li, Jing; Song, Jie; Jiang, Min-Hui; Zheng, Jin-Guo; Gao, Shu-Ping; Zhu, Jian-Hua

    2012-01-01

    There is an accumulating body of evidence indicating a strong association between inflammation and the pathogenesis of atrial fibrillation (AF). Interleukin-6 (IL-6) is a pleiotropic cytokine, functions as a mediator of inflammatory response, and has both proinflammatory and anti-inflammatory properties. The aim of the present study was to investigate the association of the −634C/G polymorphism of the IL-6 gene with AF in elderly Han Chinese patients with essential hypertension (EH). A total of 169 elderly patients with EH were eligible for this study. Patients with AF (n=75) were allocated to the AF group, and 94 subjects without AF to the control group. The polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotype frequencies. The distribution of the IL-6 −634C/G genotypes (CC, CG, and GG) was 67.02%, 30.85%, and 2.13% in the controls, and 50.67%, 40.00%, and 9.33% in AF subjects, respectively (P=0.0312). The frequency of the G allele in the AF group was significantly higher than that in the control group (29.33% vs. 17.55%, P=0.0103). Compared with the CC and CG genotypes, the GG homozygote had a 4.7353-fold increased risk of AF [95% confidence interval (CI)=0.9537–23.5116, P=0.0382]. These findings suggest that the IL-6 −634C/G polymorphism is associated with AF, and the G allele has increased risk of AF in elderly Han Chinese patients with EH. PMID:22924939

  7. A meta-analysis on correlation between interleukin-6 -174G/C polymorphism and end-stage renal disease.

    PubMed

    Feng, Ye; Tang, Yan; Zhou, Hongwei; Xie, Kaiqing

    2017-11-01

    The level of interleukin-6 (IL-6) and its gene polymorphism are associated with the end-stage renal disease (ESRD) and the related complications. This study aimed to investigate the correction between IL-6 -174G/C polymorphism and ESRD by meta-analysis. Using the databases including PubMed, Embase, Cochrane library, CNKI, and CBM, the data of case-control studies on correlation between IL-6 -174G/C polymorphism and ESRD from database establishment to January 2016 were collected. According to inclusion and exclusion criteria, the quality of literatures was evaluated. The relevant research data were extracted, followed by meta-analysis using Revman 5.3 software (London, UK). The combined odds ratio (OR) and 95% confidence interval (95%CI) of each genetic model were calculated, and the publication bias data was assessed using the Stata 12.0 software (College Station, TX). A total of five literatures were included, with 1199 cases in case group and 1089 cases in control group. Meta-analysis showed that, there was no significant correlation between each genetic model of IL-6 -174G/C polymorphism and ESRD [(C versus G): OR = 1.36, 95%CI (0.69, 2.66), p = .38; (CC + GC versus GG): OR = 1.28, 95%CI (0.58, 2.82), p = .54; (CC versus GG + GC): OR = 1.71, 95%CI (0.82, 3.54), p = .15; (CC versus GG): OR = 1.74, 95%CI (0.76, 3.99), p = .19; (GC versus GG): OR = 1.18, 95%CI (0.55, 2.54), p = .67]. The race subgroup analysis showed that, there was no significant correlation between each genetic model of IL-6 -174G/C polymorphism and ESRD in the Caucasians (p > .05). IL-6 -174G/C polymorphism has no significant correlation with the susceptibility risk of ESRD, and may not be a risk factor for ESRD.

  8. Association of interleukin-6 (-174 G/C) polymorphism with the prostate cancer risk: A meta-analysis.

    PubMed

    Yang, Mingyuan; Li, Chao; Li, Ming

    2014-09-01

    The aim of the present study was to determine whether the interleukin-6 (IL-6) (-174 G/C) gene polymorphism correlates with prostate cancer. A meta-analysis based on former studies was conducted and the results suggest that there was no significant association between IL-6 (-174 G/C) polymorphism and the prostate cancer risk. However, a recent study published in January 2014 showed that the GG genotype may be associated with an increased risk of prostate cancer in Caucasian subjects, whereas the CC genotype was associated with an increased risk in the African-American subjects, which was inconsistent with former studies. Databases, including PubMed, Embase, Web of Science, the Cochrane Library, Chinese Biomedical Literature Database and Wanfang database, were searched between January 1994 and March 2014 to determine the eligible IL-6 (-174 G/C) polymorphism studies and the susceptibility of the prostate cancer risk. A total of 11 studies with 10,745 cases and 13,473 controls fulfilled the inclusion criteria subsequent to assessment by two investigators. The pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to examine the associations, and subgroup analyses were performed according to the ethnicity. Overall, no significant association was found between the IL-6 (-174 G/C) polymorphism and prostate cancer risk, whereas the subgroup analysis suggested that the association between the IL-6 (-174 G/C) polymorphism and prostate cancer was slightly significant under the homozygote (CC vs. GG: OR, 3.43; 95% CI, 1.01-11.71; P=0.049) and recessive models (CC vs. OR, 3.51; 95% CI, 1.04-11.82; P=0.042) in African-American patients. However, no significant association was found in the Caucasian, Asian or mixed populations under the five genetic models by stratifying studies for ethnicity. In conclusion, the present study suggested that there was no significant association between the IL-6 (-174 G/C) polymorphism and prostate cancer risk in Caucasian

  9. Strong association of interleukin-6 -174G/C promoter single nucleotide polymorphism with a decreased risk of colorectal cancer in ethnic Kashmiri population: A case control study.

    PubMed

    Banday, Mujeeb Zafar; Balkhi, Henah Mehraj; Sameer, Aga Syed; Chowdri, Nissar A; Haq, Ehtishamul

    2017-03-01

    Chronic inflammation increases the risk of development of various cancers, including colorectal cancer. Interleukin-6 has been described as a key regulator of colorectal cancer development and is important in the process of colorectal tumorigenesis largely through the regulation of tumor-promoting inflammation. Several studies have reported the association of various polymorphisms in human interleukin-6 gene including IL-6 -174G/C single nucleotide polymorphism with various cancers, including colorectal cancer, but the results are mixed and inconclusive. The aim of this study was to analyze the association of IL-6 -174G/C promoter single nucleotide polymorphism with colorectal cancer risk and also to evaluate the modifying effects of possible IL-6 -174G/C single nucleotide polymorphism genotypes on different risk factors of colorectal cancer or the reciprocal effect in ethnic Kashmiri population through a case control setup. The genotype frequencies of IL-6 -174G/C promoter single nucleotide polymorphism were compared between 142 colorectal cancer patients and 184 individually matched healthy controls by using polymerase chain reaction-restriction fragment length polymorphism method. The association between the IL-6 -174G/C single nucleotide polymorphism and colorectal cancer risk was examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. The possible effect measure modification of the association between the relevant single nucleotide polymorphism genotypes and colorectal cancer risk by various colorectal cancer risk factors including age, gender, and smoking status was also evaluated. Furthermore, the associations between these single nucleotide polymorphisms and various clinicopathological parameters, demographic variables, and environmental factors within the case group subjects with regard to colorectal cancer risk were also analyzed. The overall association between the IL-6 -174G/C single

  10. Prognostic significance of interleukin-6 single nucleotide polymorphism genotypes in neuroblastoma: rs1800795 (promoter) and rs8192284 (receptor)

    PubMed Central

    Lagmay, Joanne P.; London, Wendy B.; Gross, Thomas G.; Termuhlen, Amanda; Sullivan, Nicholas; Axel, Amy; Mundy, Bethany; Ranalli, Mark; Canner, Jason; McGrady, Patrick; Hall, Brett

    2009-01-01

    Purpose Neuroblastoma is a childhood cancer of the sympathetic nervous system and many patients present with high risk disease. Risk stratification, based on pathology and tumor-derived biomarkers, has improved prediction of clinical outcomes, but overall survival rates remain unfavorable and new therapeutic targets are needed. Some studies suggest a link between interleukin-6 and more aggressive behavior in neuroblastoma tumor cells. Therefore, we examined the impact of two IL-6 single nucleotide polymorphisms (SNP) on neuroblastoma disease progression. Experimental design DNA samples from 96 high risk neuroblastoma patients were screened for two SNP that are known to regulate the serum levels of IL-6 and the soluble IL-6 receptor (IL-6R), rs1800795 and rs8192284 respectively. The genotype for each SNP was determined in a blinded fashion and independent statistical analysis was performed to determine SNP-related event free survival (EFS) and overall survival (OS) rates. Results The rs1800795 IL-6 promoter SNP is an independent prognostic factor for EFS and OS in -high risk neuroblastoma patients. In contrast, the rs8192284 IL-6 receptor SNP revealed no prognostic value. Conclusions The rs1800795 SNP (-174 IL-6 (G>C) represents a novel and independent prognostic marker for both EFS and OS in high risk neuroblastoma. Since the rs1800795 SNP (-174 IL-6 (G>C) has been shown to correlate with production of IL-6, this cytokine may represent a target for development of new therapies in neuroblastoma. PMID:19671870

  11. Association between the Interleukin-6 Promoter Polymorphism −174G/C and Serum Lipoprotein(a) Concentrations in Humans

    PubMed Central

    Berthold, Heiner K.; Laudes, Matthias; Krone, Wilhelm; Gouni-Berthold, Ioanna

    2011-01-01

    Background Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism −174G/C is associated with baseline serum Lp(a) concentrations. Methodology/Principal Findings We divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations ≥60 mg/dl (n = 510), and the ones with Lp(a) <60 mg/dl (n = 1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (OR = 1.3, 95% CI 1.04 to 1.63, P = 0.02 and OR = 1.44, 95% CI 1.06 to 1.93, P = 0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations. Conclusions/Significance The IL-6 single nucleotide polymorphism −174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to be established. PMID:21935443

  12. Interleukin-6, interleukin-1 gene cluster and interleukin-1 receptor polymorphisms in Iranian patients with juvenile systemic lupus erythematosus.

    PubMed

    Ziaee, Vahid; Tahghighi, Fatemeh; Moradinejad, Mohammad Hassan; Harsini, Sara; Mahmoudi, Maryam; Rezaei, Arezou; Soltani, Samaneh; Sadr, Maryam; Aghighi, Yahya; Rezaei, Nima

    2014-06-01

    Juvenile systemic lupus erythematosus (JSLE) is a polygenic, autoimmune disorder of unknown origin. As proinflammatory cytokines, including interleukin-6 (IL-6) and the interleukin-1 (IL-1) family, seem to contribute to the pathogenesis of JSLE, this investigation was performed to assess the associations of particular single nucleotide polymorphisms (SNPs) of IL-6 and IL-1 genes in a case-control study. Fifty nine JSLE cases were recruited for this study as the patient group, and were compared against 140 healthy, unrelated, control subjects. Using the polymerase chain reaction with the sequence-specific primer method, genotyping was carried out for the IL-6 gene at positions -174 and nt565, as well as the IL-1α gene at position -889, the IL-1β gene at positions -511 and +3962, the interleukin-1 receptor (IL-1R) gene at position Pst-I 1970, and the interleukin-1 receptor antagonist (IL-1Ra) gene at position Mspa-I 11100. RESULTS of the analyzed data revealed a remarkable, positive association for the promoter sequence of the IL-1β gene at position -511 for T/T in the patient group compared with healthy controls (P value, 0.03). Furthermore, a significant negative association was found between the T/C genotype at the same position on the IL-1β gene in juvenile SLE (P value, 0.03). cytokine gene polymorphisms might play a role in the pathophysiology of JSLE. Particular IL-1 gene variants could affect individual susceptibility to JSLE.

  13. Association of interleukin-6 gene polymorphism (rs1800796) with severity and functional status of osteoarthritis in elderly individuals.

    PubMed

    Fernandes, Marcos T P; Fernandes, Karen B P; Marquez, Audrey S; Cólus, Ilce M S; Souza, Marilesia F; Santos, João Paulo M; Poli-Frederico, Regina C

    2015-10-01

    Osteoarthritis (OA) is the most prevalent disease of the musculoskeletal system and it has an important genetic component. Despite several reports have shown the involvement of pro-inflammatory cytokine such as interleukin-1β and TNF-α, the role of interleukin-6 (IL-6) in osteoarthritis is still unclear. Thus, this study aimed to analyze the relationship between the single nucleotide polymorphism in the portion -572 of the promoter region of the IL6 gene (SNP -572G/C) with hip and knee OA in the elderly. In this case-control study, 257 physically independent elderly were recruited (case group: 92 individuals with osteoarthritis and control group: 165 individuals with no osteoarthritis). Blood samples were collected from patients for the DNA fragments extraction and amplification by real-time polymerase chain reaction (PCR) by TaqMan system for subsequent genotyping of IL6 gene. The degree of joint damage was assessed by radiographic classification based on the criteria of Kellgren and Lawrence. The functional status was evaluated by Lequesne and WOMAC questionnaires. It was observed that individuals carrying the C allele have lower susceptibility to osteoarthritis (OR=0.51, 95% CI: 0.32-0.80, p=0.004) and less radiological impairment for both hip (Fisher-Freeman-Halton test=4.2 and p=0.04) and knee joints (Fisher-Freeman-Halton test=4.7 and p=0.03). Regarding functional status, individuals carrying the C allele has a lower degree of functional impairment assessed by WOMAC (Mann-Whitney test, p=0.04), although no difference was observed in the Lequesne questionnaire (p>0.05). Additionally, it was observed a marked reduction in IL-6 serum levels in individuals with GC and CC genotypes when compared to individuals harboring GG genotype. In conclusion, the polymorphism -572G/C IL6 is a protective factor for the presence and severity of hip and knee osteoarthritis in the elderly. Further prospective studies with large sample size and methods (e.g. effect of this

  14. Role of Helicobacter pylori and interleukin 6 -174 gene polymorphism in dyslipidemia: a case–control study

    PubMed Central

    Pohjanen, Vesa-Matti; Koivurova, Olli-Pekka; Niemelä, Seppo E; Karttunen, Riitta A; Karttunen, Tuomo J

    2016-01-01

    Objective To assess the role of Helicobacter pylori infection and interleukin 6 polymorphism -174 (rs1800795) in dyslipidemia. Design Case–control study comparing serum lipids between H. pylori positive and negative patients and controlling for IL-6 -174 polymorphism, age, sex and smoking. Setting 3 hospitals performing outpatient endoscopies in the city of Oulu, Finland. Participants 199 adult patients with dyspepsia symptoms fulfilling Rome criteria originating from ethnically Finnish population. Patients with an immunosuppressive disorder or malignant disease, treated H. pylori infection, immunosuppressive or anticoagulant medication, previous gastric surgery or ongoing antibiotic treatment were excluded. Primary outcome measures Association of H. pylori infection and serum lipid concentrations in the whole group or in genotype-based subgroups. The associations between peptic ulcer, gastric mucosal inflammation and serum lipid concentrations were assessed as secondary outcomes. Results The median high-density lipoprotein (HDL) serum concentration was significantly lower in the H. pylori positive group (0.81 mmol/L) than in the negative group (0.95 mmol/L; p<0.001). In the genotype subgroup analyses, a similar association between H. pylori infection and HDL serum levels was seen within the IL-6 -174 CC genotype group (HDL 0.72 vs 1.06 mmol/L, respectively; p<0.001), but no significant associations were seen in the GC or GG genotype groups. Additionally, patients with peptic ulcer demonstrated lower HDL levels (0.75 mmol/L) than H. pylori positive patients without ulcer (0.86 mmol/L; p=0.010). Conclusions H. pylori infection associated significantly with low serum levels of HDL in the IL-6 -174 CC genotype patients but not in the other genotypes. This suggests that the association between H. pylori infection and serum HDL could be transmitted through IL-6. We suggest that the role of IL-6 genotype should also be studied in relation to other

  15. Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis

    PubMed Central

    2013-01-01

    Background Because of the role of inflammation in preterm birth (PTB), polymorphisms in and near the interleukin-6 gene (IL6) have been association study targets. Several previous studies have assessed the association between PTB and a single nucleotide polymorphism (SNP), rs1800795, located in the IL6 gene promoter region. Their results have been inconsistent and SNP frequencies have varied strikingly among different populations. We therefore conducted a meta-analysis with subgroup analysis by population strata to: (1) reduce the confounding effect of population structure, (2) increase sample size and statistical power, and (3) elucidate the association between rs1800975 and PTB. Results We reviewed all published papers for PTB phenotype and SNP rs1800795 genotype. Maternal genotype and fetal genotype were analyzed separately and the analyses were stratified by population. The PTB phenotype was defined as gestational age (GA) < 37 weeks, but results from earlier GA were selected when available. All studies were compared by genotype (CC versus CG+GG), based on functional studies. For the maternal genotype analysis, 1,165 PTBs and 3,830 term controls were evaluated. Populations were stratified into women of European descent (for whom the most data were available) and women of heterogeneous origin or admixed populations. All ancestry was self-reported. Women of European descent had a summary odds ratio (OR) of 0.68, (95% confidence interval (CI) 0.51 – 0.91), indicating that the CC genotype is protective against PTB. The result for non-European women was not statistically significant (OR 1.01, 95% CI 0.59 - 1.75). For the fetal genotype analysis, four studies were included; there was no significant association with PTB (OR 0.98, 95% CI 0.72 - 1.33). Sensitivity analysis showed that preterm premature rupture of membrane (PPROM) may be a confounding factor contributing to phenotype heterogeneity. Conclusions IL6 SNP rs1800795 genotype CC is protective against PTB in

  16. Relationship between Interleukin-6 Gene Polymorphism and Hippocampal Volume in Antipsychotic-Naïve Schizophrenia: Evidence for Differential Susceptibility?

    PubMed Central

    Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan; Shivakumar, Venkataram; Gautham, S.; Subramaniam, Aditi; Jose, Dania Alphonse; Maitra, Arindam; Ravi, Vasanthapuram; Gangadhar, Bangalore N.

    2014-01-01

    Background Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. Methodology We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla – MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Results Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Conclusion Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal

  17. Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

    PubMed

    Kalmady, Sunil Vasu; Venkatasubramanian, Ganesan; Shivakumar, Venkataram; Gautham, S; Subramaniam, Aditi; Jose, Dania Alphonse; Maitra, Arindam; Ravi, Vasanthapuram; Gangadhar, Bangalore N

    2014-01-01

    Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia

  18. Replication and Meta-analysis of the Gene-Environment Interaction between Body Mass Index and the Interleukin-6 Promoter Polymorphism with Higher Insulin Resistance

    PubMed Central

    Underwood, Patricia C.; Chamarthi, Bindu; Williams, Jonathan S.; Sun, Bei; Vaidya, Anand; Raby, Benjamin A.; Lasky-Su, Jessica; Hopkins, Paul N.; Adler, Gail K.; Williams, Gordon H.

    2012-01-01

    Objective Insulin resistance (IR) is a complex disorder caused by an interplay of both genetic and environmental factors. Recent studies identified a significant interaction between body mass index (BMI) and the rs1800795 polymorphism of the Interleukin-6 (IL-6) gene that influences both IR and onset of type 2 diabetes mellitus (T2DM) with obese individuals homozygous for the C allele demonstrating the highest level of IR and greatest risk for T2DM. Replication of a gene-environment interaction is important to confirm the validity of the initial finding and extends the generalizability of the results to other populations. Thus, the objective of this study was to replicate this gene-environment interaction on IR in a hypertensive population and perform a meta-analysis with prior published results. Material and Methods The replication analysis was performed using Caucasian individuals with hypertension (HTN) from the HyperPATH cohort (N=311), genotyped for rs1800795. Phenotype studies were conducted after participants consumed two diets: high sodium (HS) (200mmol/day) and low sodium (LS) (10mmol/day) for 7 days each. Measurements for plasma glucose, insulin, and IL-6 were obtained after 8 hours of fasting. IR was characterized by the homeostatic model assessment (HOMA-IR). Results In HyperPATH, BMI was a significant effect modifier of the relationship between rs1800795 and HOMA-IR; higher BMI was associated with higher HOMA-IR among homozygote CC individuals when compared to major allele G carriers (p=0.003). Further, the meta-analysis in 1028 individuals confirmed the result demonstrating the same significant interaction between rs1800795 and BMI on HOMA-IR (p=1.05×10−6). Conclusion This rare replication of a gene-environment interaction extends the generalizability of the results to HTN while highlighting this polymorphism as a marker of IR in obese individuals. PMID:22075267

  19. Assessment of the role of serum ischemia-modified albumin in obstructive sleep apnea in comparison with interleukin-6.

    PubMed

    Dogan, Deniz; Ocal, Nesrin; Aydogan, Mehmet; Tasci, Canturk; Arslan, Yakup; Tapan, Serkan; Yetkin, Sinan; Bilgic, Hayati

    2016-08-01

    There is limited and contradictory information regarding the role of serum ischemia-modified albumin (IMA) in obstructive sleep apnea (OSA). In this study we examine the effects of OSA and obesity on IMA and interleukin-6 (IL-6), and detect whether IMA and IL-6 may be potential biomarkers in OSA. Fifty-one males who underwent all night polysomnography test were included into the study. Body-mass index (BMI) and apnea-hypopnea index (AHI) of all patients were determined. Serum IMA and IL-6 levels, erythrocyte sedimentation rate (ESR), complete blood count, routine blood biochemistry and thyroid function tests were performed. Mean IMA [0.36 (± 0.04) U/ml, 0.89 (± 0.15) U/ml], mean IL-6 [1.01 (± 0.19) pg/ml, 2.02 (± 1.19) pg/ml] and mean ESR [4.14 (± 2.5) mm/h, 14.35 (± 13.7) mm/h] levels showed significant difference between non-OSA and OSA groups (P = 0.005, P < 0.001, P < 0.001, respectively). Sensitivity of IMA in distinction of non-OSA/OSA was equal to IL-6 and higher than ESR. IMA was also a stronger predictive factor than IL-6 and ESR in the evaluation of OSA groups (severe/mild/moderate OSA and non-OSA). IMA was the sole distinctive biomarker in assessment of obese and non-obese cases. IMA correlated with IL-6, AHI and ESR. Serum IMA may be a valuable oxidative stress indicator for OSA and could act as a better biomarker than IL-6 for reflecting the presence and the severity of OSA.

  20. Association of interleukin-6-572C/G gene polymorphism and serum or cerebrospinal fluid interleukin-6 level with enterovirus 71 encephalitis in Chinese Han patients with hand, foot, and mouth disease.

    PubMed

    Yuan, Aiyun; Li, Jian; Liu, Peipei; Chen, Zongbo; Hou, Mei; Wang, Jinju; Han, Zhenliang

    2015-04-01

    Interleukin-6 (IL-6), as one of pro-inflammatory cytokines, plays a key role in Enterovirus 71 (EV71) encephalitis. We investigated the association of IL-6-572C/G polymorphism and serum or cerebrospinal fluid (CSF) IL-6 level with EV71 encephalitis in patients with hand, foot, and mouth disease (HFMD). This study was carried out in 59 Chinese Han patients with EV71 encephalitis, 128 EV71-related HFMD without complications, and 232 controls. The IL-6-572C/G polymorphism was detected by polymerase chain reaction-restricted fragment length polymorphism gene analysis. Serum or CSF IL-6 levels were determined using a commercial enzyme-linked immunosorbent assay. The patients with EV71 encephalitis had a higher frequency of IL-6-572GG/GC genotype compared to the patients with EV71-related HFMD without encephalitis complications (40.7 vs. 15.6 %, odds ratio (OR)=3.70, 95 % confidence interval (CI)=1.83-7.50, p=0.001). Similarly, the frequency of IL-6-572 G allele among the patients with EV71 encephalitis was also higher than that of patients with EV71-related HFMD without encephalitis complications (23.7 vs. 8.6 %, OR=3.31, 95 % CI=1.80-6.08, p<0.001). Serum IL-6 levels in G carries (CG + GG) (195.1 ± 11.8 pg/ml) elevated significantly compared to CC homozygotes (167.7 ± 6.7 pg/ml) in EV71-infected patients (p<0.001), but no significant differences were observed in CSF IL-6 levels among different genotypes in patients with EV71 encephalitis. Furthermore, G carriers (GG + GC) (10.6 ±.29 mg/l) had significantly higher blood CRP levels compared to CC homozygotes (9.31 ± 1.93 mg/l) in patients with EV71 encephalitis (p=0.005). These findings suggested that IL-6-572 G allele was significantly associated with the susceptibility to EV71 encephalitis in Chinese Han patients, and IL-6-572 G allele might elevate the risk to EV71 encephalitis.

  1. Relationship between Interleukin-6 (−174G/C and −572C/G) Promoter Gene Polymorphisms and Risk of Intracerebral Hemorrhage: A Meta-Analysis

    PubMed Central

    Kumar, Pradeep; Misra, Shubham; Kumar Yadav, Arun; Kumar, Amit; Sriwastva, Mukesh; Prasad, Kameshwar

    2016-01-01

    Background Polymorphisms of −174G/C and −572C/G in the Interleukin-6 (IL-6) promoter gene can affect both transcription and secretion of IL-6 and may be involved in the inflammatory mechanisms in early and delayed phases after intracerebral hemorrhage (ICH). The role of these polymorphisms remains unclear for the pathogenesis of ICH. Methods PubMed, EMBASE, MEDLINE and Google Scholar searches were conducted from January 1, 1950 to February 29, 2016 and were supplemented with relevant articles identified in the references. The following search terms were used: (‘interleukin-6’ or ‘IL-6’) and (‘genetic polymorphism’ or ‘single nucleotide polymorphisms’ or ‘SNP’) and (‘intracerebral hemorrhage’ or ‘ICH’) and (‘hemorrhagic stroke’ or ‘HS’). Fixed or random effects models were used to estimate the pooled odds ratios and 95% confidence intervals. Begg's funnel plot was used to assess the potential for publication bias. Results In our meta-analysis, three case-control studies involving 446 ICH cases and 2,322 controls were included. No significant association was observed for the IL-6 (-174G/C and −572C/G) gene polymorphisms with the risk of ICH under dominant, recessive and allelic models. Conclusion Our meta-analysis suggests that IL-6 gene polymorphisms are not associated with the risk of ICH. However, caution must be taken while considering the results of our meta-analysis due to the presence of small sample size. Our results cannot be extrapolated to represent the effect of entire IL-6 genetic polymorphism on stroke patients worldwide. Therefore, further well-designed studies with large sample size are warranted to validate our findings and provide a profound conclusion. PMID:27752477

  2. Interleukin-6 gene -174 G/C promoter polymorphism predicts severity and outcome in acute ischemic stroke patients from north India.

    PubMed

    Chakraborty, Baidarbhi; Chowdhury, Debashish; Vishnoi, Gaurav; Goswami, Binita; Kishore, Jugal; Agarwal, Sarita

    2013-07-01

    A guanine/cytosine (G/C) substitution occurring in position -174 of the interleukin-6 (IL-6) gene promoter changes the expression of IL-6 circulating proteins. We evaluated the occurrence of IL-6 -174 G/C polymorphism in patients with acute ischemic stroke and studied its association with stroke severity, outcome, and mortality. One hundred patients with acute ischemic stroke and 120 age and sex-matched healthy controls were studied. Genotyping was performed using polymerase chain reaction and restriction enzyme analysis. Serum levels of IL-6 were measured using enzyme-linked immunosorbent assay. Stroke was classified using Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Severity was assessed by the National Institutes of Health Stroke Scale. Outcome measures included modified Rankin Scale (mRS) and Barthel Index (BI) scores at 7 days and 3 and 6 months. Mortality/survival was assessed using the Kaplan-Meier analysis. The frequency of GG, GC, and CC genotypes did not differ significantly between cases and controls. No association was seen between TOAST subtype and genotype. At the time of admission, stroke was more severe in patients with the GC genotype (P = .03) and less severe in the GG genotype (P = .04). The GC genotype was also associated with higher serum IL-6 levels and poor short-term (BI P = .001; mRS P = .003) and long-term outcomes (BI P = 9 × 10(-5); mRS P = 9 × 10(-5)), while the GG genotype had significantly lower serum IL-6 levels and better short and long-term outcomes (BI P = 3 × 10(-5); mRS P = 2 × 10(-4)). There was significantly lesser mortality in the GG genotype and more in the GC genotype based on the Kaplan-Meier analysis. Patients with the GC genotype had more severe strokes with poorer short and long-term outcomes and increased mortality. The GG genotype was associated with less severe strokes, better short and long-term prognosis, and survival. The GG genotype appears to be protective against stroke severity

  3. A Functional Single-Nucleotide Polymorphism in the Promoter of the Gene Encoding Interleukin 6 Is Associated With Susceptibility to Tuberculosis

    PubMed Central

    Zhang, Guoliang; Zhou, Boping; Wang, Wenfei; Zhang, Mingxia; Zhao, Yahua; Wang, Zheng; Yang, Lin; Zhai, Jingnan; Feng, Carl G.; Wang, Junwen; Chen, Xinchun

    2012-01-01

    Background Genetic variation influences susceptibility or resistance to tuberculosis. Interleukin 6 (IL-6) contributes to protection against tuberculosis in mice. However, its role in regulating susceptibility or resistance to tuberculosis in humans is unclear. Methods Genotyping of polymorphisms in IL-6 and IL-6R (CD126) genes was performed in 2 independent cohorts, an experimental population (495 cases and 358 controls) and a validation population (1383 cases and 1149 controls). The associations of the variants with tuberculosis were tested using 2 case-control association studies. In addition, the regulatory effects of single-nucleotide polymorphism rs1800796 (-572C > G) on IL-6 production in plasma and CD14+ monocyte cultures stimulated with a Mycobacterium tuberculosis (M. tuberculosis) product were assessed. Results The rs1800796 polymorphism is associated with increased resistance to tuberculosis (odds ratio [OR], 0.771; 95% confidential interval, .684–.870). The rs1800796GG genotype is strongly associated with reduced risk to tuberculosis (OR, 0.621; 95% CI, .460–.838). Interestingly, CD14+ monocytes isolated from individuals with rs1800796GG genotype produced significantly less IL-6 in response to M. tuberculosis 19-kDa lipoprotein than those with CC or CG genotype. Conclusions We identified a genetic polymorphism in the IL-6 promoter that regulates cytokine production and host resistance to pulmonary tuberculosis in Chinese populations. PMID:22457277

  4. Rather than Rs1800796 Polymorphism, Expression of Interleukin-6 is Associated with Disease Progression of Chronic HBV Infection in a Chinese Han Population

    PubMed Central

    Tang, Shengli; Liu, Zhisu; Zhang, Yongxi; He, Yueming; Pan, Dingyu; Liu, Yuanyuan; Liu, Quanyan; Zhang, Zhonglin; Yuan, Yufeng

    2013-01-01

    Interleukin-6 plays an important role in chronic inflammation as well as tumor growth and progression. Here, a case-control study was undertaken to investigate the association of rs1800796 polymorphism of IL-6 gene and serum levels with disease progression of chronic HBV infection. Rs1800796 polymorphism was genotyped in 641 Chinese Han patients with chronic HBV infection, including 23 IT, 25 IC, 292 CHB, 153 LC, and 148 HCC patients and 265 healthy controls. Serum IL-6 levels were measured in 23 IT, 25 IC, 47 CHB, 41 LC, and 49 HCC patients and 45 healthy controls, and the classifications of HCC were accorded to BCLC staging system. We found no significant association between rs1800796 polymorphism and disease progression of chronic HBV infection; however, serum IL-6 levels showed significant statistical differences between patients with CHB, LC, and HCC. Moreover, statistical differences can be observed in patients with terminal stage HCC compared with those of early to intermediate or advanced stage HCC. Our findings suggest that rs1800796 polymorphism unlikely contribute significantly to affect the progression of chronic HBV infection, and serum IL-6 levels can act as a useful indicator for disease progression and severity of chronic HBV infection. PMID:24371367

  5. Interleukin-6 -634 C/G and -174 G/C Polymorphisms in Korean Patients Undergoing Hemodialysis

    PubMed Central

    Ryu, Jung-Hwa

    2012-01-01

    Background/Aims Chronic inflammatory status is a possible risk factor for vascular access dysfunction in hemodialysis (HD) patients, but susceptibility differences appear among individuals. Interleukin (IL)-6 is a well-known inflammatory cytokine with various polymorphisms. We examined whether IL-6 polymorphisms are associated with vascular access dysfunction in HD patients. Methods A total of 80 HD patients (including 42 diabetic patients) were enrolled. Polymorphisms in the IL-6 gene promoter (-634 C/G and -174 G/C) were studied using restriction length polymorphism polymerase chain reaction analysis. Vascular access patency was compared between the patient groups with respect to IL-6 polymorphisms. An additional 89 healthy individuals were enrolled in the control group. Plasma IL-6 levels were de termined by enzyme-linked immunosorbent assay. Results The GG genotype and G allele at position -634 in the IL-6 promoter were more frequently observed in HD patients than in controls. Furthermore, the distribution of the -634 polymorphism differed according to vascular access patency in non-diabetic HD patients. However, the G allele was not a significant risk factor for early access failure. No significant association appeared between the IL-6 -634 C/G polymorphism and plasma IL-6 levels. The C allele of the IL-6 -174 G/C polymorphism was not detected in our study population. Conclusions The IL-6 -634 G allele appears with greater frequently in patients with end-stage renal disease and may be associated with vascular access dysfunction in non-diabetic HD patients. PMID:23019398

  6. Analysis of Polymorphisms in Interleukin-10, Interleukin-6, and Interleukin-1 Receptor Antagonist in Mexican-Mestizo Women with Pre-eclampsia

    PubMed Central

    Valencia Villalvazo, Elith Yazmin; Canto-Cetina, Thelma; Romero Arauz, Juan Fernando; Coral-Vázquez, Ramón Mauricio; Canizales-Quinteros, Samuel; Coronel, Agustín; Carlos Falcón, Juan; Hernández Rivera, Jaime; Ibarra, Roberto; Polanco Reyes, Lucila

    2012-01-01

    Due to the fact that studies seeking associations of polymorphisms in regulatory regions of cytokine genes with pre-eclampsia (PE) have not always been consistent in different population analyses, the aim of this study was to investigate the possible association between rs1800896 of interleukin-10 (IL-10), rs1800795 of interleukin-6 (IL-6), and the variable number of tandem repeats (VNTR) in intron 2 of interleukin-1 receptor antagonist (IL-1Ra), as well as gene–gene interactions between these three polymorphisms with the presence of PE in Mexican-Mestizo women and one Amerindian population from México (Maya). A case–control study was performed where 411 pre-eclamptic cases and 613 controls were genotyped. For the rs1800896 of IL-10 and rs1800795 of IL-6, we used real-time polymerase chain reaction (PCR) allelic discrimination and for the VNTR of IL-1Ra, PCR. Allele frequency differences were assessed by Chi-squared test; logistic regression was used to test for associations; a gene–gene interaction was conducted. Genotypic and allelic distribution of the polymorphisms was similar in our population. The estimated of the gene–gene interaction between the polymorphisms did not differ significantly. However, we observed important differences in the distribution of the alleles and genotypes of the three polymorphisms analyzed between Mestiza-Mexicanas and Maya-Mestizo women. In conclusion, we did not find an association between polymorphisms in IL-10, IL-6, and IL-1Ra and PE in Mexican-Mestizo and Maya-Mestizo women. To our knowledge, this is the first time that these three polymorphisms were analyzed together with gene–gene interaction in women with PE. PMID:23013217

  7. Interleukin-6 gene -174G>C and -636G>C promoter polymorphisms and prostate cancer risk.

    PubMed

    Magalhães, J F; Cortinhas, A J; Albuquerque, C M; Baptista, C S; Ribeiro, R; Viegas, Carlos; Matos, Augusto; Machado, João; Pires, Maria A; Guedes-Pinto, Henrique; Martins-Bessa, A; Leitão, J C; Bastos, E

    2013-01-01

    Prostate cancer (PCa) is one of the most commonly diagnosed internal malignancies affecting men. Due to the important roles of IL-6 in different physiological and pathophysiological processes, IL-6 polymorphisms may modulate PCa risk. IL-6 -174 G>C (rs 1800795, also designated -236 G>C) and -636 G>C (rs 1800796, also designated -572 G>C) promoter polymorphisms have been implicated in PCa susceptibility, albeit still controversial. A literature search using PubMed and Highwire databases was conducted, resulting in eight case-control studies concerning the IL-6 -174 G>C polymorphism (11,613 PCa cases and 13,992 controls) and four case-control publications regarding the IL-6 -636 G>C polymorphism (1,941 PCa cases and 3,357 controls). In order to derive a more precise estimation, a meta-analysis based upon these selected case-control studies was performed. There was no significant association between IL-6 -174 G>C polymorphism and PCa increased risk. Nevertheless, the presence of allele C and the CC genotype were statistically significantly associated with decreased PCa risk in the overall analysis for IL-6 -636 G>C polymorphism. Additional studies in larger samples and analyses of functional repercussions of these SNPs in prostate tumor cells are necessary to validate these findings.

  8. Association of Estrogen Receptor Alpha and Interleukin 6 Polymorphisms with Lymphovascular Invasion, Extranodal Extension, and Lower Disease-Free Survival in Thai Breast Cancer Patients.

    PubMed

    Sa-Nguanraksa, Doonyapat; Suntiparpluacha, Monthira; Kulprom, Anchalee; Kummalue, Tanawan; Chuangsuwanich, Tuenjai; Avirutnan, Panissadee; O-Charoenrat, Pornchai

    2016-01-01

    Breast cancer is the most frequent type of cancer diagnosed among women worldwide and also in Thailand. Estrogen and estrogen receptors exert important roles in its genesis and progression. Several cytokines have been reported to be involved in the microenvironment that promotes distant metastasis via modulation of immune and inflammatory responses to tumor cells. Estrogen receptor genetic polymorphisms and several cytokines have been reported to be associated with breast cancer susceptibility and aggressiveness. To investigate roles of genetic polymorphisms in estrogen receptor alpha (ESR1) and interleukin 6 (IL6), breast cancer patients and control subjects were recruited from the Division of Head, Neck and Breast Surgery (Siriraj Hospital, Bangkok, Thailand). Polymorphisms in ESR1 (rs3798577) and IL6 (rs1800795 and rs1800797) were evaluated by real-time PCR in 391 breast cancer patients and 79 healthy controls. Associations between genetic polymorphisms and clinicopathological data were determined. There was no association between genetic polymorphisms and breast cancer susceptibility. However the ESR1 rs3798577 CT genotype was associated with presence of lymphovascular invasion (OR=2.07, 95%CI 1.20-3.56, p=0.009) when compared to the TT genotype. IL6 rs1800795 CC genotype was associated with presence of extranodal extension (OR= 2.30, 95%CI 1.23-4.31, p=0.009) when compared to the GG genotype. Survival analysis showed that IL6 rs1800797 AG or AA genotypes were associated with lower disease-free survival. These findings indicate that polymorphisms in ESR1 and IL6 contribute to aggressiveness of breast cancer and may be used to identify high risk patients.

  9. [Association between interleukin-6 polymorphism in the -174 G/C region and hearing loss in the elderly with a history of occupational noise exposure].

    PubMed

    Braga, Miula Portelinha; Maciel, Sandra Mara; Marchiori, Luciana Lozza de Moraes; Poli-Frederico, Regina Célia

    2014-01-01

    The biological processes involved in noise-induced hearing loss (NIHL) are still unclear. The involvement of inflammation in this condition has been suggested. To investigate the association between interleukin - 6 (IL-6) polymorphism and susceptibility to NIHL. This was a cross-sectional study with a sample of 191 independent elderly individuals aged >60 years of age. Information on exposure to occupational noise was obtained by interviews. Audiological evaluation was performed using pure tone audiometry and genotyped through PCR by restriction fragment length polymorphism - PCR-RFLP. Data were analyzed using the chi-square test and the odds ratio (OR), with the significance level set at 5%. Among elderly with hearing loss (78.0%), 18.8% had a history of exposure to occupational noise. There was a statistically significant association between the genotype frequencies of the IL-6 -174 and NIHL. The elderly with the CC genotype were less likely to have hearing loss due to occupational noise exposure when compared to those carrying the GG genotype (OR=0.0124; 95% CI 0.0023-0.0671; p<0.001). This study suggests there is an association of polymorphisms in the IL-6 gene at position - G174C with susceptibility to noise-induced hearing loss. Copyright © 2014 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

  10. Association between Interleukin-6 Gene Polymorphisms and Rheumatoid Arthritis in Chinese Han Population: A Case-Control Study and A Meta-analysis

    PubMed Central

    Li, Feng; Xu, Jing; Zheng, Jiatian; Sokolove, Jeremy; Zhu, Kai; Zhang, Yuanchao; Sun, Hongsheng; Evangelou, Evangelos; Pan, Zhenglun

    2014-01-01

    The aim of this study was to investigate the possible association in the interleukin-6 (IL-6) gene with Rheumatoid arthritis (RA) in Chinese Han population from Shandong Province. Target regions of IL-6 gene were amplified by polymerase chain reaction (PCR) and genotyped. A logistic regression analysis was performed to detect potential associations in our case-control sample, the odd ratio(OR) and 95% confidence intervals(CIs) were calculated. Furthermore, we systematically tracked all the published studies in the field and performed a meta-analysis for the single nucleotide polymorphisms (SNPs) under study. 256 RA patients and 331 healthy controls were recruited into the case-control study. We found allele frequencies of rs1800795, rs1800797 and rs1474347 in RA patients differ from control subjects (P = 0.016, 0.024, 0.020, respectively). Significant difference was observed in haplotype frequencies of GCCGCT between RA patients and controls (P = 0.0001, OR = 4.066, 95%CI = 1.891 ~ 8.746), while GGCGCT frequencies was found lower in RA than controls (P = 0.006, OR = 0.669, 95%CI = 0.501 ~ 0.894). The results of the meta-analysis showed association polymorphism within the IL-6 promoter with RA. These findings suggest that rare IL-6 gene polymorphisms may associate with RA susceptibility in Han Chinese populations; however further studies are needed to assess the validity of the association of IL-6 with RA. PMID:25030201

  11. CD38 and interleukin 6 gene polymorphism in egyptians with diffuse large B-cell lymphoma (DLBCL).

    PubMed

    Talaat, Roba M; Abdel-Aziz, Amal M; El-Maadawy, Eman A; Abdel-Bary, Naser

    2015-01-01

    Given the importance of understanding the genetic variations involved in the pathogenesis of non-Hodgkin's lymphoma (NHL), this pilot study was designed to investigate the impact of CD38 (184C/G; rs6449182) and IL-6 (-174 G/C; rs1800795) gene polymorphism on susceptibility of Egyptians to diffuse large B cell lymphoma (DLBCL); major types of NHL. To the best of our knowledge, this study is the first one that examines CD38 polymorphism in the NHL. Genotyping polymorphism is performed using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) for CD38 and Mutagenically separated PCR (MS-PCR) for IL-6 in 100 Egyptian NHL patients with DLBCL subtype and 119 normal controls. The serum level of IL-6 was measured using Enzyme-linked immunosorbent assay (ELISA). CD38 (184C/G) genotype is significantly increased in NHL patients (p < 0.01), while the GG genotype is significantly increased in controls (p < 0.05). Only two genotypes were found (GG and GC) in IL-6 (-174), no CC in our NHL patients and only one case in the controls. Insignificant change in IL-6 (-174 G/C) genotypes was recorded. Significantly increased serum IL-6 (p < 0.05) was positively correlated (r = 0.17; p < 0.05) with the disease. Taken together, our data stressed the importance of CD38 gene polymorphism in developing DLBCL. Our pilot study indicates that CD38 (184) CG genotype might play a role in DLBCL susceptibility in Egyptians. Additional prospective studies on larger population are needed to confirm our findings.

  12. Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation.

    PubMed

    Cavet, J; Dickinson, A M; Norden, J; Taylor, P R; Jackson, G H; Middleton, P G

    2001-09-01

    Proinflammatory cytokines including interferon-gamma (IFNgamma), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFalpha) are implicated in the pathogenesis of acute graft-versus-host disease (aGVHD). Cytokine gene polymorphism is associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. Polymorphism in the IFNgammaIntron1 microsatellite (CA)n repeat has been linked with in vitro IFNgamma production and renal transplant rejection. The IL-6(-174)(G/C) single nucleotide polymorphism has been linked to in vitro and in vivo IL-6 production, juvenile chronic arthritis, and renal transplant rejection. This study examined the potential association of GVHD with IFNgamma and IL-6 polymorphisms in 80 sibling bone marrow transplant (BMT) donor/recipient pairs. Patients homozygous for the IFNgammaIntron1 allele 3 had more severe (grade III-IV) aGVHD. Patients possessing the IL-6(-174)G allele had a trend toward higher grades of aGVHD, and those homozygous for the IL-6(-174)G allele were more likely to develop chronic GVHD (cGVHD). The associations of previously identified aGVHD severity-associated cytokine gene polymorphisms (TNFd and IL-10(-1064)) with severe aGVHD were reconfirmed. Logistic regression analysis confirmed the association of severe aGVHD with recipient genotype at IFNgammaIntron1 (odds ratio [OR] 3.92; P =.02), IL-10(-1064) (OR 4.61; P =.026) and TNFd (OR 3.29; P =.039), and that of cGVHD with recipient IL-6(-174) genotype (OR 4.25; P =.007), in addition to age, gender mismatch, and underlying disease. Assessment of cytokine genotype may potentially allow more accurate prediction of GVHD and appropriate adjustment of GVHD prophylaxis, as well as indicating novel areas for future studies of GVHD pathogenesis.

  13. Interleukin-6 Gene Polymorphisms, Dietary Fat Intake, Obesity and Serum Lipid Concentrations in Black and White South African Women

    PubMed Central

    Joffe, Yael T.; van der Merwe, Lize; Evans, Juliet; Collins, Malcolm; Lambert, Estelle V.; September, Alison; Goedecke, Julia H.

    2014-01-01

    This study investigated interactions between dietary fat intake and IL-6 polymorphisms on obesity and serum lipids in black and white South African (SA) women. Normal-weight and obese, black and white women underwent measurements of body composition, serum lipids and dietary fat intake, and were genotyped for the IL-6 −174 G>C, IVS3 +281 G>T and IVS4 +869 A>G polymorphisms. In black women the IVS4 +869 G allele was associated with greater adiposity, and with increasing dietary fat intake adiposity increased in the IVS3 +281 GT+GG and IVS4 +869 AA or AG genotypes. In white women, with increasing omega-3 (n-3) intake and decreasing n-6:n-3 ratio, body mass index (BMI) decreased in those with the −174 C allele, IVS3 +281 T allele and IVS4 +869 AG genotype. In the white women, those with the IVS3 +281 T allele had lower triglycerides. Further, with increasing n-3 polyunsaturated fatty acid (PUFA); triglyceride and total cholesterol:high-density lipoprotein cholesterol (T-C:HDL-C) ratio decreased in those with the −174 C allele. In black women, with increasing total fat intake, triglycerides and T-C:HDL-C ratio increased in those with the IVS4 +869 G allele. This study is the first to show that dietary fat intake modulates the relationship between the IL-6 −174 G>C, IVS3 +281 G>T and IVS4 +869 A>G polymorphisms on obesity and serum lipids in black and white SA women. PMID:24962479

  14. Interleukin-6 gene polymorphisms, dietary fat intake, obesity and serum lipid concentrations in black and white South African women.

    PubMed

    Joffe, Yael T; van der Merwe, Lize; Evans, Juliet; Collins, Malcolm; Lambert, Estelle V; September, Alison V; Goedecke, Julia H

    2014-06-24

    This study investigated interactions between dietary fat intake and IL-6 polymorphisms on obesity and serum lipids in black and white South African (SA) women. Normal-weight and obese, black and white women underwent measurements of body composition, serum lipids and dietary fat intake, and were genotyped for the IL-6 -174 G>C, IVS3 +281 G>T and IVS4 +869 A>G polymorphisms. In black women the IVS4 +869 G allele was associated with greater adiposity, and with increasing dietary fat intake adiposity increased in the IVS3 +281 GT+GG and IVS4 +869 AA or AG genotypes. In white women, with increasing omega-3 (n-3) intake and decreasing n-6:n-3 ratio, body mass index (BMI) decreased in those with the -174 C allele, IVS3 +281 T allele and IVS4 +869 AG genotype. In the white women, those with the IVS3 +281 T allele had lower triglycerides. Further, with increasing n-3 polyunsaturated fatty acid (PUFA); triglyceride and total cholesterol:high-density lipoprotein cholesterol (T-C:HDL-C) ratio decreased in those with the -174 C allele. In black women, with increasing total fat intake, triglycerides and T-C:HDL-C ratio increased in those with the IVS4 +869 G allele. This study is the first to show that dietary fat intake modulates the relationship between the IL-6 -174 G>C, IVS3 +281 G>T and IVS4 +869 A>G polymorphisms on obesity and serum lipids in black and white SA women.

  15. Association study of interleukin-1 family and interleukin-6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis.

    PubMed

    Najafi, S; Yousefi, H; Mohammadzadeh, M; Bidoki, A Z; Firouze Moqadam, I; Farhadi, E; Amirzargar, A A; Rezaei, N

    2015-12-01

    Recurrent aphthous stomatitis (RAS) is a common painful, ulcerative oral inflammatory disorder with unknown aetiology. Immune system and aberrant cytokine cascade deemed to be critical in outbreaks of RAS ulcers. Interleukin-1 (IL-1) and IL-6 are the most potent pro-inflammatory cytokines. Single nucleotide polymorphisms (SNPs) of IL-1 and IL-6 genes can affect the secretion of these cytokines. The aim of this study was to investigate the association between RAS and IL-6 and IL-1 in Iranian subjects with minor RAS. Genomic DNA was obtained from 64 Iranian patients with RAS. IL-1α C -889 T, IL-1β C -511 T, IL-1β C +3962 T, IL-1R C pst-I 1970 T, IL-1Ra C Mspa-I11100 T, IL-6 C -174 G and IL-6 A nt +565 G polymorphisms were determined using polymerase chain reaction with sequence-specific primers (PCR-SSP). The frequency of C -174 C genotype in the patients group was significantly different from the healthy control. No other significant differences were found in genotype and alleles frequencies between the two groups. These results indicate that certain SNPs of IL-6 gene at position -174 which located in promoter have association with predisposition of individuals to RAS. © 2015 John Wiley & Sons Ltd.

  16. Effect of maternal and neonatal interleukin-6 - 174 G/C polymorphism on preterm birth and neonatal morbidity.

    PubMed

    Karakaş, N Mutlu; Ecevit, Ayse N; Yalçın, Yaprak; Özdemir, Beril; Verdi, Hasibe; Tekindal, M Ağah; Özbek, Namık Y; Tarcan, Aylin; Ataç, Fatma B; Haberal, Ali

    2017-03-23

    The aim of this study was to analyze maternal and neonatal interleukin 6 (IL-6) (-174 G/C) polymorphism and to determine effect on preterm birth and neonatal morbidity. One hundred and sixty-four mothers (100 term births, 64 preterm births) and 183 newborn infants who were 100 healthy term and 83 preterm babies followed in newborn intensive care units were evaluated. PCR-RFLP was performed for IL-6 (-174 G/C) genotyping. The rate of GG genotype in mothers of term and preterm infants were 54% (n = 54/100), 75% (n = 48/64), respectively (p > .05) and the rate of GC + CC genotype was 46% (n = 46/100) and 25% (n = 16/64) in mothers giving term and preterm birth (PTB), respectively (p < .05). Additionally, the rate of GG genotype was 65% (n = 65/100) and 81.9% (n = 68/83) in term infants and preterm infants, respectively. GC + CC genotype was 35% (n = 35/100) in term infants and 18.1% (n = 15/83) in preterm infants (p < .05). The effect of IL-6 (-174) GC + CC genotype on PTB was statistically significant. The IL-6 174 G/C gene polymorphism was significantly different between mothers who were giving to term and preterm birth. The presence of polymorphism is protective against preterm birth and was not associated with neonatal outcome.

  17. Association between polymorphism of interleukin-6 in the region -174G/C and tinnitus in the elderly with a history of occupational noise exposure

    PubMed Central

    Doi, Marcelo Yugi; Dias, Ana Carolina Marcotti; Poly-Frederico, Regina Célia; Maria, Maira Gabriela Sasso Rosa; de Oliveira, Maria Nazaré; de Moraes Marchiori, Luciana Lozza

    2015-01-01

    Tinnitus is a symptom usually related to cochlear change that may arise from noise exposure and induces expression of proinflammatory cytokines including interleukin-6 (IL6). This study aimed to evaluate the association between the polymorphism of the IL6 gene in the region 174G/C and tinnitus in elderly with history of occupational noise exposure. Settings and Design: This was a cross-sectional study with a sample of 179 independent elderly individuals aged >60 years. Information on exposure to occupational noise was obtained by interviews. Audiological evaluation was performed using pure tone audiometry and genotyped through polymerase chain reaction by restriction fragment length polymorphism (PCR-RFLP). Data were analyzed using the chi-square test and the odds ratio (OR), with the significance level set at 5%. Among the study subjects, 24.6% were homozygous for the G allele, 39.7% were homozygous for the C allele, and 35.8% were heterozygous for IL6 (P > 0.05). Of these, 33.5% reported noise exposure history, with 42.5% having tinnitus. We found significant association between the genotype and allele frequencies of the IL6 −174 gene (rs1800795) and tinnitus among the elderly with history of exposure to occupational noise (P = 0.03). The elderly with the C allele were less likely to have tinnitus associated with history of exposure to occupational noise [OR = 0.167, confidence interval (CI) 95% 0.167-0.749; P = 0.004] when compared to those carrying the G allele. This study suggests that there is an association between polymorphisms in the IL6 gene at region – 174G/C and susceptibility to tinnitus. PMID:26572700

  18. Association between polymorphism of interleukin-6 in the region -174G/C and tinnitus in the elderly with a history of occupational noise exposure.

    PubMed

    Doi, Marcelo Yugi; Dias, Ana Carolina Marcotti; Poly-Frederico, Regina Célia; Maria, Maira Gabriela Sasso Rosa; de Oliveira, Maria Nazaré; de Moraes Marchiori, Luciana Lozza

    2015-01-01

    Tinnitus is a symptom usually related to cochlear change that may arise from noise exposure and induces expression of proinflammatory cytokines including interleukin-6 (IL6). This study aimed to evaluate the association between the polymorphism of the IL6 gene in the region 174G/C and tinnitus in elderly with history of occupational noise exposure. This was a cross-sectional study with a sample of 179 independent elderly individuals aged >60 years. Information on exposure to occupational noise was obtained by interviews. Audiological evaluation was performed using pure tone audiometry and genotyped through polymerase chain reaction by restriction fragment length polymorphism (PCR-RFLP). Data were analyzed using the chi-square test and the odds ratio (OR), with the significance level set at 5%. Among the study subjects, 24.6% were homozygous for the G allele, 39.7% were homozygous for the C allele, and 35.8% were heterozygous for IL6 (P > 0.05). Of these, 33.5% reported noise exposure history, with 42.5% having tinnitus. We found significant association between the genotype and allele frequencies of the IL6 -174 gene (rs1800795) and tinnitus among the elderly with history of exposure to occupational noise (P = 0.03). The elderly with the C allele were less likely to have tinnitus associated with history of exposure to occupational noise [OR = 0.167, confidence interval (CI) 95% 0.167-0.749; P = 0.004] when compared to those carrying the G allele. This study suggests that there is an association between polymorphisms in the IL6 gene at region - 174G/C and susceptibility to tinnitus.

  19. Body composition changes after laparoscopic adjustable gastric banding: what is the role of -174G>C interleukin-6 promoter gene polymorphism in the therapeutic strategy?

    PubMed

    Di Renzo, L; Carbonelli, M G; Bianchi, A; Iacopino, L; Fiorito, R; Di Daniele, N; De Lorenzo, A

    2012-03-01

    There is growing evidence that interleukin-6 (IL-6) is linked to the regulation of fat mass (FM). Our previous data define the common -174G>C IL-6 polymorphism as a marker for 'vulnerable' individuals at risk of age- and obesity-related diseases. An association between -174G>C IL-6 polymorphism and weight loss after bariatric surgery has been demonstrated. We investigated the impact of -174G>C IL-6 polymorphism on weight loss, body composition, fluid distribution and cardiometabolic changes in obese subjects, after laparoscopic adjustable gastric banding (LAGB) surgery. A total of 40 obese subjects were studied at baseline and at 6 months follow-up after LAGB surgery. Cardiometabolic and genetic assessment of -174G>C IL-6 polymorphism, anthropometric, body composition and fluid distribution analysis were performed. After LAGB surgery, significant reductions in weight (Δ%=-11.66 ± 7.78, P<0.001), body mass index (P<0.001), total and trunk FM (kg, %) (Δ% of total FM=-22.22 ± 12.15, P<0.01), bone mineral density (T-score) (P<0.001), resting metabolic rate (RMR) (P<0.01), and total body water and intracellular water (TBW, ICW) (P<0.05) were observed. At baseline, C(-) carriers of IL-6 polymorphism had a significantly higher RMR (P<0.05), free FM (kg), but less total and trunk FM (%), higher body cell mass (BCM), content of TBW (L) and ECW (extracellular water)/ICW ratio compared with C(+) carriers (P<0.001). After LAGB, C(+) carriers had a significantly stronger reduction of total FM (kg), but lower bone density, compared with C(-) carriers (P<0.05). Beyond the relationship between -174G>C IL-6 polymorphism and body composition, this study provides first evidence about the association of IL-6 variant with fluid distribution, at baseline, and FM and bone density loss in obese subjects at 6 months follow-up after LAGB surgery. LAGB was less effective if the subjects were carrying risk genotypes, C(-) carriers, for obesity, suggesting a role of genetic variations on

  20. Interleukin-6-174G/C Polymorphism Contributes to Periodontitis Susceptibility: An Updated Meta-Analysis of 21 Case-Control Studies

    PubMed Central

    Fu, Min; Guo, Wushuang; Yuan, Yifang; Yuan, He; Zhang, Suhan

    2016-01-01

    Introduction. Chronic Periodontitis (CP) is suggested to be related to gene variations. Present study aims to quantitatively estimate the association between interleukin-6- (IL-6-) 174G/C polymorphism and CP susceptibility. Materials and Methods. Pubmed, Embase, and Web of Science were searched up to May 2016. The meta-analyses were performed using STATA 12.0. Results. 21 studies were yielded. Significant associations were found under heterozygote comparison and dominant model in studies fulfilling HWE (GC versus GG: OR = 0.690, 95% CI = 0.560–0.849, P = 0.000; CC + GC versus GG: OR = 0.690, 95% CI = 0.568–0.838, P < 0.001); significant associations were found under heterozygote comparison and dominant model in Caucasian studies fulfilling HWE (GC versus GG: OR = 0.752, 95% CI = 0.577–0.980, P = 0.035; CC + GC versus GG: OR = 0.737, 95% CI = 0.576–0.944, P = 0.016); significant associations were found under allele comparison, heterozygote comparison, and dominant model in Brazilian population (C versus G: OR = 0.648, 95% CI = 0.497–0.845, P = 0.001; GC versus GG: OR = 0.621, 95% CI = 0.441–0.876, P = 0.007; CC + GC versus GG: OR = 0.649, 95% CI = 0.470–0.896, P = 0.009). Conclusion. IL-6 174 polymorphism is associated with CP susceptibility. In Brazilian and Caucasian population, IL-6 174 GG genotype plays as a risk factor to CP. PMID:28050060

  1. Polymorphisms of α1-antitrypsin and Interleukin-6 genes and the progression of hepatic cirrhosis in patients with a hepatitis C virus infection

    PubMed Central

    Motawi, T; Shaker, OG; Houssen, M

    2016-01-01

    Abstract Hepatitis C virus (HCV) infection represents a serious health problem. The –174 G/C mutation in the pro inflammatory cytokine interleukin-6 (IL-6) is associated with developing liver diseases. Likewise, the S and Z mutations in the serine protease inhibitor α1-antitrypsin (A1AT) are associated with pulmonary emphysema and/or liver cirrhosis. We explored the distribution of the single nucleotide polymorphisms (SNPs) of IL-6 and A1AT genes in chronic HCV-infected patients and evaluated their impact on the progression of liver cirrhosis. One hundred and fifty Egyptian HCV-infected patients together with 100 healthy controls were enrolled in this study. The patient groups were subdivided into chronic hepatitis patients (n = 85) and cirrhotic patients (n = 65). The SNP of IL-6 (–174 G/C, rs1800795), A1AT Z mutation (342 Glu/Lys, rs28929474) and A1AT S mutation (264 Glu/Val, rs17580) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Cirrhotic patients exhibited significantly increased frequency of the A1AT S allele compared with the controls (34.6 vs. 5.0%), while the chronic hepatitis patients showed a higher frequency of the A1AT Z allele compared with the controls (14.7 vs. 2.5%). Remarkably, IL-6 (CC genotype) was detected only in the chronic hepatitis patients. Multivariate regression analysis showed that aspartate transaminase (AST) and the S alleles of A1AT, represented as SS+MS genotypes, were significantly independent predictors for development of liver cirrhosis. We concluded that inheritance of deficient S and Z alleles of the A1AT gene but not IL-6 (–174 G/C), were associated with progressive liver diseases. PMID:28289587

  2. Interleukin-6 -174G/C gene polymorphism affects muscle damage response to acute eccentric resistance exercise in elderly obese women.

    PubMed

    Funghetto, Silvana Schwerz; Prestes, Jonato; Silva, Alessandro de Oliveira; Farias, Darlan L; Teixeira, Tatiane G; Vieira, Denis Cesar Leite; Souza, Vinícius C; Sousa, Nuno M F; Navalta, James W; Melo, Gislane F; Karnikowski, Margô Gomes de Oliveira

    2013-11-01

    The IL-6 gene polymorphism has been associated with disease prevalence and different physiological responses to exercise. Eccentric resistance exercise (ERE) is considered a nonpharmacological tool to prevent the chronic degenerative profile associated with aging and obesity. Consequently, the aim of the present study was to investigate the influence of IL-6 -174G/C polymorphism on acute interleukin-6 (IL-6) and creatine kinase (CK) temporal response to ERE in elderly obese women. Ninety women completed seven sets of ten repetitions (eccentric only) of an acute ERE session at 110% of the ten repetitions maximum (10RM). IL-6 genotypes displayed no difference at baseline. ERE induced changes in CK concentration over time occurred only in the GG group, F(2.619, 136.173)=5.199, p=0.003, with CK activity increased from 106.8±6.9 U/l pre-intervention to 122.7±11.2 U/l at 24 h and 131.9±14.4 U/l at 48 h post-exercise. IL-6 concentration in the GG group was lower than the CC/CG group only at 0 h post-exercise (3.78±0.58 pg/ml versus 6.51±1.91 pg/ml, p=0.030). Only the GG genotype group had higher CK activity 24-48 h following ERE and greater CK integral values, while IL-6 activity over 48 h was higher in the CC/CG genotype group. In conclusion, IL-6 genotype affects CK and IL-6 in response to ERE. It is of interest that the ERE protocol induced an elevation in CK, indicating possible muscle damage without exacerbating IL-6 and CK for the GG genotype. © 2013.

  3. A functional single-nucleotide polymorphism in interleukin-6 promoter is associated with p wave dispersion in hypertensive subjects with atrial fibrillation.

    PubMed

    Geng, Hai-Hua; Li, Rui; Su, Ya-Min; Pan, Hai-Yan; Pan, Min; Ji, Xiao-Ping

    2014-01-01

    Inflammation has been shown to be implicated in the pathophysiology of atrial fibrillation (AF). Interleukin-6 (IL-6) is a pleiotropic cytokine, functions as a mediator of inflammatory response and has both pro-inflammatory and anti-inflammatory properties. Little is known about genetic factors of inflammation in the accompanying atrial electrical remodeling expressed by P wave dispersion (Pdisp). The aim of the present study is to evaluate the association of -634C/G polymorphism of IL-6 gene with Pdisp in Han Chinese hypertensive patients with AF. A total of 100 patients with essential hypertension (EH) were eligible for this study. Patients with paroxysmal AF (n=50) were allocated to the AF group, and 50 subjects without AF to the control group. The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-6 -634C/G genotypes (CC, CG, and GG) was 68.00%, 28.00%, and 4.00% in the controls, and 44.00%, 40.00%, and 16.00% in AF subjects, respectively (P=0.0269). The frequency of the G allele in the AF group was significantly higher than that in the control group (36.00% vs 18.00%, P=0.0041). Compared to the wild type CC, the G allele carriers (CG + GG genotypes) had a 2.7045-fold increased risk of AF (odds ratio =2.7045, 95% confidence interval =1.1966-6.1126, P=0.0156). AF patients with the CG + GG genotype had longer Pdisp (P=0.0032) than did patients with the CC genotype. The longer Pdisp in the subjects with the CG + GG genotype was also found in the control group (P=0.0016). These findings support that IL-6 -634C/G polymorphism is associated with Pdisp and AF, suggesting an active implication of inflammation in the atrial electrophysiological remodeling predisposing to AF.

  4. A base substitution in the promoter associated with the human haptoglobin 2-1 modified phenotype decreases transcriptional activity and responsiveness to interleukin-6 in human hepatoma cells

    SciTech Connect

    Grant, D.J.; Maeda, N. )

    1993-05-01

    An A-to-C base substitution at nucleotide position -61 in the promoter region of the human haptoglobin gene (Hp) has been shown to be strongly associated with the haptoglobin 2-1 modified (Hp2-1mod) phenotype. In order to investigate whether this base substitution is the cause of reduced expression of the Hp[sup 2] allele relative to the Hp[sup 1] allele in individuals with the Hp2-1mod phenotype, the authors used the chloramphenicol acetyl transferase (CAT) expression system to evaluate promoter function. In HepG2 cells, which normally express their endogenous haptoglobin genes, CAT plasmid constructs with the -61C base change in the promoter had about 10-fold-lower transcriptional activity after transfection than did the Hp control construct. The -61C substitution also rendered the construct unresponsive to treatment by interleukin-6 after transfection into Hep3B2 cells, which normally do not express haptoglobin but do so in response to stimulation by acute-phase reactants. In addition, two base substitutions, T to A and A to G, at positions -104 and -55G, respectively, in the promoter region of the Hp[sup 1] allele, are also associated with the Hp2-1mod phenotype. CAT constructs with both substitutions (-104A-55G) and with one substitution (-55G) showed activity similar to that in the Hp control when transfected into both HepG2 and Hep3B2 cells, although interleukin-6 induction was less than with the Hp control construct. These results further support the hypothesis that the Hp2-1mod phenotype results, in part, from the -61C mutation in the promoter region of the Hp[sup 2] gene.

  5. Interleukin 6 (IL-6) and IL-10 Promoter Region Polymorphisms Are Associated with Risk of Lumbar Disc Herniation in a Northern Chinese Han Population.

    PubMed

    Huang, Xiangye; Chen, Feng; Zhao, Jing; Wang, Dezhang; Jing, Shenfeng; Li, Hongmei; Meng, Chunyang

    2017-01-01

    This study assessed the association of single-nucleotide polymorphisms (SNPs) in the proinflammatory cytokines interleukin 6 (IL-6) and IL-10 with the risk of lumbar disc herniation in a Chinese Han population. We collected blood samples from 267 patients with lumbar disc herniation (case group) and 300 normals (control group) and performed analyses of the IL-6 572C/G and 174G/C SNPs as well as the IL-10 592A/C and 1082G/A SNPs using TaqMan technology. The frequencies of the IL-6-572 GG, GC, and CC genotypes were 5.99%, 42.3%, and 51.6%, respectively, in the case group, and 1.6%, 24%, and 64.3%, respectively, in the control group. Thus, the relative risk of the IL-6-572 G genotype (GG plus GC) was 1.69-fold higher for developing lumbar disc herniation compared to the CC genotype (95% confidence interval: 1.16-2.39, p < 0.01). The risks associated with the IL-6-572 CG and GG genotypes were 1.55- and 4.48-fold higher, respectively, versus the CC genotype for developing lumbar disc herniation (p < 0.01). The IL-10-1082 AG genotype was significantly higher in the case group (26.22%) versus the control group (11.67%); whereas the AA genotype was lower in the case group (73.78%) versus the control group (88.33%; p < 0.05). The IL-10-1082 G allele frequency was significantly higher in the case group (13.11%) versus the control group (5.83%; p < 0.05). This study demonstrates that genetic variants in the promoter regions of the IL-6 and IL-10 genes are associated with lumbar disc herniation risk in this Northern Chinese Han population.

  6. Rs12976445 Polymorphism is Associated with Risk of Diabetic Nephropathy Through Modulating Expression of MicroRNA-125 and Interleukin-6R

    PubMed Central

    Li, Cunjie; Lei, Ting

    2015-01-01

    Background Diabetic nephropathy (DN) is one of the most significant long-term complications of diabetes mellitus (DM), and it is a primary risk factor for end-stage renal disease. MicroRNAs (miRNAs) play important roles in regulating the expression of genes, including interleukin-6R (IL-6R), which has been reported to be involved in the development of DNDN. The aim of this study was to identify the dysregulation of miRNA and its target responsible for the development of DN in DM. Material/Methods We collected the kidney tissues from patients with DN (N=36) and control patients (N=28), and performed real-time PCR and Western blot analysis to determine the expression of IL-6R. Computational analysis and luciferase assay were used to identify the miRNA that regulates IL-6R. To explore the association between rs12976445 polymorphism and risk of DN, we enrolled 594 DM patients with (N=282) or without DN (N=312), and studied the association between a variant in miR-125a and risk of DN in DM. Results The expression of IL-6R was barely detected in the control groups, while in the DN group, the IL-6R was clearly detectable. Next, miR-125a was identified as a regulator of IL-6R by using informatics analysis and luciferase assay. A single-nucleotide polymorphism (rs12976445) in pri-miR-125a has been shown to compromise the mature processing of miR-125a, and we showed that the expression levels of miR-125a was comparable between individuals carrying TT and CT, and when combined into 1 group, the miR-125a expression was approximately 3 times lower than in the CC group. We found significant differences regarding rs12976445 genotype distribution between the DN and the control (OR=1.45, 95% C.I.=1.02–2.08, p<0.05) with the possible confounding factors adjusted for by using logistic regression analysis. Conclusions We identified miR-125a as a direct regulator of IL-6R, and the genotype of rs12976445 might be a novel predictor of the development of DN in DM. PMID:26563755

  7. Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis.

    PubMed

    Dar, Sajad Ahmad; Haque, Shafiul; Mandal, Raju Kumar; Singh, Taru; Wahid, Mohd; Jawed, Arshad; Panda, Aditya K; Akhter, Naseem; Lohani, Mohtashim; Areeshi, Mohammed Yahya; Rai, Gargi; Datt, Shyama; Bhattacharya, Sambit Nath; Ramachandran, Vishnampettai Ganapathysubramanian; Das, Shukla

    2017-05-01

    The association of interleukin-6 (IL-6)-174G > C (rs1800795) single nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) is a relevant issue because of conflicting and consensus lacking reports published in literature. We investigated IL-6-174G > C promoter polymorphism in 34 RA patients, attending a tertiary care hospital in north India. We also performed a meta-analysis, of the previously published studies reporting this genetic relationship, in overall population, and independently in Asian and Caucasian ethnicities to further elucidate this association. A total of 13 studies, including the current one, involving 3291 RA cases and 3812 controls were analyzed. Out of the 13 studies, 6 were from Asian, 6 from Caucasian and 1 from a mixed population. Our case-control study showed significant association of IL-6-174G > C SNP with increased RA risk: allelic (OR = 3.750, 95% CI = 1.800-7.813, p < 0.001); dominant (OR = 2.800, 95% CI = 1.167-6.721, p = 0.021); and recessive (OR = 36.72, 95% CI = 2.004-672.7, p = 0.015). The meta-analysis revealed the increased RA risk associated with IL-6-174G > C SNP in overall population: allelic (OR = 1.650, 95% CI = 1.169-2.329, p = 0.004); homozygous (OR = 1.380, 95% CI = 0.906-2.101, p = 0.133); heterozygous (OR = 1.559, 95% CI = 1.001-2.428, p = 0.049); dominant (OR = 1.663, 95% CI = 1.078-2.567, p = 0.022); and recessive (OR = 1.366, 95% CI = 0.964-1.935, p = 0.079). Subgroup analysis also showed this polymorphism to be associated with increased RA risk in Asian population: allelic (OR = 3.724, 95% CI = 1.361-10.190, p = 0.010); dominant (OR = 3.823, 95% CI = 1.320-11.074, p = 0.013); and recessive (OR = 4.357, 95% CI = 1.634-11.623, p = 0.003), but not in Caucasian population. This meta-analysis shows that IL-6-174G > C SNP is significantly

  8. Influence of the interleukin-6 -174 G/C gene polymorphism on exercise training-induced changes in glucose tolerance indexes.

    PubMed

    McKenzie, Jennifer A; Weiss, Edward P; Ghiu, Ioana A; Kulaputana, Onanong; Phares, Dana A; Ferrell, Robert E; Hagberg, James M

    2004-10-01

    A polymorphism in the IL-6 gene, a G-to-C substitution 176 bp upstream of the ATG translation initiation site, has been associated with diabetes prevalence and insulin resistance. Interventions including exercise training are frequently used to modify cardiovascular disease risk factors. Consequently, this project examined associations between the IL-6 -174 genotype and oral glucose tolerance test outcomes in 50- to 75-yr-old sedentary men and postmenopausal women before and after aerobic exercise training. Among the 87 individuals who started the study, 56 were retested after 6 mo of aerobic exercise training. Subject characteristics at baseline did not differ between the IL-6 genotype groups with the exception of fasting glucose, which was higher (P = 0.02, covariates age, gender, and ethnicity) in the CC genotype group. The training-induced change in glucose area under the curve during the oral glucose tolerance test varied between the IL-6 -174 genotype groups (P = 0.05, covariates age, gender, ethnicity, baseline glucose area under the curve, and percent body fat change) with a significant decrease occurring only in the GG genotype group. Insulin outcomes did not differ among the groups at baseline or after training. Training-induced changes in weight, percent body fat, maximal oxygen consumption, fasting glucose, and an insulin sensitivity index also changed similarly among the genotype groups. In conclusion, fasting glucose and the extent to which glucose tolerance changes with exercise training may be influenced by the IL-6 -174 gene polymorphism.

  9. Association between -174G/C and -572G/C interleukin 6 gene polymorphisms and severe radiographic damage to the hands of Mexican patients with rheumatoid arthritis: a preliminary report.

    PubMed

    Zavaleta-Muñiz, S A; Gonzalez-Lopez, L; Murillo-Vazquez, J D; Saldaña-Cruz, A M; Vazquez-Villegas, M L; Martín-Márquez, B T; Vasquez-Jimenez, J C; Sandoval-Garcia, F; Ruiz-Padilla, A J; Fajardo-Robledo, N S; Ponce-Guarneros, J M; Rocha-Muñoz, A D; Alcaraz-Lopez, M F; Cardona-Müller, D; Totsuka-Sutto, S E; Rubio-Arellano, E D; Gamez-Nava, J I

    2016-12-19

    Several interleukin 6 gene (IL6) polymorphisms are implicated in susceptibility to rheumatoid arthritis (RA). It has not yet been established with certainty if these polymorphisms are associated with the severe radiographic damage observed in some RA patients, particularly those with the development of joint bone ankylosis (JBA). The objective of the present study was to evaluate the association between severe radiographic damage in hands and the -174G/C and -572G/C IL6 polymorphisms in Mexican Mestizo people with RA. Mestizo adults with RA and long disease duration (>5 years) were classified into two groups according to the radiographic damage in their hands: a) severe radiographic damage (JBA and/or joint bone subluxations) and b) mild or moderate radiographic damage. We compared the differences in genotype and allele frequencies of -174G/C and -572G/C IL6 polymorphisms (genotyped using polymerase chain reaction-restriction fragment length polymorphism) between these two groups. Our findings indicated that the -174G/C polymorphism of IL6 is associated with severe joint radiographic damage [maximum likelihood odds ratios (MLE_OR): 8.03; 95%CI 1.22-187.06; P = 0.03], whereas the -572G/C polymorphism of IL6 exhibited no such association (MLE_OR: 1.5; 95%CI 0.52-4.5; P = 0.44). Higher anti-cyclic citrullinated peptide antibody levels were associated with more severe joint radiographic damage (P = 0.04). We conclude that there is a relevant association between the -174G/C IL6 polymorphism and severe radiographic damage. Future studies in other populations are required to confirm our findings.

  10. The −174G/C and −572G/C Interleukin 6 Promoter Gene Polymorphisms in Mexican Patients with Rheumatoid Arthritis: A Case-Control Study

    PubMed Central

    Zavaleta-Muñiz, S. A.; Martín-Márquez, B. T.; Gonzalez-Lopez, L.; Gonzalez-Montoya, N. G.; Díaz-Toscano, M. L.; Ponce-Guarneros, J. M.; Ruiz-Padilla, A. J.; Mercado, M. Vázquez-Del; Maldonado-González, M.; Fafutis-Morris, M.; Flores-Martínez, S. E.; Martínez-García, E. A.; Gamez-Nava, J. I.

    2013-01-01

    Objective. There is a lack of information about the genotype frequencies of IL-6 −174G/C and −572G/C polymorphisms in Mexicans with rheumatoid arthritis (RA). Therefore, the aim of this study was to evaluate the association of the IL-6 −174G/C and −572G/C polymorphisms in Mexican mestizo with RA. Methods. We included 137 patients with RA and 102 healthy controls. Patients were assessed for clinical characteristics. IL-6 −174G/C and −572G/C polymorphisms were genotyped using PCR-RFLP analysis. Allele and genotype frequencies and the Hardy-Weinberg equilibrium were computed. Odds ratios (ORs) were computed to identify the risk for RA associated with the presence of GG genotype in comparison with the GC or CC genotypes. Results. The genotype −174GG occurred at a higher frequency in cases and controls (77.4% versus 78.4%, P = 0.845). We found similar results for the genotype −572GG (54% in patients versus 60.8% in controls, P = 0.295). Conclusions. This is the first study to evaluate the association of −174G/C and −572G/C polymorphisms of the IL-6 gene with RA in Mexican mestizo patients. These two polymorphisms were not associated with RA in the studied sample. Additional studies are required to evaluate if these IL-6 polymorphisms have relevance to the development of more severe disease. PMID:24223608

  11. Cytokine gene polymorphism (interleukin-1β +3954, Interleukin-6 [-597/-174] and tumor necrosis factor-α -308) in chronic periodontitis with and without type 2 diabetes mellitus.

    PubMed

    Sharma, Nitin; Joseph, Rosamma; Arun, R; Chandni, R; Srinivas, K Lekshmy; Banerjee, Moinak

    2014-01-01

    Pro-inflammatory cytokine gene polymorphisms are potential candidates for susceptibility for both type 2 diabetes mellitus (DM) and chronic periodontitis (CHP). This study explored the association of interleukin-1 beta (IL-1 β) +3954, interleukin-6 (IL-6) -597/-174 and tumor necrosis factor-alpha (TNF-α) -308 single nucleotide polymorphisms in CHP with and without type 2 DM in Malayalam speaking subjects of Dravidian ethnicity. This case control study consisted of 51 chronic periodontitis with type 2 diabetes mellitus (CHPDM) and 51 CHP patients as cases and 51 healthy subjects as controls. Polymorphisms were identified by polymerase chain reaction amplification followed by restriction enzyme digestion and gel electrophoresis. IL-1 β (+3954) TT genotype and T allele were significantly associated with CHPDM group when compared with CHP (P = 0.001), whereas CC genotype and allele C was higher in CHP subjects (P = 0.001). For IL-6 (-597) frequency of genotype GA/AA (P = 0.04) and allele A (P = 0.01) was lower in CHPDM group, and for TNF-α -308 the frequency of genotype GA (P = 0.01) and allele A (P = 0.01) was higher in CHP subjects when compared with controls. In Malayalam speaking Dravidian population, IL-6 (-597) genotype GA/AA and allele A appears to be protective for CHP with type 2 DM. Allele C of IL-1 β +3954 and allele A of TNF-α -308 appears to be risk factors for CHP individuals.

  12. The -174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis

    PubMed Central

    Ruiz-Padilla, A. J.; Saldaña-Cruz, A. M.; Murillo-Vazquez, J. D.; Vazquez-Villegas, M. L.; Ponce-Guarneros, J. M.; Flores-Chavez, A.; Sandoval-Garcia, F.; Vasquez-Jimenez, J. C.; Totsuka-Sutto, S. E.

    2016-01-01

    Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07–1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05–2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07–3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03–1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF. PMID:27738630

  13. The -174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis.

    PubMed

    Ruiz-Padilla, A J; Gamez-Nava, J I; Saldaña-Cruz, A M; Murillo-Vazquez, J D; Vazquez-Villegas, M L; Zavaleta-Muñiz, S A; Martín-Márquez, B T; Ponce-Guarneros, J M; Rodriguez Jimenez, N A; Flores-Chavez, A; Sandoval-Garcia, F; Vasquez-Jimenez, J C; Cardona-Muñoz, E G; Totsuka-Sutto, S E; Gonzalez-Lopez, L

    2016-01-01

    Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07-1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05-2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07-3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03-1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF.

  14. Interleukin-6 Detection with a Plasmonic Chip

    NASA Astrophysics Data System (ADS)

    Tawa, Keiko; Sumiya, Masashi; Toma, Mana; Sasakawa, Chisato; Sujino, Takuma; Miyaki, Tatsuki; Nakazawa, Hikaru; Umetsu, Mitsuo

    Interleukin-6, a cytokine relating inflammatory and autoimmune activity, was detected with three fluorescence assays using a plasmonic chip. In their assays, the way of surface modification, sample volume, incubation time and mixing solution, were found to influence the detection sensitivity. When the assay was revised in the point of a rapid and easy process, the detection sensitivity was not compromised compared to assays with sufficient sample volume and assay time. To suit the purpose of immunosensing, the assay conditions should be determined.

  15. Involvement of Interleukin 6 in Hepatitis B Viral Infection.

    PubMed

    Xia, Caixia; Liu, Yanning; Chen, Zhi; Zheng, Min

    2015-01-01

    Hepatitis B is a major global health problem and a potentially life-threatening liver infection caused by hepatitis B virus (HBV). Many cytokines including interleukin 6 (IL-6) have been shown to be involved in the HBV infection process. IL-6 is a typical cytokine made up of 184 amino acids, and the gene is located in chromosome 7p21. For healthy people, serum IL-6 levels are usually too low to be detected. However, dysregulated synthesis of IL-6 has been discovered in chronic inflammatory diseases such as hepatitis B, Crohn's disease and rheumatoid arthritis. IL-6 also plays an important role in HBV replication and in the development of hepatitis B disease. This review aims to present the latest discoveries concerning the role of IL-6 in hepatitis B disease progression, and HBV entry and replication, and evaluate polymorphisms that are associated with the development of hepatitis B disease.

  16. Targeting interleukin-6 for noninfectious uveitis.

    PubMed

    Lin, Phoebe

    2015-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in the pathogenesis of many immune-mediated disorders including several types of non-infectious uveitis. These uveitic conditions include Vogt-Koyanagi-Harada syndrome, uveitis associated with Behçet disease, and sarcoidosis. This review summarizes the role of IL-6 in immunity, highlighting its effect on Th17, Th1, and plasmablast differentiation. It reviews the downstream mediators activated in the process of IL-6 binding to its receptor complex. This review also summarizes the biologics targeting either IL-6 or the IL-6 receptor, including tocilizumab, sarilumab, sirukumab, olokizumab, clazakizumab, and siltuximab. The target, dosage, potential side effects, and potential uses of these biologics are summarized in this article based on the existing literature. In summary, anti-IL-6 therapy for non-infectious uveitis shows promise in terms of efficacy and side effect profile.

  17. Polymorphisms of −174G>C and −572G>C in the Interleukin 6 (IL-6) Gene and Coronary Heart Disease Risk: A Meta-Analysis of 27 Research Studies

    PubMed Central

    Zheng, Guo-hua; Chen, Hai-ying; Xiong, Shang-Quan

    2012-01-01

    Objective Elevated serum IL-6 level is a risk factor for coronary heart disease (CHD). The −174G>C and −572G>C polymorphisms in the IL-6 gene have previously been shown to modulate IL-6 levels. But the association between the −174G>C and −572G>C polymorphisms and the risk of CHD is still unclear. A meta-analysis of all eligible studies was carried out to clarify the role of IL-6 gene polymorphisms in CHD. Methods and Results PubMed, EMBASE, Vip, CNKI and CBM-disc were searched for eligible articles in English and Chinese that were published before October 2010. 27 studies involving 11580 patients with CHD and 17103 controls were included. A meta-analysis was performed for the included articles using the RevMan 5.0 and Stata 10.0 softwares. Overall, the −174C allele was not significantly associated with CHD risk (ORs = 1.04, 95%CI = 0.98 to 1.10) when compared with the −174G allele in the additive model, and meta-analysis under other genetic models (dominant, recessive, CC versus GG, and GC versus GG) also did not reveal any significant association. On the contrary, the −572C allele was associated with a decreased risk of CHD when compared with the −572G allele (ORs = 0.79, 95%CI = 0.68 to 0.93). Furthermore, analyses under the recessive model (ORs = 0.69, 95% = 0.59 to 0.80) and the allele contrast model (genotype of CC versus GG, ORs = 0.49, 95% = 0.35 to 0.70) yielded similar results. However, statistical significance was not found when the meta-analysis was restricted to studies focusing on European populations, studies with large sample size, and cohort studies by using subgroup analysis. Conclusions The −174G>C polymorphism in the IL-6 gene is not significantly associated with increased risks of CHD. However, The −572G>C polymorphism may contribute to CHD development. Future investigations with better study design and large number of subjects are needed. PMID:22509361

  18. Association between interleukin 6 -174 G/C promoter gene polymorphism and runners' responses to the dietary ingestion of antioxidant supplementation based on pequi (Caryocar brasiliense Camb.) oil: a before-after study

    PubMed Central

    Miranda-Vilela, Ana Luisa; Ribeiro, Ieler Ferreira; Grisolia, Cesar Koppe

    2016-01-01

    Abstract Exercise is a double-edged sword: when practiced in moderation, it increases the expression of antioxidant enzymes, but when practiced strenuously it causes oxidative stress and cell damage. In this context, polymorphisms in the interleukin (IL)-6 gene should be investigated better because they can influence performance, at least in exercise that generates oxidative stress and leads to muscular injuries with consequent inflammation. In this work, we investigated the influence of IL-6 –174 G/C polymorphism on tissue damage and inflammation markers, lipid peroxidation, hemogram and lipid profile of runners before and after ingestion of 400 mg of pequi oil in capsules supplied daily for 14 consecutive days. The IL-6 genotypes were associated with significant differences in lipid peroxidation, with the CC mutant having lower values. There were also significant differences among these genotypes in the response to supplementation with pequi oil, exercise-induced damage and C-reactive protein (CRP) levels. The best protection against damage was observed with the heterozygous genotype. Although the CC genotype showed an increase in CRP levels after supplementation, the lack of a positive correlation between triglycerides and high-sensitivity CRP in this mutant genotype after supplementation indicated a protective effect of pequi. These findings deserve further investigation, particularly with regard to the quantification of circulating IL-6 concentrations. PMID:27727360

  19. Interleukin-6 blockade in ocular inflammatory diseases

    PubMed Central

    Mesquida, M; Leszczynska, A; Llorenç, V; Adán, A

    2014-01-01

    Interleukin-6 (IL-6) is a key cytokine featuring redundancy and pleiotropic activity. It plays a central role in host defence against environmental stress such as infection and injury. Dysregulated, persistent interleukin (IL)-6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers. Significant elevation of IL-6 has been found in ocular fluids derived from refractory/chronic uveitis patients. In experimental autoimmune uveitis models with IL-6 knock-out mice, IL-6 has shown to be essential for inducing inflammation. IL-6 blockade can suppress acute T helper type 17 (Th17) responses via its differentiation and, importantly, can ameliorate chronic inflammation. Tocilizumab, a recombinant humanized anti-IL-6 receptor antibody, has been shown to be effective in several autoimmune diseases, including uveitis. Herein, we discuss the basic biology of IL-6 and its role in development of autoimmune conditions, focusing particularly on non-infectious uveitis. It also provides an overview of efficacy and safety of tocilizumab therapy for ocular inflammatory diseases. PMID:24528300

  20. Interleukin-6, age, and corpus callosum integrity.

    PubMed

    Bettcher, Brianne M; Watson, Christa L; Walsh, Christine M; Lobach, Iryna V; Neuhaus, John; Miller, Joshua W; Green, Ralph; Patel, Nihar; Dutt, Shubir; Busovaca, Edgar; Rosen, Howard J; Yaffe, Kristine; Miller, Bruce L; Kramer, Joel H

    2014-01-01

    The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories.

  1. Interleukin-6: a cytokine to forget.

    PubMed

    Balschun, D; Wetzel, W; Del Rey, A; Pitossi, F; Schneider, H; Zuschratter, W; Besedovsky, H O

    2004-11-01

    It is known that proinflammatory cytokines such as interleukin-6 (IL-6) are expressed in the central nervous system (CNS) during disease conditions and affect several brain functions including memory and learning. In contrast to these effects observed during pathological conditions, here we describe a physiological function of IL-6 in the "healthy" brain in synaptic plasticity and memory consolidation. During long-term potentiation (LTP) in vitro and in freely moving rats, IL-6 gene expression in the hippocampus was substantially increased. This increase was long lasting, specific to potentiation, and was prevented by inhibition of N-methyl-D-aspartate receptors with (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Blockade of endogenous IL-6 by application of a neutralizing anti-IL-6 antibody 90 min after tetanus caused a remarkable prolongation of LTP. Consistently, blockade of endogenous IL-6, 90 min after hippocampus-dependent spatial alternation learning resulted in a significant improvement of long-term memory. In view of the suggested role of LTP in memory formation, these data implicate IL-6 in the mechanisms controlling the kinetics and amount of information storage.

  2. Interleukin-6: structure-function relationships.

    PubMed Central

    Simpson, R. J.; Hammacher, A.; Smith, D. K.; Matthews, J. M.; Ward, L. D.

    1997-01-01

    Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-11, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor, and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affinity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines. PMID:9144766

  3. Interleukin-6, Age, and Corpus Callosum Integrity

    PubMed Central

    Bettcher, Brianne M.; Watson, Christa L.; Walsh, Christine M.; Lobach, Iryna V.; Neuhaus, John; Miller, Joshua W.; Green, Ralph; Patel, Nihar; Dutt, Shubir; Busovaca, Edgar; Rosen, Howard J.; Yaffe, Kristine; Miller, Bruce L.; Kramer, Joel H.

    2014-01-01

    The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories. PMID:25188448

  4. Circulating interleukin-6 and rheumatoid arthritis

    PubMed Central

    Li, Bing; Xiao, Yu; Xing, Dan; Ma, Xin-long; Liu, Jun

    2016-01-01

    Abstract Interleukin-6 (IL-6), as a pleiotropic cytokine, has been demonstrated to be closely associated with the pathogenisis of rheumatoid arthritis (RA). However, whether this association is causal or not remains unclear, because of the multifactorial role of IL-6 and related confounding factors. We aimed to evaluate the causal relevance between circulating IL-6 levels and the risk of RA through meta-analytical Mendelian randomization approach. IL-6 gene -174G/C variant was selected as an instrument in this Mendelian randomization meta-analysis. Article identification and data collection were conducted in duplicate and independently by 2 authors. The STATA software was used for data analysis. In total, 15 and 5 articles on the association of the -174G/C variant with RA risk and circulating IL-6 level, respectively, were included. The overall analysis showed that C allelic and GC+CC genotype were significantly with 1.59-fold (95% CI: 1.19–2.14) and 1.63-fold (95% CI: 1.17–2.26) increased risk of developing RA, respectively. Asian populations showed stronger association with 4.55-fold (95% CI: 1.62–12.75), 1.84-fold (95% CI: 1.13–2.99), and 4.69-fold (95% CI: 1.68–13.14) increased RA risk in carriers of -174C allelic, CC, and GC+CC genotype, respectively. Carriers of GC+CC genotype showed significant reduction in the circulating IL-6 level compared with GG carriers (WMD = −0.77; 95% CI: −1.16 to −0.38; P = 0.000) in overall populations. Mendelian randomization presented 6% and 22% increased risk of RA with 0.1 pg/mL reduction of circulating IL-6 level in overall and Asian populations, respectively. This Mendelian randomization meta-analysis demonstrated that the long-term genetically reduced circulating IL-6 level might be causally related to a higher risk of RA, especially in Asian populations. PMID:27281095

  5. Essential role of interleukin-6 in post-stroke angiogenesis

    PubMed Central

    Gertz, Karen; Kronenberg, Golo; Kälin, Roland E.; Baldinger, Tina; Werner, Christian; Balkaya, Mustafa; Eom, Gina D.; Hellmann-Regen, Julian; Kröber, Jan; Miller, Kelly R.; Lindauer, Ute; Laufs, Ulrich; Dirnagl, Ulrich; Heppner, Frank L.

    2012-01-01

    Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6−/−) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6−/− mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6−/− mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6−/− mice. In addition, systemic neoangiogenesis was impaired in IL-6−/− mice. Transplantation of interleukin-6 competent bone marrow into IL-6−/− mice (IL-6chi) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6chi mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case

  6. Aptamer conjugated silver nanoparticles for the detection of interleukin 6

    NASA Astrophysics Data System (ADS)

    Locke, Andrea K.; Norwood, Nicole; Marks, Haley L.; Schechinger, Monika; Jackson, George W.; Graham, Duncan; Coté, Gerard L.

    2016-03-01

    The controlled assembly of plasmonic nanoparticles by a molecular binding event has emerged as a simple yet sensitive methodology for protein detection. Metallic nanoparticles (NPs) coated with functionalized aptamers can be utilized as biosensors by monitoring changes in particle optical properties, such as the LSPR shift and enhancement of the SERS spectra, in the presence of a target protein. Herein we test this method using two modified aptamers selected for the protein biomarker interleukin 6, an indicator of the dengue fever virus and other diseases including certain types of cancers, diabetes, and even arthritis. IL6 works by inducing an immunological response within the body that can be either anti-inflammatory or pro-inflammatory. The results show that the average hydrodynamic diameter of the NPs as measured by Dynamic Light Scattering was ~42 nm. After conjugation of the aptamers, the peak absorbance of the AgNPs shifted from 404 to 408 nm indicating a surface modification of the NPs due to the presence of the aptamer. Lastly, preliminary results were obtained showing an increase in SERS intensity occurs when the IL-6 protein was introduced to the conjugate solution but the assay will still need to be optimized in order for it to be able to monitor varying concentration changes within and across the desired range.

  7. Metabolites associated with circulating interleukin-6 in older adults

    USDA-ARS?s Scientific Manuscript database

    Background: Circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) levels are elevated in older adults, but mechanisms are unclear. In the current study, we used an untargeted metabolomic approach to develop an improved understanding about mechanisms related to circulating IL-6 in ...

  8. Hemiconvulsion-hemiplegia syndrome and elevated interleukin-6: case report.

    PubMed

    Kimura, Masahiko; Tasaka, Masaru; Sejima, Hitoshi; Takusa, Yuichi; Ichiyama, Takashi; Yamaguchi, Seiji

    2002-09-01

    We report a 2-year-old boy who developed hemiconvulsion-hemiplegia syndrome with left-sided hemiplegia after a seizure lasting 35 minutes. The interleukin-6 level in the cerebrospinal fluid 2 hours after seizure onset was elevated to levels seen in patients with encephalitis. At 1 year after onset of the seizure, the patient remained hemiplegic on the left side, and magnetic resonance imaging showed severe right hemispheric atrophy. Acute changes seen on imaging studies and electroencephalograms in this patient were consistent with seizure-induced brain damage. Elevation of cerebrospinal fluid interleukin-6 may be related to the severe neurologic sequelae of our patient despite the relatively short seizure duration.

  9. Induction of Interleukin-6 During Human Immunodeficiency Virus Infection

    DTIC Science & Technology

    1990-12-01

    is induced by a harbored HIV capable of replicating in T cells but not in variety of stimuli, including bacteria , viruses , and other monocyte...different signals, such as bacteria , serum IL-6 levels. bacterial products, viruses , and certain cytokines." IL-6 stimulates liver cell cultures to produce a...COVERED "’I’ ~ ~ ~ ~ 99 Reprint1 111 111111 itli S. FUNDING NUMBERS Induction of Interleukin-6 During Human Immunodeficiency . G/ ) Virus Infection

  10. [POEMS syndrome: role and value of interleukin-6].

    PubMed

    Andrès, E; Courouau, F; Kaltenbach, G; Maloisel, F; Imler, M

    1996-01-01

    POEMS syndrome is a systemic disorder with peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. The association of POEMS syndrome with lympho-proliferative disorder is very commun. The pathogenesis remains poorly understood but implication of cytokines (interleukins 1 and 6) is suspected. We report a case of a classic POEMS syndrome (with polyneuropathy, hepatomegaly, diabetes melitus, hyperpigmentation, monoclonal IgG lambda, anasarca and solitary plasmocytoma), associated with high serum levels of interleukin 6.

  11. Mechanisms by which interleukin-6 attenuates cell invasion and tumorigenesis in human bladder carcinoma cells.

    PubMed

    Tsui, Ke-Hung; Wang, Shyi-Wu; Chung, Li-Chuan; Feng, Tsui-Hsia; Lee, Tzu-Yi; Chang, Phei-Lang; Juang, Horng-Heng

    2013-01-01

    Interleukin-6, a multifunctional cytokine, contributes to tumor cell proliferation and differentiation. However, the biological mechanisms that are affected by the expression of interleukin-6 in bladder cancer cells remain unclear. We evaluated the effects of interleukin-6 expression in human bladder carcinoma cells in vitro and in vivo. The results of interleukin-6-knockdown experiments in T24 cells and interleukin-6-overexpression experiments in HT1376 cells revealed that interleukin-6 reduced cell proliferation, migration, and invasion in vitro. Xenograft animal studies indicated that the overexpression of interleukin-6 downregulated tumorigenesis of bladder cells and that interleukin-6 knockdown reversed this effect. The results of RT-PCR, immunoblotting, and reporter assays indicated that the overexpression of interleukin-6 upregulated the expression of the mammary serine protease inhibitor (MASPIN), N-myc downstream gene 1 (NDRG1), and KAI1 proteins in HT1376 cells and that interleukin-6 knockdown reduced the expression of these proteins in T24 cells. In addition, results of immunoblotting assays revealed that interleukin-6 modulated epithelial-mesenchymal transitions by upregulating the expression of the E-cadherin, while downregulation N-cadherin and vimentin proteins. Our results suggest that the effects of interleukin-6 on the regulation of epithelial-mesenchymal transitions and the expressions of the MASPIN, NDRG1, and KAI1 genes attribute to the modulation of tumorigenesis in human bladder carcinoma cells.

  12. Random amplified polymorphic DNA analysis of genetically modified organisms.

    PubMed

    Yoke-Kqueen, Cheah; Radu, Son

    2006-12-15

    Randomly amplified polymorphic DNA (RAPD) was used to analyzed 78 samples comprises of certified reference materials (soya and maize powder), raw seeds (soybean and maize), processed food and animal feed. Combination assay of two arbitrary primers in the RAPD analysis enable to distinguish genetically modified organism (GMO) reference materials from the samples tested. Dendrogram analysis revealed 13 clusters at 45% similarity from the RAPD. RAPD analysis showed that the maize and soybean samples were clustered differently besides the GMO and non-GMO products.

  13. CSF interleukin-6 in neonatal Citrobacter ventriculitis after meningitis.

    PubMed

    Baumeister, F A; Hofer, M; Küster, H; Belohradsky, B H

    2000-01-01

    An infant with neonatal severe Citrobacter koseri (formerly Citrobacter diversus) meningoencephalitis developed necrosis with multicystic regression of both hemispheres. The ventriculitis persisted over months in spite of antibiotic therapy. The treatment succeeded with cefotaxime in a high dose (300 mg/kg/day) without surgical intervention. The infant had been previously treated with cefotaxime (200 mg/kg/day) over 5 weeks. High levels of CSF interleukin-6 (IL-6) permitted to attribute persisting CSF pleocytosis in spite of sterile CSF cultures to chronic infection and not to reminiscence of brain necrosis. This report reveals two main points. On the one hand, the importance of therapy monitoring with IL-6 in CSF for the consequent treatment of Citrobacter meningitis and on the other hand, high-dose cefotaxime (300 mg/kg/day) treatment of Citrobacter ventriculitis, which succeeded without surgical intervention.

  14. Interleukin-6 serum levels in patients with Parkinson's disease.

    PubMed

    Hofmann, Kerly Wollmeister; Schuh, Artur Francisco Schumacher; Saute, Jonas; Townsend, Raquel; Fricke, Daniele; Leke, Renata; Souza, Diogo O; Portela, Luis Valmor; Chaves, Márcia Lorena Fagundes; Rieder, Carlos R M

    2009-08-01

    Several lines of evidence suggest that neuroimmune mechanisms may be involved in the neurodegenerative process of Parkinson's disease (PD). Interleukin-6 (IL-6) is increased in the nigrostriatal region and in the cerebrospinal fluid of patients with PD. IL-6 serum level was evaluated in PD patients. The effects of levodopa treatment and disease severity on IL-6 were also studied. The IL-6 levels were similar between PD patients (treated and not treated) and controls. However, there was a negative correlation of IL-6 levels and the activities of daily living scale (P < 0.05), indicating that patients with more severe disease have higher levels of this cytokine. No correlation involving levodopa treatment and IL-6 serum level was found. The results suggest that only marginal effects of IL-6 occur on the peripheral immune system, and that the role of IL-6 and others neuroimmune factors needs to be well elucidated on PD.

  15. Interleukin-6-producing dermoid cyst associated with multicentric Castleman's disease.

    PubMed

    Ebara, Shigeyuki; Song, Soken-Nakazawa J; Mizuta, Hiroyuki; Ito, Yasushi; Hasegawa, Kenji; Kamata, Tsuneko; Matsumura-Nishikawa, Teppei; Ogawa, Takafumi; Soneda, Jyunichi; Yoshizaki, Kazuyuki

    2012-02-01

    Dysregulated overproduction of interleukin-6 (IL-6) from activated B cells in affected lymph nodes has been implicated in the pathogenesis of multicentric Castleman's disease (MCD), a rare lymphoproliferative disorder accompanied by systemic manifestations. We here report the case of a 32-year-old female presenting with MCD associated with a dermoid cyst in the pelvic cavity. The co-occurrence of MCD and dermoid cyst has not been reported before. Immunohistochemical analysis of the tissue sections showed IL-6 production in CD68-positive macrophage cells, which had infiltrated the dermoid cyst. Removal of the cyst resulted in partial improvement in systemic symptoms accompanied by a decrease in serum IL-6, while complete improvement was obtained by treatment with an anti-IL-6 receptor antibody following resection of the dermoid cyst. To the best of our knowledge, this is the first study to provide evidence of IL-6 production by CD68(+) cells in a dermoid cyst involved in MCD.

  16. Intraperitoneal secretion of interleukin-6 during continuous ambulatory peritoneal dialysis.

    PubMed

    Goldman, M; Vandenabeele, P; Moulart, J; Amraoui, Z; Abramowicz, D; Nortier, J; Vanherweghem, J L; Fiers, W

    1990-01-01

    Interleukin-6 (IL-6) was determined in serum and peritoneal dialysis effluent (PDE) of patients on chronic ambulatory peritoneal dialysis (CAPD) by a biological assay measuring the proliferation of the IL-6-dependent 7TD1 cell line. Six patients free of peritonitis displayed low but significant levels of IL-6 (mean +/- 42 pg/ml) in PDE, while IL-6 was undetectable in serum. In 6 patients with staphylococcal peritonitis, a tremendous increase in PDE levels of IL-6 was noted (range: 5,832-37,491 pg/ml), while serum IL-6 remained either undetectable or on a low level except in one case. After 5 days of antibiotic treatment, IL-6 levels in PDE returned to basal values. We conclude that CAPD results in an intraperitoneal secretion of IL-6 which is markedly but transiently increased during peritonitis episodes.

  17. Interleukin-6 participation in pathology of ocular diseases.

    PubMed

    Zahir-Jouzdani, Forouhe; Atyabi, Fatemeh; Mojtabavi, Nazanin

    2017-09-01

    Interleukin-6 (IL-6) is a multifunctional cytokine that affects a variety of cells in the body such as osteoclasts, hepatocytes, endothelial cells, epithelial cells, white and red blood cells and etc. Elevated levels of IL-6 have been detected in many ocular diseases. Studies show that IL-6 has a major role in the pathology of glaucoma, CRVO, macular edema, ocular neovascularization, posterior capsule opacity formation, keratitis, dry eye disease, allergic eye disease, ocular autoimmune disease, corneal chemical burn, ocular inflammation and so on. IL-6 does its effects through the classic or trans-signal pathways in cells. Blocking of IL-6 signal pathways via Tocilizumab or other chemicals and therapeutics will help to overcome complications related to ocular diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. An interleukin-6-producing cardiac myxoma associated with mediastinal lymphadenopathy.

    PubMed

    Takizawa, T; Sumino, H; Kanda, T; Kobayashi, I; Nagai, R; Ichikawa, S

    1999-01-01

    We report our experience with a patient whose mediastinal lymphadenopathy resolved after resection of a cardiac myxoma that secreted interleukin-6 (IL-6). The patient was a 68-year-old female who complained of nocturnal chest discomfort related to congestive heart failure. An echocardiogram demonstrated a large left atrial mass. A computed tomogram showed not only the left atrial mass but multiple enlarged mediastinal lymph nodes. The serum IL-6 level was markedly elevated at 13.7 pg/ml. After resection of the cardiac myxoma, serum IL-6 returned to the normal range. A repeat computed tomogram showed no mediastinal lymphadenopathy. We believe that overproduction of IL-6 by the cardiac myxoma was the cause of the mediastinal lymphadenopathy.

  19. Fatigue and interleukin-6 - a multi-faceted relationship.

    PubMed

    Grygiel-Górniak, Bogna; Puszczewicz, Mariusz

    2015-01-01

    Many connective tissue diseases are characterized by fatigue, which is described in the literature as prostration, weakness, lassitude or asthenia. In many other diseases (autoimmune, neurologic or metabolic) fatigue impinges on daily activities and thus influences the quality of life. Different molecular backgrounds are involved in the development of fatigue. Not only does the immunosuppressive treatment of autoimmune diseases reduce fatigue, but also selective nutritional components may have an effect on secretion of cytokines which are responsible for development of the sensation of tiredness (e.g. secretion of interleukin-6). The beneficial influence of selected food components (such as polyunsaturated omega-3 fatty acids, nutritional antioxidants or adequate fat intake with the diet) on proinflammatory cytokine secretion has been demonstrated in many studies. In this review, the biochemical, neurological and nutritional aspects of fatigue in autoimmune diseases are underlined.

  20. The intrinsic microglial clock system regulates interleukin-6 expression.

    PubMed

    Nakazato, Ryota; Hotta, Shogo; Yamada, Daisuke; Kou, Miki; Nakamura, Saki; Takahata, Yoshifumi; Tei, Hajime; Numano, Rika; Hida, Akiko; Shimba, Shigeki; Mieda, Michihiro; Hinoi, Eiichi; Yoneda, Yukio; Takarada, Takeshi

    2017-01-01

    Similar to neurons, microglia have an intrinsic molecular clock. The master clock oscillator Bmal1 modulates interleukin-6 upregulation in microglial cells exposed to lipopolysaccharide. Bmal1 can play a role in microglial inflammatory responses. We previously demonstrated that gliotransmitter ATP induces transient expression of the clock gene Period1 via P2X7 purinergic receptors in cultured microglia. In this study, we further investigated mechanisms underlying the regulation of pro-inflammatory cytokine production by clock molecules in microglial cells. Several clock gene transcripts exhibited oscillatory diurnal rhythmicity in microglial BV-2 cells. Real-time luciferase monitoring also showed diurnal oscillatory luciferase activity in cultured microglia from Per1::Luciferase transgenic mice. Lipopolysaccharide (LPS) strongly induced the expression of pro-inflammatory cytokines in BV-2 cells, whereas an siRNA targeting Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), a core positive component of the microglial molecular clock, selectively inhibited LPS-induced interleukin-6 (IL-6) expression. In addition, LPS-induced IL-6 expression was attenuated in microglia from Bmal1-deficient mice. This phenotype was recapitulated by pharmacological disruption of oscillatory diurnal rhythmicity using the synthetic Rev-Erb agonist SR9011. Promoter analysis of the Il6 gene revealed that Bmal1 is required for LPS-induced IL-6 expression in microglia. Mice conditionally Bmal1 deficient in cells expressing CD11b, including microglia, exhibited less potent upregulation of Il6 expression following middle cerebral artery occlusion compared with that in control mice, with a significant attenuation of neuronal damage. These results suggest that the intrinsic microglial clock modulates the inflammatory response, including the positive regulation of IL-6 expression in a particular pathological situation in the brain, GLIA 2016. GLIA 2017;65:198-208.

  1. An autoinflammatory neurological disease due to interleukin 6 hypersecretion

    PubMed Central

    2013-01-01

    Autoinflammatory diseases are rare illnesses characterized by apparently unprovoked inflammation without high-titer auto-antibodies or antigen-specific T cells. They may cause neurological manifestations, such as meningitis and hearing loss, but they are also characterized by non-neurological manifestations. In this work we studied a 30-year-old man who had a chronic disease characterized by meningitis, progressive hearing loss, persistently raised inflammatory markers and diffuse leukoencephalopathy on brain MRI. He also suffered from chronic recurrent osteomyelitis of the mandible. The hypothesis of an autoinflammatory disease prompted us to test for the presence of mutations in interleukin-1−pathway genes and to investigate the function of this pathway in the mononuclear cells obtained from the patient. Search for mutations in genes associated with interleukin-1−pathway demonstrated a novel NLRP3 (CIAS1) mutation (p.I288M) and a previously described MEFV mutation (p.R761H), but their combination was found to be non-pathogenic. On the other hand, we uncovered a selective interleukin-6 hypersecretion within the central nervous system as the likely pathogenic mechanism. This is also supported by the response to the anti-interleukin-6−receptor monoclonal antibody tocilizumab, but not to the recombinant interleukin-1−receptor antagonist anakinra. Exome sequencing failed to identify mutations in other genes known to be involved in autoinflammatory diseases. We propose that the disease described in this patient might be a prototype of a novel category of autoinflammatory diseases characterized by prominent neurological involvement. PMID:23432807

  2. Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults1–3

    PubMed Central

    Mukamal, Kenneth J; Jenny, Nancy S; Tracy, Russell P; Siscovick, David S

    2007-01-01

    Background Whether alcohol intake is associated with concentrations of interleukin-6 (IL-6) and serum amyloid P (SAP) is uncertain. Objective We determined how alcohol intake and apolipoprotein E (apo E) and IL-6 promoter (IL-6 -174G→C) polymorphisms interact for concentrations of IL-6 and SAP. Design In the Cardiovascular Health Study, 2454 older adults reported their intake of beer, wine, and liquor and underwent measurements of circulating IL-6 and SAP. Results Alcohol intake was not associated with IL-6 concentrations among apo E4-negative or IL-6C-positive participants but was positively associated among both apo E4-positive and IL-6C-negative participants (P for trend = 0.02 for both). The corresponding interactions on SAP were not significant for alcohol overall but were similar for liquor intake. Conclusions Among older adults free of clinical cardiovascular disease, specific IL-6 promoter and apo E alleles appeared to confer positive associations of alcohol consumption with IL-6 concentrations. Genetic heterogeneity should be considered in understanding the cardiovascular effects of alcohol intake. PMID:17684217

  3. Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth

    PubMed Central

    Burger, Renate; Günther, Andreas; Klausz, Katja; Staudinger, Matthias; Peipp, Matthias; Penas, Eva Maria Murga; Rose-John, Stefan; Wijdenes, John; Gramatzki, Martin

    2017-01-01

    Interleukin-6 has an important role in the pathophysiology of multiple myeloma where it supports the growth and survival of the malignant plasma cells in the bone marrow. It belongs to a family of cytokines which use the glycoprotein 130 chain for signal transduction, such as oncostatin M or leukemia inhibitory factor. Targeting interleukin-6 in plasma cell diseases is currently evaluated in clinical trials with monoclonal antibodies. Here, efforts were made to elucidate the contribution of interleukin-6 and glycoprotein 130 signaling in malignant plasma cell growth in vivo. In the xenograft severe combined immune deficiency model employing our interleukin-6-dependent plasma cell line INA-6, the lack of human interleukin-6 induced autocrine interleukin-6 production and a proliferative response to other cytokines of the glycoprotein 130 family. Herein, mice were treated with monoclonal antibodies against human interleukin-6 (elsilimomab/B-E8), the interleukin-6 receptor (B-R6), and with an antibody blocking glycoprotein 130 (B-R3). While treatment of mice with interleukin-6 and interleukin-6 receptor antibodies resulted in a modest delay in tumor growth, the development of plasmacytomas was completely prevented with the anti-glycoprotein 130 antibody. Importantly, complete inhibition was also achieved using F(ab’)2-fragments of monoclonal antibody B-R3. Tumors harbor activated signal transducer and activator of transcription 3, and in vitro, the antibody inhibited leukemia inhibitory factor stimulated signal transducer and activator of transcription 3 phosphorylation and cell growth, while being less effective against interleukin-6. In conclusion, the growth of INA-6 plasmacytomas in vivo under interleukin-6 withdrawal remains strictly dependent on glycoprotein 130, and other glycoprotein 130 cytokines may substitute for interleukin-6. Antibodies against glycoprotein 130 are able to overcome this redundancy and should be explored for a possible therapeutic window

  4. Hepatocyte Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis

    DTIC Science & Technology

    2005-03-01

    AD Award Number: DAMD17-02-1-0159 TITLE: Hepatocyte Growth Factor and Interleukin - 6 in Prostate Cancer Bone Metastasis PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE 5. FUNDING NUMBERS Hepatocyte Growth Factor and Interleukin - 6 in Prostate DAMD17-02-1-0159 Cancer Bone Metastasis 6 . AUTHOR(S...DAMD17-02-1-0159 "Hepatocyte Growth Factor and Interleukin - 6 in Prostate Cancer Bone Metastasis" INTRODUCTION: The hypothesis of this grant proposal

  5. Interleukin 6 stimulates hepatic glucose release from prelabeled glycogen pools

    SciTech Connect

    Ritchie, D.G. )

    1990-01-01

    Cytokines, derived from a wide variety of cell types, are now believed to initiate many of the physiological responses accompanying the inflammatory phase that follows either Gram-negative septicemia or thermal injury. Because hypoglycemia (after endotoxic challenge) and hyperglycemia (after thermal injury) represent well-characterized responses to these injuries, we sought to determine whether hepatic glycogen metabolism could be altered by specific cytokines. Cultured adult rat hepatocytes were prelabeled with ({sup 14}C)glucose for 24 h, a procedure that resulted in the labeling of hepatic glycogen pools that subsequently could be depleted (with concomitant ({sup 14}C)glucose release) by either glucagon or norepinephrine. After the addition of a highly concentrated human monocyte-conditioned medium (MCM) or various cytokines to these prelabeled cells, ({sup 14}C)glucose release was stimulated by MCM and recombinant human interleukin 6 (IL-6) but was not stimulated by other cytokines tested. Furthermore, only antisera to IL-6 were capable of reducing the glucose-releasing factor activity found in MCM. These data therefore suggest a novel glucoregulatory role for IL-6.

  6. Interleukin 6 in intact and injured mouse peripheral nerves.

    PubMed

    Reichert, F; Levitzky, R; Rotshenker, S

    1996-03-01

    The multifunctional cytokine interleukin 6 (IL-6) has direct growth, survival and differentiation effects on peripheral and central neurons. Furthermore, it can modulate the production by non-neuronal cells of other cytokines and growth factors, and thereby affect nerve cells indirectly. We have studied IL-6 expression and production in intact and injured peripheral nerves of C57/BL/6NHSD mice, which display the normal rapid progression of Wallerian degeneration. The IL-6 mRNA was detected in nerves degenerating in vitro or in vivo, but not in intact nerves. In vitro- and in vivo-degenerating nerve segments and neuroma nerve segments synthesized and secreted IL-6. The onset of IL-6 production was rapid and prolonged. It was detected as early as 2 h after injury and persisted for the entire period of 21 days tested after the injury. Of the non-neuronal cells that reside in intact and injured nerves, macrophages and fibroblasts were the major contributors to IL-6 production. We also studied IL-6 production in intact and injured nerves of mutant C57BL/6-WLD/OLA/NHSD mice, which display very slow progression of Wallerian degeneration. Injured nerves of C57BL/6-WLD/OLA/NHSD mice produced significantly lower amounts of IL-6 than did rapidly degenerating nerves of C57/BL/6NHSD mice.

  7. Interleukin-6 stimulates neutrophil production of platelet-activating factor.

    PubMed

    Biffl, W L; Moore, E E; Moore, F A; Barnett, C C; Silliman, C C; Peterson, V M

    1996-04-01

    Interleukin-6 (IL-6) is an integral mediator of the acute phase response to injury and infection; an exaggerated IL-6 response has been associated with adverse clinical events. The precise role of IL-6 is unclear, but it appears capable of modulating the functional repertoire of mature neutrophils (PMNs). Our previous work demonstrated that IL-6 -stimulated PMNs are primed by lower concentrations of platelet-activating factor (PAF) than nonstimulated PMNs. Recently, we have found that IL-6 suppresses PMN apoptosis via a PAF-like mechanism. We hypothesized that IL-6 stimulates PMNs to produce PAF. PMNs isolated from healthy human donors were incubated with IL-6 (0.1-100 ng/ml) at 37 degrees C. Lipid production was measured by use of thin-layer chromatography, and PAF quantitated with a scintillation proximity assay. IL-6 (1 and 10 ng/ml) stimulated PMNs to produce increase quantities of PAF. PAF production was associated with an increase in PMN cytosolic calcium. These data may provide mechanistic insight into IL-6 regulation of PMN-mediated cytotoxicity and the role of PAF in mediating IL-6 effects on PMNs.

  8. Interleukin-6 as a therapeutic target in human ovarian cancer.

    PubMed

    Coward, Jermaine; Kulbe, Hagen; Chakravarty, Probir; Leader, David; Vassileva, Vessela; Leinster, D Andrew; Thompson, Richard; Schioppa, Tiziana; Nemeth, Jeffery; Vermeulen, Jessica; Singh, Naveena; Avril, Norbert; Cummings, Jeff; Rexhepaj, Elton; Jirström, Karin; Gallagher, William M; Brennan, Donal J; McNeish, Iain A; Balkwill, Frances R

    2011-09-15

    We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. ©2011 AACR.

  9. Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

    PubMed Central

    Smith, Stephen E. P.; Li, Jennifer; Garbett, Krassimira; Mirnics, Karoly; Patterson, Paul H.

    2008-01-01

    Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism. PMID:17913903

  10. Interleukin-6, a Major Cytokine in the Central Nervous System

    PubMed Central

    Erta, María; Quintana, Albert; Hidalgo, Juan

    2012-01-01

    Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies. PMID:23136554

  11. [Oral or trandsdermanl hormone replacement therapy reduces interleukine-6 levels].

    PubMed

    Saucedo García, Renata; Basurto Acevedo, Lourdes; Rico Rosillo, Guadalupe; Galván, Rosa E; Zárate Treviño, Arturo

    2006-03-01

    To compare the effect of oral and transdermal estrogen replacement therapy (ET) on circulating interleukin-6 (IL-6) in post-menopausal women. Prospective open trial study in 55 healthy hysterectomized postmenopausal women with a mean age of 52 years. Twenty-seven women received oral conjugated equine estrogens (0.625 mg daily) and the remaining 28 received transdermal estrogen replacement therapy (50 microg/day) during 6 months. At baseline both groups were similar as to age, body weight, and body mass index as well as serum levels of LH, FSH, 17-beta estradiol (E2) and IL-6. Baseline elevated IL-6 levels decreased significantly (p<0.05) after both oral and transdermal estrogen replacement therapy; this decrement showed no difference between the two groups. After the follow-up there were no differences in body weight and body mass index between groups; however, in the oral group there was a trend to increment this parameters. Serum levels of E2 and IL-6 were negatively correlated in the two groups and IL-6 was positively correlated with body mass index in untreated women and this correlation was the same in women with estrogen replacement therapy. The decrement of IL-6 after estrogen replacement therapy was similar for both routes of administration; in addition IL-6 had a negative correlation with E2 and a positive correlation with body mass index.

  12. Social relationships, sleep quality, and interleukin-6 in aging women.

    PubMed

    Friedman, Elliot M; Hayney, Mary S; Love, Gayle D; Urry, Heather L; Rosenkranz, Melissa A; Davidson, Richard J; Singer, Burton H; Ryff, Carol D

    2005-12-20

    This study examined the interplay of social engagement, sleep quality, and plasma levels of interleukin-6 (IL-6) in a sample of aging women (n = 74, aged 61-90, M age = 73.4). Social engagement was assessed by questionnaire, sleep was assessed by using the NightCap in-home sleep monitoring system and the Pittsburgh Sleep Quality Index, and blood samples were obtained for analysis of plasma levels of IL-6. Regarding subjective assessment, poorer sleep (higher scores on the Pittsburgh Sleep Quality Index) was associated with lower positive social relations scores. Multivariate regression analyses showed that lower levels of plasma IL-6 were predicted by greater sleep efficiency (P < 0.001), measured objectively and by more positive social relations (P < 0.05). A significant interaction showed that women with the highest IL-6 levels were those with both poor sleep efficiency and poor social relations (P < 0.05). However, those with low sleep efficiency but compensating good relationships as well as women with poor relationships but compensating high sleep efficiency had IL-6 levels comparable to those with the protective influences of both good social ties and good sleep.

  13. Interleukin-6 and Soluble Interleukin-6 Receptor Levels in Posttraumatic Stress Disorder: Associations with Lifetime Diagnostic Status and Psychological Context

    PubMed Central

    Newton, Tamara L.; Fernandez-Botran, Rafael; Miller, James J.; Burns, Vicki Ellison

    2014-01-01

    This study correlated lifetime PTSD diagnostic status with interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) levels, and tested whether these correlations are sensitive to psychological context. Midlife women attended two research visits where blood was drawn (beginning of visits) and saliva and oral mucosal transudate were collected (beginning and end of visits) to measure IL-6 and sIL-6R. Women were classified as PTSD−/− (past and current symptoms below subsyndromal levels), PTSD+/− (past symptoms at or above subsyndromal levels), or PTSD +/+ (past and current symptoms at or above subsyndromal levels). PTSD+/+ women, compared to the other women, showed more negative emotion at the beginning of the visits, higher salivary IL-6 levels at the beginning versus end of visits, and positive correlations between negative emotion, salivary IL-6, and plasma sIL-6R. Their plasma sIL-6R levels exceeded those of the PTSD+/− women. Overall, IL-6 sensitivity to anticipation and to negative emotions, and higher sIL-6R levels, differentiated persistent versus remitted PTSD. PMID:24695006

  14. Predictive value of urinary interleukin-6 for symptomatic urinary tract infections in a nursing home population.

    PubMed

    Sundén, Fredrik; Wullt, Björn

    2016-02-01

    To study urinary interleukin-6, interleukin-8 and pyuria during episodes of asymptomatic bacteriuria and symptomatic urinary tract infection in the institutionalized elderly, and to investigate the role of interleukin-6 as a biomarker for differential diagnosis. Levels of interleukin-6, interleukin-8 and pyuria were assessed in 35 older adults with asymptomatic bacteriuria and symptomatic urinary tract infection to define possible diagnostic thresholds. In a two-phase intervention study, the antibiotic treatment for urinary tract infection before and after introduction of urinary interleukin-6 as a biomarker was then assessed. Asymptomatic bacteriuria patients had no or low levels of interleukin-6, and low levels of interleukin-8 and pyuria. Women had lower interleukin-6 and interleukin-8 than men (P = 0.05). Interleukin-6 was the only marker showing significant increases during urinary tract infection episodes in patients with both asymptomatic bacteriuria and urinary tract infection, in pooled (P = 0.042) and in paired intra-individual (P = 0.017) comparisons. In the intervention study lectures, the increased use of urine cultures and the introduction of interleukin-6 as a biomarker reduced antibiotic treatments by 20%. Antibiotic-treated urinary tract infection episodes had increased interleukin-6 as compared with urinary tract infection episodes not treated (P = 0.02), and as compared with asymptomatic bacteriuria patients (P < 0.0001). The sensitivity and specificity of interleukin-6 (cut-off 25 pg/mL) differentiating asymptomatic bacteriuria from urinary tract infection was 57% and 80%, respectively. Urinary interleukin-6 shows promise as a biomarker to detect the transition from asymptomatic bacteriuria to symptomatic urinary tract infection in older adults. Further larger studies with robust methodology are warranted to determine whether development for near to patient testing would be worthwhile. © 2015 The Japanese Urological Association.

  15. Interleukin-6 receptor pathways in abdominal aortic aneurysm

    PubMed Central

    Harrison, Seamus C.; Smith, Andrew J.P.; Jones, Gregory T.; Swerdlow, Daniel I.; Rampuri, Riaz; Bown, Matthew J.; Folkersen, Lasse; Baas, Annette F.; de Borst, Gert Jan; Blankensteijn, Jan D.; Price, Jacqueline F.; van der Graaf, Yolanda; McLachlan, Stela; Agu, Obi; Hofman, Albert; Uitterlinden, Andre G.; Franco-Cereceda, Anders; Ruigrok, Ynte M.; van't Hof, F.N.; Powell, Janet T.; van Rij, Andre M.; Casas, Juan P.; Eriksson, Per; Holmes, Michael V.; Asselbergs, Folkert W.; Hingorani, Aroon D.; Humphries, Steve E.

    2013-01-01

    Methods We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. Results Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25–0.66, I2 = 70%, P = 1.1 × 10–5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80–0.89, I2 = 0%, P = 2.7 × 10–11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers. Conclusions A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management. PMID:23111417

  16. Interleukin-6 and development of vasospasm after subarachnoid haemorrhage.

    PubMed

    Osuka, K; Suzuki, Y; Tanazawa, T; Hattori, K; Yamamoto, N; Takayasu, M; Shibuya, M; Yoshida, J

    1998-01-01

    The authors characterized the role of interleukins in the cerebrospinal fluid (CSF) in the development of vasospasm after subarachnoid haemorrhage (SAH), particularly interleukin-6 (IL-6). Concentrations of interleukin-1 beta (IL-1 beta), IL-6, and interleukin-8 (IL-8) were measured serially in CSF of 24 patients and in serum of 9 patients with SAH and correlated clinically. Additionally, the effects of the same cytokines on the cerebral arteries of dogs were analyzed on angiograms after intracisternal injection. Changes in levels of eicosanoids, angiogenic factors, and soluble cell adhesion molecules were investigated in the CSF of injected dogs. CSF concentrations of IL-6 and IL-8 were elevated significantly above control levels from the acute stage of SAH until the chronic stage. Patients with symptomatic vasospasm had significantly higher levels of IL-6 as well as IL-8 in CSF on days 5 and 7. Intracisternal injection of IL-6 induced long-lasting vasoconstriction in five out of eight dogs, while IL-8 did not. The diameter of canine basilar artery after IL-6 was reduced 29 +/- 5% from pretreatment diameter at 8 hours. Prostaglandins E2 and I2 were elevated in CSF for the first 4.5 hour of this IL-6-induced vasospasm. Neither angiogenic factors such as platelet-derived growth factor-AB and vascular endothelial growth factor nor soluble cell adhesion molecules were significantly elevated in CSF. IL-6, which increases to very high concentrations in CSF after SAH, may be important in inducing vasospasm, as IL-6 produced long-lasting vasoconstriction in the canine cerebral artery, which may be partly related to activation of the prostaglandin cascade.

  17. Salivary and serum interleukin-6 levels in proliferative verrucous leukoplakia.

    PubMed

    Bagan, Leticia; Sáez, Guillermo T; Tormos, M Carmen; Labaig-Rueda, Carlos; Murillo-Cortes, Judith; Bagan, Jose V

    2016-05-01

    Cytokines and chemokines have been analysed in patients with oral squamous cell carcinoma and potentially malignant disorders. We selected interleukin-6 (IL-6) because it is a multifunctional interleukin reported to be altered in potentially malignant oral disorders and in malignant lesions. To date, this has not been evaluated or tested in proliferative verrucous leukoplakia (PVL), however. This study aimed to analyse the differences in serum and saliva IL-6 levels among patients with PVL, oral squamous cell carcinoma (OSCC) and healthy controls and to examine the relationship between salivary IL-6 levels and the extent of the verrucous area. Using an enzyme-linked immunosorbent assay, we determined the serum and saliva IL-6 levels in three groups: 20 patients with PVL, 20 with OSCC and 20 healthy controls. There were significant (p < 0.01) differences in the serum and saliva IL-6 levels among the three groups and among the three grades of extent of the verrucous areas (p = 0.01). In the OSCC group, there was a significant difference in the saliva IL-6 levels between patients with and without lymph node metastasis at diagnosis (p = 0.02). We found that patients with OSCC had the highest salivary and serum IL-6 levels, while PVL had lower values than OSCC, but higher than the controls, and these altered levels were associated with the extent of the verrucous areas. Salivary and plasma IL-6 are altered in patients with PVL, with more extensive verrucous areas being associated to the highest IL-6 levels. This could be a significant tool for monitoring patients with PVL, their progression to more advances stages and their recurrences.

  18. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers.

    PubMed

    Yao, Xin; Huang, Jiaqi; Zhong, Haihong; Shen, Nan; Faggioni, Raffaella; Fung, Michael; Yao, Yihong

    2014-02-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine with significant functions in the regulation of the immune system. As a potent pro-inflammatory cytokine, IL-6 plays a pivotal role in host defense against pathogens and acute stress. However, increased or deregulated expression of IL-6 significantly contributes to the pathogenesis of various human diseases. Numerous preclinical and clinical studies have revealed the pathological roles of the IL-6 pathway in inflammation, autoimmunity, and cancer. Based on the rich body of studies on biological activities of IL-6 and its pathological roles, therapeutic strategies targeting the IL-6 pathway are in development for cancers, inflammatory and autoimmune diseases. Several anti-IL-6/IL-6 receptor monoclonal antibodies developed for targeted therapy have demonstrated promising results in both preclinical studies and clinical trials. Tocilizumab, an anti-IL-6 receptor antibody, is effective in the treatment of various autoimmune and inflammatory conditions notably rheumatoid arthritis. It is the only IL-6 pathway targeting agent approved by the regulatory agencies for clinical use. Siltuximab, an anti-IL-6 antibody, has been shown to have potential benefits treating various human cancers either as a single agent or in combination with other chemotherapy drugs. Several other anti-IL-6-based therapies are also under clinical development for various diseases. IL-6 antagonism has been shown to be a potential therapy for these disorders refractory to conventional drugs. New strategies, such as combination of IL-6 blockade with inhibition of other signaling pathways, may further improve IL-6-targeted immunotherapy of human diseases. © 2013.

  19. Chronic Low Back Pain, Sleep Disturbance, and Interleukin-6

    PubMed Central

    Heffner, Kathi L.; France, Christopher R.; Trost, Zina; Mei Ng, H.; Pigeon, Wilfred R.

    2010-01-01

    Objectives Sleep disturbance is a common co-morbidity of chronic pain. Inflammatory processes are dysregulated in sleep disturbance and also contribute to pain sensitivity. Thus, inflammation may play an important role in bi-directional associations between pain and sleep. Little is known about concurrent relationships among chronic pain, sleep, and inflammation. The aim of our study was to examine associations among sleep disturbance and circulating levels of the inflammatory cytokine, interleukin-6 (IL-6), in individuals with and without chronic low back pain. Methods Gender and age-matched adults with chronic low back pain (CLBP; n = 25) or without chronic pain (controls; n = 25) completed measures of sleep quality in the past month and depressive symptoms in the past week, and provided a blood draw for IL-6. The next morning, participants reported their sleep quality the previous night and their current experience of morning pain. Results Individuals with CLBP had more sleep disturbance than controls. Circulating IL-6 levels were similar for the two groups; however, in adults with CLBP, poorer sleep quality was associated with higher IL-6 levels, and both sleep and IL-6 related to pain reports. Unlike CLBP participants, controls showed normal, age-related increases in IL-6 levels, whereas sleep quality was unrelated to IL-6 levels. Depressive symptoms could not fully explain the observed associations. Discussion Inflammatory processes may play a significant role in cycles of pain and sleep disturbance. Clinical interventions that improve sleep and reduce concomitant inflammatory dysregulation hold promise for chronic pain management. PMID:21188850

  20. Interleukin-6 as an early marker for fat embolism

    PubMed Central

    Yoga, R; Theis, JC; Walton, M; Sutherland, W

    2009-01-01

    Background Fat Embolism is a complication of long bone fractures, intramedullary fixation and joint arthroplasty. It may progress to fat embolism syndrome, which is rare but involves significant morbidity and can occasionally be fatal. Fat Embolism can be detected at the time of embolization by transoesophageal echocardiography or atrial blood sampling. Later, a combination of clinical signs and symptoms will point towards fat embolism but there is no specific test to confirm the diagnosis. We investigated serum Interleukin-6 (IL-6) as a possible early marker for fat embolism. Methods An animal study was conducted to simulate a hip replacement in 31 adult male Sprague Dawley rats. The procedure was performed under general anesthesia and the animals divided into 3 groups: control, uncemented and cemented. Following surgery and recovery from anaesthesia, the rats allowed to freely mobilize in their cages. Blood was taken before surgery and at 6 hours, 12 hours and 24 hours to measure serum IL-6 levels. The rats were euthanized at 24 hours and lungs removed and stained for fat. The amount of fat seen was then correlated with serum IL-6 levels. Results No rats in the control group had fat emboli. Numerous fat emboli were seen in both the uncemented and cemented implant groups. The interleukin levels were raised in all groups reaching a peak at 12 hours after surgery reaching 100 pg/ml in the control group and around 250 pg/ml in the uncemented and cemented implant groups. The IL-6 levels in the control group were significantly lower than any of the implant groups at 12 and 24 hours. At these time points, the serum IL-6 correlated with the amount of fat seen on lung histology. Conclusion Serum IL-6 is a possible early marker of fat embolism. PMID:19523233

  1. Central nervous system administration of interleukin-6 produces splenic sympathoexcitation

    PubMed Central

    Helwig, Bryan G.; Craig, Robin A.; Fels, Richard J.; Blecha, Frank; Kenney, Michael J.

    2008-01-01

    Interleukin-6 (IL-6) is a multifunctional cytokine that has been shown to play a pivotal role in centrally-mediated physiological responses including activation of the hypothalamic-pituitary-adrenal axis. Cerebral spinal fluid (CSF) concentrations of IL-6 are elevated in multiple pathophysiological conditions including Alzheimer’s disease, autoimmune disease, and meningitis. Despite this, the effect of IL-6 on central regulation of sympathetic nerve discharge (SND) remains unknown which limits understanding of sympathetic-immune interactions in health and disease. In the present study we determined the effect of intracerebroventricular (icv, lateral ventricle) administration of IL-6 on splenic SND in urethane-chloralose-anesthetized rats. A second goal was to determine if icv injected IL-6 enters the brain parenchyma and acts as a volume transmission signal to access areas of the brain involved in regulation of sympathetic nerve outflow. Icv administration of IL-6 (10 ng, 100 ng, and 400 ng) significantly and progressively increased splenic SND from control levels in baroreceptor denervated Sprague-Dawley rats. Administration of 100 ng and 400 ng IL-6 resulted in significantly higher SND responses when compared to those elicited with a 10 ng dose. Sixty minutes following icv administration, fluorescently labeled IL-6 was not distributed throughout the parenchyma of the brain but was localized to the periventricular areas of the ventricular system. Brain sections counter-stained for the IL-6 receptor (IL-6R) revealed that IL-6 and the IL-6R were co-localized in periventricular areas adjoining the third ventricle. These results demonstrate that icv IL-6 administration increases splenic SND, an effect likely achieved via signaling mechanisms originating in the periventricular cells. PMID:18547874

  2. Interleukin-6-mediated signaling in adrenal medullary chromaffin cells.

    PubMed

    Jenkins, Danielle E; Sreenivasan, Dharshini; Carman, Fiona; Samal, Babru; Eiden, Lee E; Bunn, Stephen J

    2016-12-01

    The pro-inflammatory cytokines, tumor necrosis factor-α, and interleukin-1β/α modulate catecholamine secretion, and long-term gene regulation, in chromaffin cells of the adrenal medulla. Since interleukin-6 (IL6) also plays a key integrative role during inflammation, we have examined its ability to affect both tyrosine hydroxylase activity and adrenomedullary gene transcription in cultured bovine chromaffin cells. IL6 caused acute tyrosine/threonine phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), and serine/tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Consistent with ERK1/2 activation, IL6 rapidly increased tyrosine hydroxylase phosphorylation (serine-31) and activity, as well as up-regulated genes, encoding secreted proteins including galanin, vasoactive intestinal peptide, gastrin-releasing peptide, and parathyroid hormone-like hormone. The effects of IL6 on the entire bovine chromaffin cell transcriptome were compared to those generated by G-protein-coupled receptor (GPCR) agonists (histamine and pituitary adenylate cyclase-activating polypeptide) and the cytokine receptor agonists (interferon-α and tumor necrosis factor-α). Of 90 genes up-regulated by IL6, only 16 are known targets of IL6 in the immune system. Those remaining likely represent a combination of novel IL6/STAT3 targets, ERK1/2 targets and, potentially, IL6-dependent genes activated by IL6-induced transcription factors, such as hypoxia-inducible factor 1α. Notably, genes induced by IL6 include both neuroendocrine-specific genes activated by GPCR agonists, and transcripts also activated by the cytokines. These results suggest an integrative role for IL6 in the fine-tuning of the chromaffin cell response to a wide range of physiological and paraphysiological stressors, particularly when immune and endocrine stimuli converge. © 2016 International Society for Neurochemistry.

  3. Retinoic acid suppresses interleukin 6 production in normal human osteoblasts.

    PubMed

    Ahmed, N; Sammons, J; Khokher, M A; Hassan, H T

    2000-03-01

    Systemic long-term retinoid therapy for chronic skin diseases significantly reduced bone turnover markers within days and led to bone abnormalities. Retinoic acid (RA) plays a key role in the regulation of mouse bone cell proliferation, differentiation and functions. Meanwhile, there is little information of RA effect on human osteoblast and osteoclast cell development and function. Interleukin 6 (IL-6) is a pleiotropic cytokine with profound effects on bone metabolism. Thus, the present study examined the RA effect on cell differentiation, alkaline phosphatase and osteocalcin production as well as IL-6 production in normal human osteoblasts. The number of large differentiated osteoblast cells decreased in RA-treated cultures P<0.05. The production of bone specific markers, alkaline phosphatase and osteocalcin, was also reduced in RA-treated cultures. Normal human osteoblasts produced 31.0+/-4.8 pg IL-6 per ml in control cultures. Within 24 h, RA at all four concentrations reduced Il-6 production from normal human osteoblasts. The pharmacological concentration of 10(-5) M RA suppressed 90% of IL-6 production. The present study shows for the first time that RA profoundly inhibits IL-6 production in normal human osteoblasts within 24 h and in a dose-dependent manner. RA was shown previously to inhibit IL-6 production in several other normal and malignant human cell types. The associated decrease in osteoblast cell differentiation, alkaline phosphatase and osteocalcin production could result from the rapid RA-inhibition of IL-6 production. Thus, RA inhibition of IL-6 production in normal human osteoblasts may contribute to the bone abnormalities seen after systemic long-term retinoid therapy in some patients. Copyright 2000 Academic Press.

  4. A non-canonical function of eukaryotic elongation factor 1A1: regulation of interleukin-6 expression.

    PubMed

    Schulz, Ingo; Engel, Claudia; Niestroj, André J; Kehlen, Astrid; Rahfeld, Jens-Ulrich; Kleinschmidt, Martin; Lehmann, Karola; Roßner, Steffen; Demuth, Hans-Ulrich

    2014-05-01

    Interleukin-6 is one of the most prominent triggers of inflammatory processes. We have shown recently that heteroarylketones (HAKs) interfere with stimulated interleukin-6 expression in astrocytes by suppression of STAT3 phosphorylation at serine 727. Surprisingly, this effect is not based on the inhibition of STAT3-relevant kinases. Therefore, we here used the structurally modified HAK compound biotin-HAK-3 in a reverse chemical approach to identify the relevant molecular target in UV-mediated cross-linking experiments. Employing streptavidin-specific 2D-immunoblotting followed by mass spectrometry we identified nine proteins putatively interacting with biotin-HAK-3. After co-immunoprecipitation, co-immunofluorescence, surface plasmon resonance analyses and RNAi-mediated knock-down, the eukaryotic elongation factor 1A1 (eEF1A1) was verified as the relevant target of HAK bioactivity. eEF1A1 forms complexes with STAT3 and PKCδ, which are crucial for STAT3(S727) phosphorylation and for NF-κB/STAT3-enhanced interleukin-6 expression. Furthermore, the intracellular HAK accumulation is strongly dependent on eEF1A1 expression. Taken together, the results reveal a novel molecular mechanism for a non-canonical role of eEF1A1 in signal transduction via direct modulation of kinase-dependent phosphorylation events.

  5. Interleukin-6 genotype and risk for cerebral palsy in term and near-term infants.

    PubMed

    Wu, Yvonne W; Croen, Lisa A; Torres, Anthony R; Van De Water, Judy; Grether, Judith K; Hsu, Nathaniel N

    2009-11-01

    Chorioamnionitis is associated with increased risk for cerebral palsy (CP) in term infants. A functional polymorphism in the interleukin-6 (IL-6) gene has been implicated in newborn brain injury. We studied whether the IL-6 -174 G/C polymorphism confers increased risk for CP in term infants. This population-based case-control study included 334,333 live-born infants born at >or=36 weeks gestation within Kaiser Permanente Medical Care Program from 1991 to 2002. Case patients (n = 250) were identified from electronic records and confirmed by chart review, and comprised all infants with spastic or dyskinetic CP not caused by developmental abnormalities who had a neonatal blood specimen available for study. Control patients (n = 305) were randomly selected from the study population. Compared with genotype GG, the less common CC genotype was associated with increased risk for overall CP (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.6), quadriparetic CP (OR, 4.1; 95% CI, 1.8-9.3), and hemiparetic CP (OR, 2.7; 95% CI, 1.3-5.7), after controlling for race. The C allele conferred increased risk for CP in both recessive and additive genetic models. In multivariate analysis controlling for race, independent risk factors for CP included CC genotype compared with GG (OR, 2.4; 95% CI, 1.3-4.4), clinical chorioamnionitis (OR, 4.6; 95% CI, 2.1-10.4), maternal age >or= 35 (OR, 2.6; 95% CI, 1.6-4.1), and male sex (OR, 1.6; 95% CI, 1.1-2.4). Our data suggest that a functional polymorphism in the IL-6 gene is a risk factor for CP among term and near-term infants.

  6. Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

    PubMed Central

    2012-01-01

    Background Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted. PMID:22695063

  7. Interleukin 6 SNP rs1800797 associates with the risk of adult-onset asthma.

    PubMed

    Lajunen, T K; Jaakkola, J J K; Jaakkola, M S

    2016-04-01

    Interleukin 6 (IL6) is an inflammatory cytokine that has been suggested to have an important role in the pathogenesis of asthma. IL6 single-nucleotide polymorphisms (SNPs) have been associated with levels of IL6, and with childhood and prevalent adult asthma. A recent study also suggested that IL6 SNPs associate especially with atopic asthma. However, association of IL6 SNPs with adult-onset asthma has not been studied. In a population-based study of 467 incident adult-onset asthma cases and 613 disease-free controls from South Finland, we analyzed association of 6 tagging SNPs of the IL6 locus with the risk of adult-onset asthma and with atopy. Asthma was clinically diagnosed, and atopy was defined based on Phadiatop test. IL6 SNP rs1800797 associated with the risk of adult-onset asthma in a log additive model, with adjusted odds ratio (aOR) 1.31 (95% confidence interval 1.09-1.57), and especially with the risk of atopic adult-onset asthma when compared with non-atopic controls, aOR 1.46 (95% CI 1.12-1.90). This is the first study to show an association of IL6 with adult-onset asthma, and especially with atopic adult-onset asthma.

  8. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer

    PubMed Central

    Casneuf, Tineke; Axel, Amy E; King, Peter; Alvarez, John D; Werbeck, Jillian L; Verhulst, Tinne; Verstraeten, Karin; Hall, Brett M; Sasser, A Kate

    2016-01-01

    Introduction Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-α (ERα)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. Methods The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ERα-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ERα-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ERα-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ERα-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. Results In eight of nine ERα-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ERα-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (≥10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7

  9. Association of interleukin-6 (IL-6) haplotypes with plaque-induced gingivitis in children.

    PubMed

    Holla, Lydie Izakovicova; Musilova, Kristina; Vokurka, Jan; Klapusová, Lucie; Pantuckova, Pavla; Kukletova, Martina; Kukla, Lubomir; Znojil, Vladimir

    2008-04-01

    The proinflammatory cytokine interleukin-6 (IL-6) is a key regulator of the host response to microbial infection and major modulator of extracellular matrix catabolism and bone resorption. The aim of this case-control study was to test differences between children with and without gingivitis in the distribution of IL-6 alleles at positions -174, -572, and -597 and their haplotypes. A total of 455 Caucasian children, aged 11 to 13 years, were enrolled in this study. According to gingival bleeding on probing indices, 183 were classified as healthy subjects and 272 as children with plaque-induced gingivitis. DNA for genetic analysis was obtained from buccal epithelial cells and PCR-RFLP methods were used for genotyping three selected IL-6 promoter polymorphisms. Complex analysis revealed significant differences in haplotype frequencies between patients and healthy subjects (p<0.01). The CGA haplotype was significantly more frequent in children with gingivitis than in healthy subjects (41.5% versus 34.1%). In subanalyses, we found that IL-6 -174C allele was more frequent in patients (44.3%) than in healthy children (36.1%, p=0.016, P(corr)<0.05). Multivariate logistic regression analysis showed that allele C remained a risk factor for gingivitis in children (p=0.03) regardless of plaque or gender. However, the proportions of the IL-6 -597 and -572 genotypes were comparable between the two groups. CONCLUSIONS. Our results indicate that the three promoter polymorphisms in the IL-6 gene act in a cooperative fashion and suggest that IL-6 haplotypes could play a role in the pathogenesis of gingivitis in Caucasian children.

  10. [Diagnostic value of interleukin 6 for neonatal sepsis: a Meta analysis].

    PubMed

    Hu, Jing; DU, Peng-Fei; Bei, Dan-Dan

    2015-11-01

    To evaluate the diagnostic value of interleukin 6 for neonatal sepsis. The databases of CNKI, VIP, Wangfang, Pubmed, Embase, Web of Science, Cochrane Library were searched (by September 2014) to identify relevantly published studies about estimating the diagnostic value of interleukin 6 for neonatal sepsis. QUADAS tools were used for quality evaluation of the studies. A Meta analysis was performed by employing Meta Disc 1.4 and Stata11.0 software. Heterogeneity of the included articles was tested to select proper efficacy model for calculating pooled weighted sensitivity, specificity and 95%CI. Summary receiver operating characteristic (SROC) curve was made and the area under the curve and Q(*) index were calculated. A total of 33 studies including 3 135 neonates were enrolled. The sensitivity and specificity of interleukin 6 for the diagnosis of neonatal sepsis were 0.79 (95%CI: 0.76-0.81) and 0.83 (95%CI: 0.81-0.85) respectively. The area under SROC curve of interleukin 6 for the diagnosis of neonatal sepsis was 0.89 and Q(*) index was 0.83. The post-test probability of diagnosing neonatal sepsis indicated by negative interleukin 6 was 5%, while that of positive interleukin 6 was 60%. Interleukin 6 measurement is useful for the diagnosis of neonatal sepsis with a high sensitivity and specificity.

  11. Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice.

    PubMed

    Sakata, Hiroyuki; Narasimhan, Purnima; Niizuma, Kuniyasu; Maier, Carolina M; Wakai, Takuma; Chan, Pak H

    2012-11-01

    Transplantation of neural stem cells provides a promising therapy for stroke. Its efficacy, however, might be limited because of massive grafted-cell death after transplantation, and its insufficient capability for tissue repair. Interleukin 6 is a pro-inflammatory cytokine involved in the pathogenesis of various neurological disorders. Paradoxically, interleukin 6 promotes a pro-survival signalling pathway through activation of signal transducer and activator of transcription 3. In this study, we investigated whether cellular reprogramming of neural stem cells with interleukin 6 facilitates the effectiveness of cell transplantation therapy in ischaemic stroke. Neural stem cells harvested from the subventricular zone of foetal mice were preconditioned with interleukin 6 in vitro and transplanted into mouse brains 6 h or 7 days after transient middle cerebral artery occlusion. Interleukin 6 preconditioning protected the grafted neural stem cells from ischaemic reperfusion injury through signal transducer and activator of transcription 3-mediated upregulation of manganese superoxide dismutase, a primary mitochondrial antioxidant enzyme. In addition, interleukin 6 preconditioning induced secretion of vascular endothelial growth factor from the neural stem cells through activation of signal transducer and activator of transcription 3, resulting in promotion of angiogenesis in the ischaemic brain. Furthermore, transplantation of interleukin 6-preconditioned neural stem cells significantly attenuated infarct size and improved neurological performance compared with non-preconditioned neural stem cells. This interleukin 6-induced amelioration of ischaemic insults was abolished by transfecting the neural stem cells with signal transducer and activator of transcription 3 small interfering RNA before transplantation. These results indicate that preconditioning with interleukin 6, which reprograms neural stem cells to tolerate oxidative stress after ischaemic reperfusion

  12. Triggered Urine Interleukin-6 Correlates to Severity of Symptoms in Nonfebrile Lower Urinary Tract Infections.

    PubMed

    Sundén, Fredrik; Butler, Daniel; Wullt, Björn

    2017-07-01

    Objective diagnosis of symptomatic urinary tract infections in patients prone to asymptomatic bacteriuria is compromised by local host responses that are already present and the positive urine culture. We investigated interleukin-6 as a biomarker for nonfebrile urinary tract infection severity and diagnostic thresholds for interleukin-6 and 8, and neutrophils to differentiate between asymptomatic bacteriuria and urinary tract infection. Patients with residual urine and neurogenic bladders due to spinal lesions included in a long-term Escherichia coli 83972 asymptomatic bacteriuria inoculation trial were monitored for 2 years. Symptom scoring and urine sampling to estimate interleukin-6 and 8, and neutrophils were performed regularly monthly and at urinary tract infection episodes. Patients were followed in the complete study for a mean of 19 months (range 10 to 27) and those with asymptomatic bacteriuria with E. coli 83972 were followed a mean of 11 months (range 4 to 19). A total of 37 nonfebrile urinary tract infection episodes with complete data on interleukin-6 and 8, neutrophils and symptom scoring were documented. Interleukin-6 was the only marker that persistently increased during urinary tract infection compared to asymptomatic bacteriuria in pooled and paired intra-individual comparisons (p <0.05). Interleukin-6 above the threshold (greater than 25 ng/l) correlated to more severe urinary tract infection symptoms (p <0.05). The sensitivity and specificity of all biomarkers were poor/moderate when differentiating asymptomatic bacteriuria vs all urinary tract infection episodes. However, in urinary tract infections with worse symptoms interleukin-6 and neutrophils demonstrated equal good/excellent outcomes. Triggered interleukin-6 correlated to urinary tract infection symptom severity and demonstrated a promising differential diagnostic capacity to discriminate urinary tract infection from asymptomatic bacteriuria. Future studies should explore interleukin-6

  13. Hepatocyte Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis

    DTIC Science & Technology

    2006-06-01

    LHRH agonist on the bone marrow environment. Another strategy of reducing androgen levels is by the downregulation of GnRH receptors in the...Interleukin-6 in Prostate Cancer Bone Metastasis PRINCIPAL INVESTIGATOR: Beatrice S. Knudsen, M.D., Ph.D. CONTRACTING ORGANIZATION...Growth Factor and Interleukin-6 in Prostate Cancer Bone Metastasis 5a. CONTRACT NUMBER 5b. GRANT NUMBER DAMD17-02-1-0159 5c. PROGRAM ELEMENT

  14. Effects of Cell Type and Culture Media on Interleukin-6 Secretion in Response to Environmental Particles

    PubMed Central

    Veranth, John M.; Cutler, N. Shane; Kaser, Erin G.; Reilly, Christopher A.; Yost, Garold S.

    2008-01-01

    Cultured lung cells provide an alternative to animal exposures for comparing the effects of different types of air pollution particles. Studies of particulate matter in vitro have reported proinflammatory cytokine signaling in response to many types of environmental particles, but there have been few studies comparing identical treatments in multiple cell types or identical cells with alternative cell culture protocols. We compared soil-derived, diesel, coal fly ash, titanium dioxide, and kaolin particles along with soluble vanadium and lipopolysaccharide, applied to airway-derived cells grown in submerged culture. Cell types included A549, BEAS-2B, RAW 264.7, and primary macrophages. The cell culture models (specific combinations of cell types and culture conditions) were reproducibly different in the cytokine signaling responses to the suite of treatments. Further, Interleukin-6 (IL-6) response to the treatments changed when the same cells, BEAS-2B, were grown in KGM versus LHC-9 media or in media containing bovine serum. The effect of changing media composition was reversible over multiple changes of media type. Other variables tested included culture well size and degree of confluence. The observation that sensitivity of a cell type to environmental agonists can be manipulated by modifying culture conditions suggests a novel approach for studying biochemical mechanisms of particle toxicity. PMID:18178371

  15. Interleukin-6-related genotypes, body mass index, and risk of multiple myeloma and plasmacytoma.

    PubMed

    Cozen, Wendy; Gebregziabher, Mulugeta; Conti, David V; Van Den Berg, David J; Coetzee, Gerhard A; Wang, Sophia S; Rothman, Nathaniel; Bernstein, Leslie; Hartge, Patricia; Morhbacher, Ann; Coetzee, Simon G; Salam, Muhammad T; Wang, Wei; Zadnick, John; Ingles, Sue A

    2006-11-01

    Interleukin-6 (IL-6) promotes normal plasma cell development and proliferation of myeloma cells in culture. We evaluated IL-6 genotypes and body mass index (BMI) in a case-control study of multiple myeloma and plasmacytoma. DNA samples and questionnaires were obtained from incident cases of multiple myeloma (n = 134) and plasmacytoma (n = 16; plasma cell neoplasms) ascertained from the Los Angeles County population-based cancer registry and from siblings or cousins of cases (family controls, n = 112) and population controls (n = 126). Genotypes evaluated included IL-6 promoter gene single nucleotide polymorphisms (SNP) at positions -174, -572, and -597; one variable number of tandem repeats (-373 A(n)T(n)); and one SNP in the IL-6 receptor (IL-6ralpha) gene at position -358. The variant allele of the IL-6 promoter SNP -572 was associated with a roughly 2-fold increased risk of plasma cell neoplasms when cases were compared with family [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 0.7-4.7] or population controls (OR, 2.4; 95% CI, 1.2-4.7). The -373 9A/9A genotype was associated with a decreased risk compared with the most common genotype (OR for cases versus family controls, 0.4; 95% CI, 0.1-1.7; OR for cases versus population controls, 0.3; 95% CI, 0.1-0.9). No other SNPs were associated with risk. Obesity (BMI >or= 30 kg/m(2)) increased risk nonsignificantly by 40% and 80% when cases were compared with family controls or population controls, respectively, relative to persons with a BMI of <25 kg/m(2). These results suggest that IL-6 promoter genotypes may be associated with increased risk of plasma cell neoplasms.

  16. Remodeling of plasma lipoproteins in patients with rheumatoid arthritis: Interleukin-6 receptor-alpha inhibition with tocilizumab.

    PubMed

    Lee, Janet S; Chapman, M John; Piraino, Paolo; Lamerz, Jens; Schindler, Thomas; Cutler, Paul; Dernick, Gregor

    2016-02-01

    Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, mediated in part by elevated circulating interleukin-6 levels and proinflammatory changes in plasma lipoproteins. We hypothesized that RA patients acquire inflammation-induced modifications to the protein cargo of circulating lipoproteins that may be reversed by tocilizumab, an interleukin-6 receptor-alpha inhibitor. Size-exclusion chromatography and reverse-phase protein arrays using 29 antibodies against 26 proteins were applied at baseline and after tocilizumab treatment to analyze the distributions of apolipoproteins, enzymes, lipid transfer proteins, and other associated proteins in plasma lipoprotein fractions from 20 women with RA. A 30% reduction in high-density lipoprotein (HDL)-associated serum amyloid A4 and complement C4 occurred with tocilizumab. Levels of C-reactive protein, associated or comigrating with HDL and low-density lipoprotein (LDL) peaks, were reduced on treatment by approximately 80% and 24%, respectively. Reductions in lipoprotein-associated phospholipase A2, lipoprotein (a), and cholesteryl ester transfer protein in the LDL fraction suggest reductions in LDL-associated proatherogenic factors. Elevations in very low-density lipoprotein (VLDL) enriched with apolipoprotein E were equally observed. Tocilizumab treatment led to reductions in proinflammatory components and proatherogenic proteins associated with HDL. Whether changes in the proteome of VLDL, LDL, and HDL induced by anti-inflammatory tocilizumab treatment in RA patients modify cardiovascular disease risk requires further investigation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Interleukin-6 and lung inflammation: evidence for a causative role in inducing respiratory system resistance increments.

    PubMed

    Rubini, Alessandro

    2013-10-01

    Interleukin-6 is a multifunctional cytokine that has been shown to be increased in some pathological conditions involving the respiratory system such as those experimentally induced in animals or spontaneously occurring in humans. Experimental data demonstrating that interleukin-6 plays a significant role in commonly occurring respiratory system inflammatory diseases are reviewed here. Those diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by mechanical derangements of the respiratory system, for the most part due to increased elastance and airway resistance. Recent findings showing that interleukin-6 has a causative role in determining an increase in airway resistance are reviewed. The end-inflation occlusion method was used to study the mechanical properties of the respiratory system before and after interleukin-6 administration. The cytokine was shown to induce significant, dose-dependent increments in both the resistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance) and the additional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elastic resistance). There were no alterations in respiratory system elastance. Even when administered to healthy mammals, interleukin-6 determines a significant effect on respiratory system resistance causing an increase in the mechanical work of breathing during inspiration. IL-6 hypothetically plays an active role in the pathogenesis of respiratory system diseases and the mechanisms that may be involved are discussed here.

  18. Interleukin-6 and Lung Inflammation: Evidences of A Causing Role in Inducing Respiratory System Resistance Increments.

    PubMed

    Rubini, Alessandro

    2013-07-10

    Interleukin-6 has been shown to be increased in various pathological conditions involving the lungs, both experimentally induced in animals, or spontaneously occurring in humans. Experimental data demonstrating a significant role of interleukin-6 in commonly occurring respiratory system inflammatory diseases are reviewed. These diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by respiratory system mechanical derangement, most of all because increased elastance and airway resistance. Recent findings showing a causative role of interleukin-6 in determining an airway resistance increment are reviewed. By applying the end-inflation occlusion method to study respiratory system mechanical properties before and after interleukin-6 administration, it was shown that this cytokine induced significant increments in both the resistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance), and in the additional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elastic resistance). A dose-dependent effect was also demonstrated. No effects were instead detected on respiratory system elastance. Even solely administrated in healthy mammals, interleukin-6 exhibits a significant effect on respiratory system resistances, leading to increased inspiratory muscle mechanical work of breathing. Thus, IL-6 may play an active role in the pathogenesis of respiratory system diseases. The possible involved mechanisms are discussed.

  19. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation.

    PubMed

    Hodge, David R; Peng, Benjamin; Cherry, James C; Hurt, Elaine M; Fox, Stephen D; Kelley, James A; Munroe, David J; Farrar, William L

    2005-06-01

    A strong association exists between states of chronic inflammation and cancer, and it is believed that mediators of inflammation may be responsible for this phenomenon. Interleukin 6 (IL-6) is an inflammatory cytokine known to play a role in the growth and survival of many types of tumors, yet the mechanisms employed by this pleomorphic cytokine to accomplish this feat are still poorly understood. Another important factor in tumor development seems to be the hypermethylation of CpG islands located within the promoter regions of tumor suppressor genes. This common epigenetic alteration enables tumor cells to reduce or inactivate the expression of important tumor suppressor and cell cycle regulatory genes. Here we show that in the IL-6-responsive human multiple myeloma cell line KAS 6/1, the promoter region of p53 is epigenetically modified by methyltransferases, resulting in decreased levels of expression. Furthermore, cells treated with IL-6 exhibit an increase in the expression of the DNA maintenance methylation enzyme, DNMT-1. The DNA methyltransferase inhibitor zebularine reverses the methylation of the p53 promoter, allowing the resumption of its expression. However, when zebularine is withdrawn from the cells, the reestablishment of the original CpG island methylation within the p53 promoter does not occur in the absence of IL-6, and cells which do not receive IL-6 eventually die, as p53 expression continues unchecked by remethylation. Interestingly, this loss of viability seems to involve not the withdrawal of cytokine, but the inability of the cell to resilence the promoter. Consistent with this model, when cells that express IL-6 in an autocrine fashion are subjected to identical treatment, p53 expression is reduced shortly after withdrawal of zebularine. Therefore, it seems IL-6 is capable of maintaining promoter methylation thus representing one of the possible mechanisms used by inflammatory mediators in the growth and survival of tumors.

  20. Synergistic inhibition of interleukin-6 production in adipose stem cells by tart cherry anthocyanins and atorvastatin

    USDA-ARS?s Scientific Manuscript database

    Studies have shown positive correlations between inflammatory cytokines such as interleukin-6 (IL-6) and the development of chronic diseases including cardiovascular disease by activating C-reactive prorein (CRP). Both atorvastatin calcium (lipitor) as well as flavonoid rich fruit such as tart cherr...

  1. Interleukin-6 and Delayed Onset Muscle Soreness Do Not Vary during the Menstrual Cycle

    ERIC Educational Resources Information Center

    Chaffin, Morgan E.; Berg, Kris E.; Meendering, Jessica R.; Llewellyn, Tamra L.; French, Jeffrey A.; Davis, Jeremy E.

    2011-01-01

    The purpose of this study was to determine if a difference in interleukin-6 (IL-6) and delayed onset muscles soreness (DOMS) exists in two different phases of the menstrual cycle. Nine runners performed one 75-min high-intensity interval running session during the early follicular (EF) phase and once during the midluteal (ML) phase of the…

  2. Interleukin-6 and Delayed Onset Muscle Soreness Do Not Vary during the Menstrual Cycle

    ERIC Educational Resources Information Center

    Chaffin, Morgan E.; Berg, Kris E.; Meendering, Jessica R.; Llewellyn, Tamra L.; French, Jeffrey A.; Davis, Jeremy E.

    2011-01-01

    The purpose of this study was to determine if a difference in interleukin-6 (IL-6) and delayed onset muscles soreness (DOMS) exists in two different phases of the menstrual cycle. Nine runners performed one 75-min high-intensity interval running session during the early follicular (EF) phase and once during the midluteal (ML) phase of the…

  3. Interleukin 1B variant -1473G/C (rs1143623) influences triglyceride and interleukin 6 metabolism

    USDA-ARS?s Scientific Manuscript database

    Interleukin 1b (IL1B or IL-1ß), is a key modulator of the immune response which exerts its functions mainly via interleukin 6 (IL6) regulation. Fatty meals cause transient hypertriglyceridemia and are considered to be proinflammatory, but the extent of these responses shows high interindividual susc...

  4. Interleukin-6 in cerebrospinal fluid as a biomarker of acute meningitis.

    PubMed

    García-Hernández, Pablo; Prieto, Belén; Martínez-Morillo, Eduardo; Rodríguez, Verónica; Álvarez, Francisco V

    2016-01-01

    Microbiological culture of cerebrospinal fluid is the gold standard to differentiate between aseptic and bacterial meningitis, but this method has low sensitivity. A fast and reliable new marker would be of interest in clinical practice. Interleukin-6, secreted by T cells in response to meningeal pathogens and quickly delivered into cerebrospinal fluid, was evaluated as a marker of acute meningitis. A total of 150 cerebrospinal fluid samples were analysed by an electrochemiluminescence method, selected according to patient diagnosis: (a) bacterial meningitis confirmed by positive culture (n = 26); (b) bacterial meningitis with negative culture or not performed (n = 15); (c) viral meningitis confirmed by polymerase chain reaction or immunoglobulin G determination (n = 23); (d) viral meningitis with polymerase chain reaction negative or not performed (n = 42); and (e) controls (n = 44). Cerebrospinal fluid interleukin-6 concentration showed significant differences between all pathologic groups and the control group (P < 0.001). As a diagnostic tool for bacterial meningitis, interleukin-6 showed an area under the curve of 0.937 (95% confidence intervals: 0.895-0.978), significantly higher than those of classical biomarkers. An interleukin-6 cutoff of 1418 pg/mL showed 95.5% sensitivity and 77.5% specificity, whereas a value of 15,060 pg/mL showed 63.6% sensitivity and 96.7% specificity, for diagnosis of bacterial meningitis. Interleukin-6 measured by electrochemiluminescence method is a promising marker for early differentiation between aseptic and bacterial meningitis. More studies are needed to validate clinical implications for future practice in an emergency laboratory. © The Author(s) 2015.

  5. Joint Analysis of Individual Participants’ Data from 17 Studies on the Association of the IL6 Variant -174G>C with Circulating Glucose Levels, Interleukin-6 Levels, and Body-Mass Index

    PubMed Central

    Huth, Cornelia; Illig, Thomas; Herder, Christian; Gieger, Christian; Grallert, Harald; Vollmert, Caren; Rathmann, Wolfgang; Hamid, Yasmin H.; Pedersen, Oluf; Hansen, Torben; Thorand, Barbara; Meisinger, Christa; Döring, Angela; Klopp, Norman; Gohlke, Henning; Lieb, Wolfgang; Hengstenberg, Christian; Lyssenko, Valeriya; Groop, Leif; Ireland, Helen; Stephens, Jeffrey W.; Asterholm, Ingrid Wernstedt; Jansson, John-Olov; Boeing, Heiner; Möhlig, Matthias; Stringham, Heather M.; Boehnke, Michael; Tuomilehto, Jaakko; Fernandez-Real, Jose-Manuel; Lopez-Bermejo, Abel; Gallart, Luis; Vendrell, Joan; Humphries, Steve E.; Kronenberg, Florian; Wichmann, H.-Erich; Heid, Iris M.

    2013-01-01

    Background Several studies have investigated associations between the -174G>C polymorphism (rs1800795) of the IL6-gene, but presented inconsistent results. Aims This joint analysis aimed to clarify whether IL6 -174G>C was associated with type 2 diabetes mellitus (T2DM) related quantitative phenotypes. Methods Individual-level data from all studies of the IL6-T2DM consortium on Caucasian subjects with available BMI were collected. As study-specific estimates did not show heterogeneity (P>0.1), they were combined by using the inverse-variance fixed-effect model. Results The main analysis included 9440, 7398, 24,117, or 5659 nondiabetic and manifest T2DM subjects for fasting glucose, 2-hour glucose, BMI or circulating interleukin-6 levels, respectively. IL6 -174 C-allele carriers had significantly lower fasting glucose (−0.091mmol/L, P=0.014). There was no evidence for association between IL6 -174G>C and BMI or interleukin-6. In an additional analysis of 641 subjects known to develop T2DM later on, the IL6 -174 CC-genotype was associated with higher baseline interleukin-6 (+0.75pg/mL, P=0.004), which was consistent with higher interleukin-6 in the 966 manifest T2DM subjects (+0.50pg/mL, P=0.044). Conclusions Our data suggest association between IL6 -174G>C and quantitative glucose, and exploratory analysis indicated modulated interleukin-6 levels in pre-diabetic subjects, being in-line with this SNP’s previously reported T2DM association and a role of circulating interleukin-6 as intermediate phenotype. PMID:18752089

  6. The role of interleukin-6 in cases of cardiac myxoma. Clinical features, immunologic abnormalities, and a possible role in recurrence.

    PubMed

    Mendoza, C E; Rosado, M F; Bernal, L

    2001-01-01

    We performed this prospective study to evaluate the correlation of interleukin-6 serum levels with preoperative constitutional symptoms and immunologic abnormalities, and the possible role played by this cytokine in tumor recurrence. Eight patients with atrial myxoma were evaluated at our institution from July 1993 to November 1998. We measured their interleukin-6 serum levels by enzyme-linked immunosorbent assay method preoperatively and 1 and 6 months after surgery. Two of the cases involved recurrent tumor, 1 patient had undergone his 1st surgery at a different institution and died during the 2nd procedure, so his data were incomplete. Preoperatively the whole group of patients had elevated interleukin-6 serum levels. Although patients with a 1st occurrence of tumor demonstrated a positive correlation between interleukin-6 serum level and tumor size, the 2 patients with recurrent tumors appeared to have higher interleukin-6 levels regardless of tumor size. Once the tumor was surgically removed, interleukin-6 levels returned to normal values, and this was associated with regression of clinical manifestations and immunologic features. According to our study, the overproduction of interleukin-6 by cardiac myxomas is responsible for the constitutional symptoms and immunologic abnormalities observed in patients with such tumors and might also play a role as a marker of recurrence. This study also suggests that recurrent cardiac myxomas form a subgroup of cardiac myxomas with a highly intrinsic aggressiveness, as implied by their greater interleukin-6 production despite their smaller size. Further studies are needed to confirm these results.

  7. The Role of Interleukin-6 in Cases of Cardiac Myxoma: Clinical Features, Immunologic Abnormalities, and a Possible Role in Recurrence

    PubMed Central

    Mendoza, Cesar Emilio; Rosado, Manuel Francisco; Bernal, Leon

    2001-01-01

    We performed this prospective study to evaluate the correlation of interleukin-6 serum levels with preoperative constitutional symptoms and immunologic abnormalities, and the possible role played by this cytokine in tumor recurrence. Eight patients with atrial myxoma were evaluated at our institution from July 1993 to November 1998. We measured their interleukin-6 serum levels by enzyme-linked immunosorbent assay method preoperatively and 1 and 6 months after surgery. Two of the cases involved recurrent tumor; 1 patient had undergone his 1st surgery at a different institution and died during the 2nd procedure, so his data were incomplete. Preoperatively, the whole group of patients had elevated interleukin-6 serum levels. Although patients with a 1st occurrence of tumor demonstrated a positive correlation between interleukin-6 serum level and tumor size, the 2 patients with recurrent tumors appeared to have higher interleukin-6 levels regardless of tumor size. Once the tumor was surgically removed, interleukin-6 levels returned to normal values, and this was associated with regression of clinical manifestations and immunologic features. According to our study, the overproduction of interleukin-6 by cardiac myxomas is responsible for the constitutional symptoms and immunologic abnormalities observed in patients with such tumors and might also play a role as a marker of recurrence. This study also suggests that recurrent cardiac myxomas form a subgroup of cardiac myxomas with a highly intrinsic aggressiveness, as implied by their greater interleukin-6 production despite their smaller size. Further studies are needed to confirm these results. PMID:11330738

  8. Interleukin-6 production by human monocytes stimulated with Cryptococcus neoformans components.

    PubMed

    Delfino, D; Cianci, L; Lupis, E; Celeste, A; Petrelli, M L; Curró, F; Cusumano, V; Teti, G

    1997-06-01

    In order to ascertain if Cryptococcus neoformans components can induce interleukin-6 (IL-6) production, we stimulated human whole blood with purified capsular products. Their potencies in stimulating IL-6 release were mannoproteins > galactoxylomannan = glucuronoxylomannan > alpha(1-3)glucan. IL-6 production was tumor necrosis factor alpha independent and required the presence of monocytes and plasma. Since IL-6 can stimulate replication of the human immunodeficiency virus in monocytic cells, these findings may be clinically relevant.

  9. Interleukin-6 production by human monocytes stimulated with Cryptococcus neoformans components.

    PubMed Central

    Delfino, D; Cianci, L; Lupis, E; Celeste, A; Petrelli, M L; Curró, F; Cusumano, V; Teti, G

    1997-01-01

    In order to ascertain if Cryptococcus neoformans components can induce interleukin-6 (IL-6) production, we stimulated human whole blood with purified capsular products. Their potencies in stimulating IL-6 release were mannoproteins > galactoxylomannan = glucuronoxylomannan > alpha(1-3)glucan. IL-6 production was tumor necrosis factor alpha independent and required the presence of monocytes and plasma. Since IL-6 can stimulate replication of the human immunodeficiency virus in monocytic cells, these findings may be clinically relevant. PMID:9169790

  10. Interleukin-6 and resistin in relation to anthropometric measurements in school children.

    PubMed

    Del Pilar Escalona-Villasmil, Carolina; Leal-Montiel, Jorymar Yoselyn; Ortega-Fernindez, Pablo Antonio; Javier Chavez, Carlos

    2016-06-01

    The worldwide prevalence of childhood obesity has increased greatly over the past three decades. The increasing occurrence in children of disorders, such as type 2 diabetes, is believed to be a consequence of this obesity epidemic. Although the precise mechanisms are still unclear, dysregulated production or secretion of adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related me- tabolic diseases. The objective of the study was to determine the serum levels of interleukin-6 and resistin in relation to anthropometric measurements in school children. One hundred and three school-age children were studied. The anthropometric assessment included weight, hei- ght, triceps skinfold (TSF), waist circumference (WC), waist-to-height ratio (WiHtR) and Body Mass Index (BMI). Interleukin-6 and resistin levels were measured by ELISA. The data were analyzed using the SPSS version 20 statistical program and 95% CIs (p<0.05) was considelred significant. BMI values indicated that 15.54 % of the population was overweight, and 11.65 % was obese. We found that scholars with excess WC, WHtR and BMI (overweight) had higher levels of IL-6 and scholars with excess WC and WHtR had higher levels of resistin (p <0.05). Interleukin-6 showed positive correlation with WC (r=0.229; p = 0.020) and waist-to-height ratio (r=0.397; pinterleukin-6 and resistin).

  11. Adipose-derived stem cells inhibit epidermal melanocytes through an interleukin-6-mediated mechanism.

    PubMed

    Kim, Deok-Woo; Jeon, Byung-Joon; Hwang, Na-Hyun; Kim, Min-Sook; Park, Seung-Ha; Dhong, Eun-Sang; Yoon, Eul-Sik; Lee, Byung-Il

    2014-09-01

    Several investigators have postulated that human adipose-derived stem cells can be used for skin rejuvenation, but there have been few reports about their direct effects on human epidermal melanocytes. The authors studied the effects on melanocytes, and the causative agent of those effects was further investigated in this study. Human epidermal melanocytes were divided into three groups and cultured in adipose-derived stem cell-conditioned medium, human dermal fibroblast-conditioned medium, or control medium. Concentrations of melanogenic cytokines in these media were measured using enzyme-linked immunosorbent assay kits. After 3 and 7 days of incubation, cell proliferation, melanin content, tyrosinase activity, and melanogenic gene expression were measured. Interleukin-6-neutralizing antibodies were mixed with adipose-derived stem cell-conditioned medium in which human epidermal melanocytes were cultured, and melanocyte growth and melanogenesis were measured again. Interleukin-6 concentrations in adipose-derived stem cell- and human epidermal melanocyte-conditioned media were 1373 and 495 pg/ml, respectively. Both types of medium suppressed melanocyte proliferation and melanin synthesis (p < 0.05), but adipose-derived stem cell-conditioned medium was more effective than human dermal fibroblast-conditioned medium in inhibition of human epidermal melanocyte proliferation, melanin synthesis, and tyrosinase activity (p < 0.05). Interleukin-6-neutralizing antibody sufficiently reversed the antimelanogenic effects of adipose-derived stem cell-conditioned medium such that human epidermal melanocyte proliferation, melanin content, tyrosinase activity, and tyrosinase mRNA levels were restored (p < 0.05). Adipose-derived stem cell-conditioned medium inhibited melanocyte proliferation and melanin synthesis by down-regulating melanogenic enzymes. Interleukin-6 plays a pivotal role in inhibition of melanocytes.

  12. TNF-alpha polymorphisms as a potential modifier gene in the cystic fibrosis

    PubMed Central

    Coutinho, Cyntia AAC; Marson, Fernando AL; Marcelino, Aline RB; Bonadia, Luciana C; Carlin, Marcelo P; Ribeiro, Antonio F; Ribeiro, Jose D; Bertuzzo, Carmen S

    2014-01-01

    Modifier genes, as the TNF-α gene, can modulate the cystic fibrosis (CF) severity. Thus, -238G>A and -308G>A polymorphisms of TNF-α gene were analyzed as modifiers of CF. In this context, the present study enrolled 49 CF patients (diagnosis performed by sweat test and complete CFTR screening). The -238G>A polymorphism analysis was performed by ARMS-PCR, and -308G>A, by PCR-RFLP. In our data, the -238G>A polymorphism was not associated with clinical variability. The AA genotype for -308G>A polymorphism was a risk factor for early gastrointestinal symptoms (OR=5.98, 95%CI=1.06-49.68) and protection for the first Pseudomonas aeruginosa (OR=0.05, 95%CI=0.0003-0.007). For the first P. aeruginosa, GA genotype was a risk factor (OR=10.2, 95%CI=1.86-84.09); for the same genotype, the diagnosis was made in minor time than the AA genotype (p=0.031). Considering the -308G>A polymorphism alleles, the G allele was a risk factor for early pulmonary symptoms (OR=3.81, 95%CI=1.13-12.97) and P. aeruginosa (OR=66.77, 95%CI=15.18-482.7); however, the same allele showed better transcutaneous oxygen saturation (OR=9.24, 95%CI=1.53-206.1). The A allele was a protective factor for early pulmonary symptoms (OR=12.26, 95%CI=0.08-0.89) and P. aeruginosa (OR=12.15, 95%CI=0002-0007), however, the same allele was a risk factor for worst transcutaneous oxygen saturation (OR=7.01, 95%CI=1.14-157.4). As conclusion, the -308G>A polymorphism of the TNF-α gene was associated with the CF severity. PMID:24959313

  13. Genetic modifiers of chromatin acetylation antagonize the reprogramming of epi-polymorphisms.

    PubMed

    Abraham, Anne-Laure; Nagarajan, Muniyandi; Veyrieras, Jean-Baptiste; Bottin, Hélène; Steinmetz, Lars M; Yvert, Gaël

    2012-09-01

    Natural populations are known to differ not only in DNA but also in their chromatin-associated epigenetic marks. When such inter-individual epigenomic differences (or "epi-polymorphisms") are observed, their stability is usually not known: they may or may not be reprogrammed over time or upon environmental changes. In addition, their origin may be purely epigenetic, or they may result from regulatory variation encoded in the DNA. Studying epi-polymorphisms requires, therefore, an assessment of their nature and stability. Here we estimate the stability of yeast epi-polymorphisms of chromatin acetylation, and we provide a genome-by-epigenome map of their genetic control. A transient epi-drug treatment was able to reprogram acetylation variation at more than one thousand nucleosomes, whereas a similar amount of variation persisted, distinguishing "labile" from "persistent" epi-polymorphisms. Hundreds of genetic loci underlied acetylation variation at 2,418 nucleosomes either locally (in cis) or distantly (in trans), and this genetic control overlapped only partially with the genetic control of gene expression. Trans-acting regulators were not necessarily associated with genes coding for chromatin modifying enzymes. Strikingly, "labile" and "persistent" epi-polymorphisms were associated with poor and strong genetic control, respectively, showing that genetic modifiers contribute to persistence. These results estimate the amount of natural epigenomic variation that can be lost after transient environmental exposures, and they reveal the complex genetic architecture of the DNA-encoded determinism of chromatin epi-polymorphisms. Our observations provide a basis for the development of population epigenetics.

  14. Polymorphisms in NADPH oxidase CYBA gene modify the risk of ESRD in patients with chronic glomerulonephritis.

    PubMed

    Zhou, Hui; Chen, Min; Zhu, Ying; Wang, Bing; Liu, Xiao-ning; Zuo, Zhi; Tang, Feng-Ying

    2016-01-01

    End-stage renal disease (ESRD) was defined as start of renal replacement therapy or death due to kidney disease. However, death due to acute kidney injury was not included. It typically occurs when chronic renal failure progresses to a point where the kidneys are permanently functioning at less than 10% of their capacity. Oxidative stress (OS) plays a crucial role in ESRD. Nicotinamide adenine dinucleotide phosphate (NADPH) is one of the most important enzymes during oxidative stress. Cytochrome b light chain (CYBA), encoded by a polymorphic gene, which is a critical component of the nicotinamide adenine dinucleotide (NADH)/NADPH oxidase system and plays an important role in electron transport and superoxide anion production, is located on chromosome band 16q24 and has six exons spanning almost 7.76 kb of genomic DNA. CYBA gene polymorphisms can influence the activity of NADPH oxidase. To evaluate the association between CYBA gene polymorphisms and ESRD, we genotyped five CYBA polymorphisms using TaqMan allelic discrimination assay on DNA samples from 306 healthy controls and 332 patients with ESRD. Our results suggested that rs1049255 polymorphism of CYBA modified the risk of ESRD (p  =  0.019; OR  =  0.625; 95%CI  =  0.424-0.921). GG genotype and G allele might be a protective factor against the risk of ESRD, especially in patients with chronic glomerulonephritis.

  15. The Role of Interleukin-6 in Mucosal IgA Antibody Responses in Vivo

    NASA Astrophysics Data System (ADS)

    Ramsay, Alistair J.; Husband, Alan J.; Ramshaw, Ian A.; Bao, Shisan; Matthaei, Klaus I.; Koehler, Georges; Kopf, Manfred

    1994-04-01

    In mice with targeted disruption of the gene that encodes interleukin-6 (IL-6), greatly reduced numbers of immunoglobulin A (IgA)-producing cells were observed at mucosae and grossly deficient local antibody responses were recorded after mucosal challenge with either ovalbumin or vaccinia virus. The IgA response in the lungs was completely restored after intranasal infection with recombinant vaccinia viruses engineered to express IL-6. These findings demonstrate a critical role for IL-6 in vivo in the development of local IgA antibody responses and illustrate the effectiveness of vector-directed cytokine gene therapy.

  16. [Effects of antiorthostatic hypokinesia on blood levels of interleukine-1beta and interleukine-6 in primates].

    PubMed

    Gurin, V N; Krotov, V P; Gurin, A V; Korol'kov, V I; Gordeev, Iu V

    2007-01-01

    Investigations with Macaca mulatta of 4-5 yrs. of age with the body mass of 4.5-6.5 kg showed that 10 days of tilting with the head end at .5 degrees reduced body temperature but not levels of interleukine-1beta and interleukine-6 in blood plasma. On the next days after return of animals to cages IL-6 was found to increase sharply in more than 10 times. On subsequent 4 days both IL -1beta and IL-6 were within the normal range.

  17. Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Compensates for Interleukin-6 in Initial B Cell Activation.

    PubMed

    Sin, Sang-Hoon; Kang, Sun Ah; Kim, Yongbaek; Eason, Anthony; Tan, Kelly; An, Hyowon; Dittmer, Dirk P

    2015-12-09

    Interleukin 6 (IL-6) is considered a proliferation and survival factor for B cells. To assess the role of IL-6 in Kaposi sarcoma-associated herpesvirus (KSHV) latency, KSHV latency locus-transgenic mice (referred to as latency mice) lacking IL-6 were evaluated. IL-6(-/-) latency mice had the same phenotypes as the latency mice, i.e., increased frequency of marginal zone B cells, hyperplasia, and hyperglobulinemia, indicating that the KSHV latency locus, which includes all viral microRNAs (miRNAs), can compensate for lack of IL-6 in premalignant B cell activation.

  18. Interleukin 6 and tumour necrosis factor alpha serum levels in monoclonal gammopathy of undetermined significance.

    PubMed

    Bladé, Joan; Filella, Xabier; Montoto, Silvia; Bosch, Francesc; Rosiñol, Laura; Coca, Francesca; Giné, Eva; Nadal, Elisabeth; Aymerich, Marta; Rozman, María; Montserrat, Emili

    2002-05-01

    The objectives of the present study were to compare the interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) serum levels of individuals with monoclonal gammopathy of undetermined significance (MGUS) with those of healthy controls, and to ascertain the predictor value of these cytokines in the evolution from MGUS to multiple myeloma. After a median follow-up of 7 years from the initial cytokine measurements, nine patients with MGUS have evolved to a malignant condition. The actuarial probability of malignant transformation in patients with increased IL-6 and TNF-alpha was not significantly higher than in those with normal values.

  19. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies

    PubMed Central

    2012-01-01

    Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation. PMID:22421339

  20. Interleukin-6 and interleukin-6 receptor expression, localization, and involvement in pain-sensing neuron activation in a mouse intervertebral disc injury model.

    PubMed

    Sainoh, Takeshi; Orita, Sumihisa; Miyagi, Masayuki; Sakuma, Yoshihiro; Yamauchi, Kazuyo; Suzuki, Miyako; Kubota, Go; Oikawa, Yasuhiro; Inage, Kazuhide; Sato, Jun; Fujimoto, Kazuki; Shiga, Yasuhiro; Inoue, Gen; Aoki, Yasuchika; Takahashi, Kazuhisa; Ohtori, Seiji

    2015-10-01

    The pathological mechanism of intractable low back pain is unclear. However, intervertebral disc (IVD) degeneration is a primary cause of low back pain, and pain-related mediators, such as interleukin-6 (IL-6), have been correlated with discogenic pain. The objective of this study is to elucidate the mechanism of local IL-6 and IL-6 receptor (IL-6R) expression after IVD injury as well as determine the involvement of IL-6/IL-6 signaling in discogenic pain. To do this, quantitative and immunohistological analyses in a mouse model of IVD injury were performed. Firstly, we measured the local expression levels of IL-6 and IL-6R in IVDs by enzyme-linked immunosorbent assay (ELISA). Secondly, we immunohistochemically confirmed their localization in injured IVDs. Lastly, we evaluated the effects of intradiscal injection of an IL-6 inhibitor by evaluating pain-related protein, calcitonin gene-related peptide (CGRP), expression in dorsal root ganglia (DRG) neurons that innervate IVDs. Injured IVDs showed increased production of IL-6 and IL-6R. IL-6 and IL-6R expression in the injured IVD were predominantly localized in the annulus fibrosus and endplate, and intradiscal injection of the IL-6 inhibitor suppressed CGRP expression in the DRG neurons. These results show that IL-6 and IL-6R expression levels are responsive to IVD injury and that inhibition of IL-6/IL-6R signaling may be a promising analgesic treatment for degenerative disc diseases.

  1. The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling.

    PubMed Central

    Fischer, Patrick; Lehmann, Ute; Sobota, Radoslaw M; Schmitz, Jochen; Niemand, Claudia; Linnemann, Sonja; Haan, Serge; Behrmann, Iris; Yoshimura, Akihiko; Johnston, James A; Müller-Newen, Gerhard; Heinrich, Peter C; Schaper, Fred

    2004-01-01

    The immediate early response of cells treated with IL-6 (interleukin-6) is the activation of the signal transducer and activator of transcription (STAT)3. The Src homology domain 2 (SH2)-containing protein tyrosine phosphatase SHP2 and the feedback inhibitor SOCS3 (suppressor of cytokine signalling) are potent inhibitors of IL-6 signal transduction. Impaired function of SOCS3 or SHP2 leads to enhanced and prolonged IL-6 signalling. The inhibitory function of both proteins depends on their recruitment to the tyrosine motif 759 within glycoprotein gp130. In contrast to inactivation, desensitization of signal transduction is regarded as impaired responsiveness due to prestimulation. Usually, after activation the sensing receptor becomes inactivated by modifications such as phosphorylation, internalization or degradation. We designed an experimental approach which allows discrimination between desensitization and inactivation of IL-6 signal transduction. We observed that pre-stimulation with IL-6 renders cells less sensitive to further stimulation with IL-6. After several hours, the cells become sensitive again. We show that not only signal transduction through previously activated receptors is affected by desensitization but signalling through receptors which were not targeted by the first stimulation was also attenuated ( trans -desensitization). Interestingly, in contrast to inhibition, desensitization does not depend on the presence of functional SHP2. Furthermore, cells lacking SOCS3 show constitutive STAT3 activation which is not affected by pre-stimulation with IL-6. All these observations suggest that desensitization and inhibition of signalling are mechanistically distinct. PMID:14611646

  2. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions

    PubMed Central

    Smolen, Josef S; Schoels, Monika M; Nishimoto, Norihiro; Breedveld, Ferdinand C; Burmester, Gerd R; Dougados, Maxime; Emery, Paul; Ferraccioli, Gianfranco; Gabay, Cem; Gibofsky, Allan; Gomez-Reino, Juan Jesus; Jones, Graeme; Kvien, Tore K; Murakami, Miho; Betteridge, Neil; Bingham, Clifton O; Bykerk, Vivian; Choy, Ernest H; Combe, Bernard; Cutolo, Maurizio; Graninger, Winfried; Lanas, Angel; Martin-Mola, Emilio; Montecucco, Carlomaurizio; Ostergaard, Mikkel; Pavelka, Karel; Rubbert-Roth, Andrea; Sattar, Naveed; Scholte-Voshaar, Marieke; Tanaka, Yoshiya; Trauner, Michael; Valentini, Gabriele; Winthrop, Kevin L; de Wit, Maarten; van der Heijde, Désirée

    2013-01-01

    Background Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion. Methods Preparation of this document involved international experts in RA treatment and RA patients. A systematic literature search was performed that focused on TCZ and other IL6-pathway inhibitors in RA and other diseases. Subsequently, incorporating available published evidence and expert opinion, the steering committee and a broader expert committee (both including RA patients) formulated the current consensus statement. Results The consensus statement covers use of TCZ as combination- or monotherapy in various RA populations and includes clinical, functional and structural aspects. The statement also addresses the second approved indication in Europe JIA and non-approved indications. Also early phase trials involving additional agents that target the IL-6 receptor or IL-6 were evaluated. Safety concerns, including haematological, hepatic and metabolic issues as well as infections, are addressed likewise. Conclusions The consensus statement identifies points to consider when using TCZ, regarding indications, contraindications, screening, dose, comedication, response evaluation and safety. The document is aimed at supporting clinicians and informing patients, administrators and payers on opportunities and limitations of IL-6 pathway inhibition. PMID:23172750

  3. Fetal fibronectin, interleukin-6, and C-reactive protein are useful in establishing prognostic subcategories of idiopathic preterm labor.

    PubMed

    Burrus, D R; Ernest, J M; Veille, J C

    1995-10-01

    Our purpose was to evaluate fetal fibronectin, interleukin-6, and C-reactive protein from patients with preterm labor to establish prognostic subcategories. Thirty-seven patients with preterm labor had cervical fetal fibronectin and plasma C-reactive protein sampled. Eighteen of these patients had amniotic fluid interleukin-6 levels measured. Outcome variables were (1) delivery before 34 weeks and (2) delivery within 48 hours. Detectable cervical fetal fibronectin identified 89% of patients who were delivered before 34 weeks' gestation. Interleukin-6 > 1500 pg/ml identified 88% of patients who were delivered within 48 hours. C-reactive protein > 1.5 mg/dl correlated with elevated interleukin-6 levels (p < 0.001). Three subcategories of idiopathic preterm labor were evident: (1) fetal fibronectin nondetectable (37% likely to be delivered before 34 weeks), (2) fetal fibronectin detectable but interleukin-6 < 1500 pg/ml (79% likely to be delivered before 34 weeks but 85% with > 48 hours' latency), and (3) fetal fibronectin present and interleukin-6 > 1500 pg/ml (91% likely to be delivered with < 48 hours' latency).

  4. HSP70-hom gene polymorphisms modify the association of diethylhexyl phthalates with insulin resistance.

    PubMed

    Kim, Jin Hee; Hong, Yun-Chul

    2014-12-01

    Recent studies suggest that diethylhexyl phthalates (DEHP) could contribute to the development of insulin resistance (IR) through oxidative stress, and that heat shock protein (HSP) could be related with the association between DEHP and IR. Therefore, we evaluated the effect modification of genetic polymorphisms of HSP70-hom, an oxidative stress related gene, on the relation between exposure to DEHP and IR. We obtained repeated blood and urine samples from 414 elderly female participants and measured urinary levels of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) as metabolites of DEHP. We also measured serum levels of fasting glucose and insulin, derived the homeostatic model assessment (HOMA) index to assess IR, and genotyped two HSP70-hom polymorphisms (rs2227956 and rs2075800). A mixed effect model and penalized regression spline were used to estimate the associations between DEHP exposure and IR by genetic polymorphisms. The molar sum of MEHHP and MEOHP (∑DEHP) were significantly associated with HOMA (β = 0.30, P = 0.022). When stratified by genotype at rs2227956, the relationship between ∑DEHP and HOMA was statistically significant in participants with TT (β = 0.32, P = 0.048) or TC (β = 0.60, P = 0.008), while at rs2075800 there was a marginal association for the GA genotype (β = 0.33, P = 0.097). When haplotypes were constituted across the two HSP70-hom polymorphisms (rs2227956 and rs2075800), the association was apparent only in participants with the T-A haplotype (β = 0.39, P = 0.029). Our study suggests that HSP70-hom polymorphisms modify the association of DEHP with IR.

  5. Genetic polymorphisms in MMP 2, 9 and 3 genes modify lung cancer risk and survival

    PubMed Central

    2012-01-01

    Background Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of tumour progression, including the later stages of invasion and metastasis. Genetic variants in the MMP genes may influence the biological function of these enzymes and change their role in carcinogenesis and progression. We have investigated the association between the -735 C/T, the -1171 5A/6A, and the -1562 C/T polymorphisms in the MMP2, MMP3 and MMP9 genes, respectively, and the risk and survival of lung cancer. Methods The case-control study includes 879 lung cancer patients and 803 controls from a Caucasian population in Spain (CAPUA study). Genotypes were determined by PCR-RFLP. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. The Kaplan-Meier method, long-rank test and Cox's were used for the survival analysis. Results The MMP9 -1562 T/T genotype was associated with a statistically significant decreased risk of developing lung cancer (OR = 0.23; 95% CI: 0.06-0.85), whereas no association was found for the MMP2 -735 C/T and MMP3 -1171 5A/6A polymorphisms. The MMP2 -735 T/T genotype was statistically significantly associated with a decreased survival in non-small cell lung cancer (NSCLC) patients, identified as an independent prognosis factor of survival (hazard ratio (HR) = 1.79; 95% CI: 1.00-3.20). In contrast, no association was found between the MMP3 -1171 5A/6A and the MMP9 -1562 C/T polymorphisms and survival. Conclusions These findings support the hypothesis that the MMP9 -1562 C/T polymorphism is associated with a protective effect against the development of lung cancer and suggest that the MMP2 -735 C/T polymorphism modify the length of survival in NSCLC patients. PMID:22455335

  6. Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth.

    PubMed

    Velez, Digna R; Fortunato, Stephen J; Williams, Scott M; Menon, Ramkumar

    2008-06-01

    Spontaneous preterm birth (PTB-gestational age <37 weeks) occurs in approximately 450 000 births annually in the United States and is one of the leading causes of neonatal morbidity and mortality. Risk of PTB is affected by complex gene-environment interactions that are not well understood. We examined the PTB candidate gene, Interleukin 6 (IL-6) and its receptor (IL6-R) in both Caucasian (145 PTB and 194 term maternal; 140 PTB and 179 term fetal) and African-American (76 PTB and 191 term maternal; 66 PTB and 183 term fetal) DNA. Eight single nucleotide polymorphisms (SNPs) in IL-6 and 22 SNPs in IL6R were examined for association with IL-6 amniotic fluid (AF) concentrations, as concentration of IL-6 is a hypothesized risk factor. In addition, IL-6 and IL6-R SNPs were analyzed for associations with PTB. Haplotype associations were tested by sliding windows. No strong single marker effects were observed in Caucasians; however, in African-American maternal IL-6R marker rs4553185 associated with PTB (allele P = 4.49 x 10(-3) and genotype P = 0.01). The strongest haplotype associations were observed in IL-6R with IL-6 cytokine concentration as outcome: Caucasian fetal (rs4601580-rs4845618) P = 1.6 x 10(-3) and African-American maternal (rs4601580-rs4845618-rs6687726-rs7549338) P = 2.30 x 10(-3). Significant results converged on three regions in the two genes: in IL-6 markers rs1800797, rs1800796 and rs1800795; in IL-6R markers rs4075015, rs4601580, rs4645618, rs6687726 and rs7549338 and markers rs4845623, rs4537545 and rs4845625. In conclusion, our results suggest that IL-6 AF concentration, in situations of PTB, result from variation in IL-6 and more importantly IL-6R.

  7. Interleukin-6 Promotes the Migration and Cellular Senescence and Inhibits Apoptosis of Human Intrahepatic Biliary Epithelial Cells.

    PubMed

    Li, Ran; Dong, Juan; Bu, Xiu-Qin; Huang, Yong; Yang, Jing-Yu; Dong, Xuan; Liu, Jie

    2017-08-31

    Biliary epithelial cells (BEC) are closely related to some immune regulatory bile duct diseases. However, the complexity and polymorphism of the morphology and function of bile duct cells have hindered further investigation. Therefore, the aim of this study is to investigate how interleukin-6 (IL-6) affects the migration, cellular senescence and apoptosis of human intrahepatic biliary epithelial cells (HIBECs). The HIBECs were stimulated by different concentrations of IL-6 (0, 5, 10, 15 and 20 ng/ml, respectively). Transwell assay was performed in order to measure the migration abilities, positive β-Galactosidase staining for the cellular senescence of HIBECs, MTT assay for changes of proliferation after IL-6 treatment and flow cytometry for cell cycle and apoptosis. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were conducted in order to detect the mRNA and protein expressions of epithelial-mesenchymal transition (EMT) markers in HIBECs. In comparison to the 0 ng/ml group, in the 5, 10, 15 and 20 ng/ml groups, a significant increase in the number of migratory HIBECs, proliferation, along with mRNA and protein expressions of EMT markers was observed. While the mRNA and protein expressions of epithelial markers, the number of β-Galactosidase positive staining cells, as well as apoptosis rate of HIBECs dramatic decreased. Further, the aforementioned changes were significantly more evident in the 15 and 20 ng/ml groups in comparison to the 5 and 10 ng/ml groups. IL-6 may stimulate EMT, enhance the migration and proliferation, and inhibit apoptosis of HIBECs, thus delaying cellular senescence. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  8. Secretion of an immunoreactive single-chain variable fragment antibody against mouse interleukin 6 by Lactococcus lactis.

    PubMed

    Shigemori, Suguru; Ihara, Masaki; Sato, Takashi; Yamamoto, Yoshinari; Nigar, Shireen; Ogita, Tasuku; Shimosato, Takeshi

    2017-01-01

    Interleukin 6 (IL-6) is an important pathogenic factor in development of various inflammatory and autoimmune diseases and cancer. Blocking antibodies against molecules associated with IL-6/IL-6 receptor signaling are an attractive candidate for the prevention or therapy of these diseases. In this study, we developed a genetically modified strain of Lactococcus lactis secreting a single-chain variable fragment antibody against mouse IL-6 (IL6scFv). An IL6scFv-secretion vector was constructed by cloning an IL6scFv gene fragment into a lactococcal secretion plasmid and was electroporated into L. lactis NZ9000 (NZ-IL6scFv). Secretion of recombinant IL6scFv (rIL6scFv) by nisin-induced NZ-IL6scFv was confirmed by western blotting and was optimized by tuning culture conditions. We found that rIL6scFv could bind to commercial recombinant mouse IL-6. This result clearly demonstrated the immunoreactivity of rIL6scFv. This is the first study to engineer a genetically modified strain of lactic acid bacteria (gmLAB) that produces a functional anti-cytokine scFv. Numerous previous studies suggested that mucosal delivery of biomedical proteins using gmLAB is an effective and low-cost way to treat various disorders. Therefore, NZ-IL6scFv may be an attractive tool for the research and development of new IL-6 targeting agents for various inflammatory and autoimmune diseases as well as for cancer.

  9. Modified tetra-primer ARMS PCR as a single-nucleotide polymorphism genotyping tool.

    PubMed

    Mesrian Tanha, Hamzeh; Mojtabavi Naeini, Marjan; Rahgozar, Soheila; Rasa, Seyed Mohammad Mahdi; Vallian, Sadeq

    2015-03-01

    Genotyping of single-nucleotide polymorphisms (SNPs) has been applied in various genetic contexts. Tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) is reported as a prominent assay for SNP genotyping. However, there were published data that may question the reliability of this method on some occasions, in addition to a laborious and time-consuming procedure of the optimization step. In the current study, a new SNP genotyping method named modified tetra-primer ARMS (MTPA) PCR was developed based on tetra-primer ARMS PCR. The modified method has two improvements in its instruction, including equalization of outer primer and inner primer strength by additional mismatch in outer primers, and consideration of equal annealing temperature of specific fragments more than melting temperature of primers. Advantageously, a new computer software was provided for designing primers based on novel concepts. The usual tetra-primer ARMS PCR has a laborious process for optimization. In nonoptimal PCR programs, identification of the accurate genotype was found to be very difficult. However, in MTPA PCR, equalization of the amplicons and primer strength leads to increasing specificity and convenience of genotyping, which was validated by sequencing. In the MTPA PCR technique, a new mismatch at -2 positions of outer primers and equal annealing temperature improve the genotyping procedure. Together, the introduced method could be suggested as a powerful tool for genotyping single-nucleotide mutations and polymorphisms.

  10. A modified Stillinger-Weber potential for TlBr and its polymorphic extension

    DOE PAGES

    Zhou, Xiaowang; Foster, Michael E.; Jones, Reese E.; ...

    2015-04-30

    TlBr is promising for g- and x- radiation detection, but suffers from rapid performance degradation under the operating external electric fields. To enable molecular dynamics (MD) studies of this degradation, we have developed a Stillinger-Weber type of TlBr interatomic potential. During this process, we have also addressed two problems of wider interests. First, the conventional Stillinger-Weber potential format is only applicable for tetrahedral structures (e.g., diamond-cubic, zinc-blende, or wurtzite). Here we have modified the analytical functions of the Stillinger-Weber potential so that it can now be used for other crystal structures. Second, past modifications of interatomic potentials cannot always bemore » applied by a broad community because any new analytical functions of the potential would require corresponding changes in the molecular dynamics codes. Here we have developed a polymorphic potential model that simultaneously incorporates Stillinger-Weber, Tersoff, embedded-atom method, and any variations (i.e., modified functions) of these potentials. As a result, we have implemented this polymorphic model in MD code LAMMPS, and demonstrated that our TlBr potential enables stable MD simulations under external electric fields.« less

  11. A modified Stillinger-Weber potential for TlBr and its polymorphic extension

    SciTech Connect

    Zhou, Xiaowang; Foster, Michael E.; Jones, Reese E.; Doty, F. Patrick; Yang, Pin; Fan, Hongyou

    2015-04-30

    TlBr is promising for g- and x- radiation detection, but suffers from rapid performance degradation under the operating external electric fields. To enable molecular dynamics (MD) studies of this degradation, we have developed a Stillinger-Weber type of TlBr interatomic potential. During this process, we have also addressed two problems of wider interests. First, the conventional Stillinger-Weber potential format is only applicable for tetrahedral structures (e.g., diamond-cubic, zinc-blende, or wurtzite). Here we have modified the analytical functions of the Stillinger-Weber potential so that it can now be used for other crystal structures. Second, past modifications of interatomic potentials cannot always be applied by a broad community because any new analytical functions of the potential would require corresponding changes in the molecular dynamics codes. Here we have developed a polymorphic potential model that simultaneously incorporates Stillinger-Weber, Tersoff, embedded-atom method, and any variations (i.e., modified functions) of these potentials. As a result, we have implemented this polymorphic model in MD code LAMMPS, and demonstrated that our TlBr potential enables stable MD simulations under external electric fields.

  12. An interleukin-33 gene polymorphism is a modifier for eosinophilia in rats.

    PubMed

    Luo, H; Higuchi, K; Matsumoto, K; Mori, M

    2013-04-01

    In previous studies, we identified a loss-of-function mutation in the Cyba gene as the primary cause of hereditary eosinophilia in the Matsumoto Eosinophilia Shinshu (MES) rat strain. We also identified a modifier locus for eosinophilia named eos3 in rats. In this study, we examined the interleukin-33 (Il33) gene as a candidate for the eos3 and found a missense nucleotide substitution in the gene, which resulted in a G171S amino-acid substitution in the IL-33 protein. Recombinant IL-33 isoform with the G171S substitution had approximately 50% of activity of normal isoform in NF-κB-dependent reporter assay, and reduced bioactivity (∼65% of normal) to provoke eosinophilia when injected into mice. In a genetic association study using (ACI × MES) × MES backcross rats, we found that the effects of polymorphic Il33 alleles on blood eosinophil level were manifested only in rats with loss of Cyba function. In these rats, the blood eosinophil level was significantly lower (∼50%) in heterozygotes for the ACI allele of Il33 compared with homozygotes for the MES allele. Oddly, however, eosinophilic MES rats had blood IL-33 content below the detectable limits. These results suggest that the Il33 gene polymorphism could be a modifier of eosinophilia in rats.

  13. Interleukin-6 signaling promotes alternative macrophage activation to limit obesity-associated insulin resistance and endotoxemia

    PubMed Central

    Mauer, Jan; Chaurasia, Bhagirath; Goldau, Julia; Vogt, Merly C.; Ruud, Johan; Nguyen, Khoa D.; Theurich, Sebastian; Hausen, A. Christine; Schmitz, Joel; Brönneke, Hella S.; Estevez, Emma; Allen, Tamara L.; Mesaros, Andrea; Partridge, Linda; Febbraio, Mark A.; Chawla, Ajay; Wunderlich, F. Thomas; Brüning, Jens C.

    2014-01-01

    Obesity and insulin resistance are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation, however its role in this context remains controversial. Here, we show that mice with inactivated Il6ra gene in myeloid cells (Il6raΔmyel) displayed exaggerated deterioration of glucose homeostasis upon diet-induced obesity due to enhanced insulin resistance. Insulin target tissues showed increased inflammation and a shift in macrophage polarization. IL-6 induced IL-4-receptor expression and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6raΔmyel mice were resistant to IL-4-mediated alternative macrophage polarization and exhibited increased susceptibility to LPS-induced endotoxemia. These results reveal IL-6 signaling as an important determinant for alternative macrophage-activation and assign IL-6 an unexpected homeostatic role to limit inflammation. PMID:24681566

  14. Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies

    PubMed Central

    Sansone, Pasquale; Bromberg, Jacqueline

    2012-01-01

    The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers. PMID:22355058

  15. Trait reflection predicts interleukin-6 response to a social-evaluative stressor.

    PubMed

    Woody, Alex; Figueroa, Wilson S; Benencia, Fabian; Zoccola, Peggy M

    2016-02-01

    Past work has linked negative repetitive thought (worry, rumination) about stressors to sustained stress responses. Less is known about the effects of neutral types of repetitive thought (e.g., reflection) on physiological stress responses. The present study examined whether greater trait reflection was associated with a lower inflammatory response to an acute psychosocial stressor. Thirty-four healthy undergraduate women completed a speech stressor, and plasma interleukin-6 (IL-6), C-reactive protein, and tumor necrosis factor-α levels were assessed before and after the stressor. Higher levels of reflection predicted lower IL-6 responses 1h after the stressor. Stressor appraisal was not a significant mediator. These preliminary findings stand in contrast to existing evidence that other forms of repetitive thought like worry and rumination may exacerbate or prolong the inflammatory stress response and indicate that reflection is a notable factor worth considering when examining the relationship between stress, inflammation, and health.

  16. An immunological interleukine-6 capacitive biosensor using perturbation with a potentiostatic step.

    PubMed

    Berggren, C; Bjarnason, B; Johansson, G

    1998-11-01

    An instrument for potentiostatic capacitance measurements, based on perturbation with a potentiostatic step was used. The capacitive sensor consisted of self-assembled sulfur compounds on gold to which antibodies towards Interleukine 6, Il-6, had been immobilized. The biosensor was part of a potentiostatic three-electrode system with an extra reference electrode. Two different methods using epoxy- or carbodiimide coupling of the polyclonal antibodies were compared. The antigen Il-6 could be detected from 5 x 10(-16) to 5 x 10(-13) M with one immobilization method and to more than 5 x 10(-9) M with the other. No labels were necessary since the binding of the antigen was detected directly. The insulating properties of the different layers of the biosensor were investigated.

  17. Interleukin-6 receptor expression and localization after transient global ischemia in gerbil hippocampus.

    PubMed

    Vollenweider, Florence; Herrmann, Martina; Otten, Uwe; Nitsch, Cordula

    2003-04-24

    Ischemia results in increased interleukin-6 (IL-6) expression in the brain. To prove a connection between IL-6 upregulation and IL-6 receptor (IL-6R) expression following ischemia, we analyzed cell-type specific expression changes of IL-6R using transient global ischemia in the gerbil as a model. In sham operated animals, IL-6R mRNA and protein were mainly detected in hippocampal pyramidal cells and interneurons. After ischemia, IL-6R was expressed in neurons but there was no increase during the peak IL-6 expression. Neuronal IL-6R mRNA and protein decreased in parallel with pyramidal cell death, starting 2 days after ischemia. Double-labeling experiments revealed that in postischemic hippocampus IL-6R was not present in GFAP-reactive astrocytes but that the surviving parvalbumin containing interneurons expressed IL-6R mRNA.

  18. Anti-interleukin 6 receptor therapy for hyper-IgD syndrome.

    PubMed

    Musters, Anne; Tak, Paul Peter; Baeten, Dominique L P; Tas, Sander W

    2015-10-29

    Hyper-IgD syndrome (HIDS) is a rare, severe hereditary autoinflammatory disease characterised by periodic fevers, elevated serum IgD levels and a wide range of symptoms. Although a few randomised controlled trials have been performed in this disorder, there are no straightforward treatment protocols and none of the potential therapies are registered for this indication. We report a case of a young woman with severe HIDS who failed numerous therapies. Eventually, rational treatment with a monoclonal anti-interleukin 6 receptor antibody was initiated. This therapy resulted in an impressive clinical improvement and reduction in the number of hospital admissions per year. This case report underlines the difficulty of finding a suitable treatment for rare, severe inflammatory diseases. Furthermore, we show that treating patients with targeted therapies may result in clinical benefit for the patient, as well as simultaneously teach us more about the pathophysiology of these rare, relatively understudied diseases.

  19. Correlation of Interleukin-6 levels and lectins during Schistosoma haematobium infection.

    PubMed

    Antony, Justin S; Ojurongbe, Olusola; Meyer, Christian G; Thangaraj, Kumarasamy; Mishra, Anshuman; Kremsner, Peter G; Velavan, Thirumalaisamy P

    2015-12-01

    Urogenital schistosomiasis caused by Schistosoma haematobium induces a Th2 immune response, including expression of Interleukin-6. IL-6 confers protection from experimental Schistosoma-induced pulmonary hypertension and modulates production of mannose-binding lectin (MBL) and other lectins. We studied IL-6 levels in schistosomiasis and its effect on lectins production. Elevated IL-6 levels occurred in cases, compared to controls. IL-6 correlated with the lectins MBL, ficolin-2 and Collectin Kidney-1 (CL-K1) in cases, but correlated inversely in controls. The study shows that IL-6 levels are elevated in individuals infected with urogenital schistosomiasis. IL-6 was also found to be correlated with the production of lectins in S. haematobium infection. A similar correlation between IL-6 and MBL was observed during visceral leishmaniasis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6.

    PubMed Central

    Campbell, I L; Abraham, C R; Masliah, E; Kemper, P; Inglis, J D; Oldstone, M B; Mucke, L

    1993-01-01

    Cytokines are thought to be important mediators in physiologic and pathophysiologic processes affecting the central nervous system (CNS). To explore this hypothesis, transgenic mice were generated in which the cytokine interleukin 6 (IL-6), under the regulatory control of the glial fibrillary acidic protein gene promoter, was overexpressed in the CNS. A number of transgenic founder mice and their offspring exhibited a neurologic syndrome the severity of which correlated with the levels of cerebral IL-6 expression. Transgenic mice with high levels of IL-6 expression developed severe neurologic disease characterized by runting, tremor, ataxia, and seizure. Neuropathologic manifestations included neuro-degeneration, astrocytosis, angiogenesis, and induction of acute-phase-protein production. These findings indicate that cytokines such as IL-6 can have a direct pathogenic role in inflammatory, infectious, and neurodegenerative CNS diseases. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7694279

  1. Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction.

    PubMed

    Kaptein, A; Paillard, V; Saunders, M

    1996-03-15

    Interleukin-6 (IL-6) induces tyrosine phosphorylation and activation of the latent transcription factor Stat3 in HepG2 cells. Mutation of Stat3 tyrosine 705 to phenylalanine (Y705F) inhibits IL-6-induced tyrosine phosphorylation of this Stat3 mutant in transfected HepG2 cells. In cotransfections of HepG2 cells, the Stat3 mutant Y705F causes a reduction of the tyrosine phosphorylation of wild type Stat3-FLAG. Moreover, Y705F inhibits the action of endogenous Stat3 in cotransfected cells, reducing IL-6 induction of a Stat3-responsive reporter construct. Y705F therefore acts as a dominant negative mutation of Stat3.

  2. Associations Between Delirium and Preoperative Cerebrospinal Fluid C-Reactive Protein, Interleukin-6, and Interleukin-6 Receptor in Individuals with Acute Hip Fracture.

    PubMed

    Neerland, Bjørn Erik; Hall, Roanna J; Seljeflot, Ingebjørg; Frihagen, Frede; MacLullich, Alasdair M J; Raeder, Johan; Wyller, Torgeir Bruun; Watne, Leiv Otto

    2016-07-01

    To examine whether delirium in individuals with hip fracture is associated with high C-reactive protein (CRP), interleukin-6 (IL-6), and soluble IL-6 receptor (sIL-6R) levels in the cerebrospinal fluid (CSF). Prospective cohort study. Two university hospitals in Oslo, Norway, and Edinburgh, United Kingdom. Individuals admitted with acute hip fracture (N = 151). Participants were assessed for delirium pre- and postoperatively using the Confusion Assessment Method. Prefracture cognitive impairment was detected using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Serum was collected preoperatively and CSF just before the onset of spinal anesthesia. Cytokine levels in serum and CSF samples were determined using an enzyme-linked immunosorbent assay. Student t-tests or Mann-Whitney U-tests were used for between-group comparisons. Spearman rho was used for correlations. Sixty participants had prior cognitive impairment (IQCODE score ≥3.44). Delirium was diagnosed in 46 participants (77%) with prior cognitive impairment and 25 (29%) without. In participants without prior cognitive impairment, CSF CRP levels were higher in participants with delirium (median 0.05 μg/mL, interquartile range (IQR) 0.02-0.12 μg/mL) than in those without delirium (median 0.01 μg/mL, IQR 0.00-0.06 μg/mL) (P = .01); there were no differences in participants with prior cognitive impairment. In secondary analyses, in participants with prior cognitive impairment, the concentration of CSF sIL-6R was higher in those participants who developed delirium than in the other subgroups, but this difference was not statistically significant. Serum levels of CRP, IL-6, and sIL-6R were not different according to delirium in participants with or without prefracture cognitive impairment. High CSF levels of CRP and sIL-6R may be associated with delirium. Different pathophysiological mechanisms may operate in different subgroups, notably in relation to the presence of prior cognitive

  3. Role of Interleukin-6 in the Radiation Response of Liver Tumors

    SciTech Connect

    Chen, Miao-Fen; Hsieh, Ching-Chuan; Chen, Wen-Cheng; Lai, Chia-Hsuan

    2012-12-01

    Purpose: To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. Methods and Materials: The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6-neutralizing antibody for 24 hours or stably transfected with IL-6-silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. Results: Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6-silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. Conclusion: These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.

  4. Interleukin 6 Plasma Concentration Associates with Cognitive Decline: The Northern Manhattan Study

    PubMed Central

    Economos, Alexis; Wright, Clinton B.; Moon, Yeseon Park; Rundek, Tatjana; Rabbani, LeRoy; Paik, Myunghee C.; Sacco, Ralph L.; Elkind, Mitchell S. V.

    2013-01-01

    Background Interleukin 6 (IL-6) is an inflammatory cytokine that has been associated with vascular disease and cognitive impairment, but few studies have examined these relationships in population-based studies that include Hispanic white and black people who often have a greater prevalence of vascular risk factors and are at elevated risk of dementia. We examined relative elevations of plasma IL-6 concentrations in relation to cognitive decline in a stroke-free race/ethnically diverse community-based sample from Northern Manhattan. Methods We used mixed effects models to measure the effect of IL-6 on change in performance on the Telephone Interview for Cognitive Status (TICS-m) measured annually in our cohort, adjusting for sociodemographic and vascular risk factors. Results There were 1224 participants with IL-6 levels (median 1.5 pg/mL, interquartile range (IQR) 0.83 – 2.57 pg/mL) and TICS-m data available (mean=31.6 points, SD 6.5). The mean age was 71 (SD 9.3; 64% women, 59% Hispanic, 19% Black, 19% White) with 3,406 person- and a median 3.0 years of follow-up (IQR 1.1 – 4.0). Participants with IL-6 levels above the median showed greater cognitive decline on the TICS-m compared to those with levels below the median, adjusting for sociodemographic and vascular factors (β= −0.17 points per year, p=0.02). Decline on the TICS-m among participants with IL-6 above the median differed by age (P for interaction <0.001). There was no interaction by race-ethnicity, vascular risk factors, C-reactive protein (CRP), APOE4 allele status, or the metabolic syndrome among non-diabetics. Conclusions Interleukin 6 associated with cognitive decline among older participants in this race/ethnically diverse sample independent of other vascular risk factors and CRP. PMID:23364322

  5. Total and high molecular weight adiponectin and level-modifying polymorphisms of ADIPOQ in centenarians.

    PubMed

    Roszkowska-Gancarz, Małgorzata; Bartoszewicz, Zbigniew; Polosak, Jacek; Kurylowicz, Alina; Jonas, Marta; Mossakowska, Małgorzata; Franek, Edward; Puzianowska-Kuźnicka, Monika

    2012-01-01

    Adiponectin demonstrates a protective role against the development of obesity, type 2 diabetes mellitus, and cardiovascular disease. The -11377C 〉 G, -11391G 〉 A, and -11426A 〉 G promoter polymorphisms of ADIPOQ gene influence the level of circulating adiponectin. We examined the level of total and high molecular weight (HMW) adiponectin in centenarians and associated it with biochemical parameters. We checked if the expression and concentration-modifying polymorphisms of ADIPOQ are associated with extreme longevity. Total and HMW adiponectin were examined using ELISA in 40 female centenarians. The frequencies of the ADIPOQ polymorphisms were tested by restriction fragment length polymorphism in 148 centenarians, 414 young controls, in 207 myocardial infarction patients, and in 190 type 2 diabetes mellitus patients. The mean concentration of total adiponectin in centenarians was 13.19 ± 1.37 mg/mL and of HMW adiponectin it was 9.17 ± 1.15 mg/mL. They were positively correlated with HDL (r = 0.4696, p = 0.0025 and r = 0.3912, p = 0.015, respectively), and negatively with BMI (r = -0.3702, p = 0.034 and r = -0.3963, p = 0.025) and triglycerides (r = -0.346, p = 0.028 and r = -0.3227, p = 0.045). A very rare AA genotype of the -11391G 〉 A polymorphism was significantly more common in centenarians than in young controls (p = 0.026) and, while compared to the GG genotype, it was associated with a 2.4-fold higher mean concentration of total adiponectin (26.53 ± 13.29 mg/ mL v. 10.97 ± 4.28 mg/mL) and with an almost 3-fold higher mean HMW adiponectin (20.65 ± 12.72 mg/mL v. 7.36 ± 3.35 mg/mL). Serum adiponectin concentration in female centenarians is associated with biochemical parameters that are favourable for cardiovascular risk. We suggest that adiponectin might be of importance for extreme longevity.

  6. Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

    PubMed Central

    McCranor, Bryan J.; Langdon, Jacqueline M.; Prince, Olivier D.; Femnou, Laurette K.; Berger, Alan E.; Cheadle, Chris; Civin, Curt I.; Kim, Airie; Rivera, Seth; Ganz, Tomas; Vaulont, Sophie; Xue, Qian-Li; Walston, Jeremy D.; Roy, Cindy N.

    2013-01-01

    Anemia is common in older adults and associated with adverse health outcomes in epidemiological studies. A thorough understanding of the complex pathophysiological mechanisms driving anemia in the elderly is lacking; but inflammation, iron restriction, and impaired erythroid maturation are thought to influence the phenotype. We hypothesized that interleukin-6 contributes to this anemia, given its pro-inflammatory activities, its ability to induce hepcidin antimicrobial peptide, and its negative impact on several tissues in older adults. We tested this hypothesis by comparing changes in indices of inflammation, iron metabolism and erythropoiesis in aged C57BL/6 mice to aged mice with targeted deletions of interleukin-6 or hepcidin antimicrobial peptide. Circulating neutrophil and monocyte numbers and inflammatory cytokines increased with age. Decline in hemoglobin concentration and red blood cell number indicated that C57BL/6, interleukin-6 knockout mice, and hepcidin antimicrobial peptide knockout mice all demonstrated impaired erythropoiesis by 24 months. However, the interleukin-6 knock out genotype and the hepcidin antimicrobial peptide knock out genotype resulted in improved erythropoiesis in aged mice. Increased erythropoietic activity in the spleen suggested that the erythroid compartment was stressed in aged C57BL/6 mice compared to aged interleukin-6 knockout mice. Our data suggest C57BL/6 mice are an appropriate mammalian model for the study of anemia with age. Furthermore, although interleukin-6 and hepcidin antimicrobial peptide are not required, they can participate in the development of anemia in aging mice, and could be targeted, pre-clinically, with existing interventions to determine the feasibility of such agents for the treatment of anemia in older adults. PMID:23996485

  7. Effects of Minocycline on Urine Albumin, Interleukin-6, and Osteoprotegerin in Patients with Diabetic Nephropathy: A Randomized Controlled Pilot Trial

    PubMed Central

    Wang, Ying; Tong, Lili; Pak, Youngju; Andalibi, Ali; LaPage, Janine A.; Adler, Sharon G.

    2016-01-01

    Background We tested minocycline as an anti-proteinuric adjunct to renin-angiotensin-aldosterone system inhibitors (RAASi) in diabetic nephropathy (DN) and measured urinary biomarkers to evaluate minocycline’s biological effects. Methods Design: Prospective, single center, randomized, placebo-controlled, intention-to-treat pilot trial. Inclusion. Type 2 diabetes/DN; Baseline creatinine clearance > 30 mL/min; proteinuria ≥ 1.0 g/day; Age ≥30 years; BP <150/95 mm Hg; intolerant of/at maximum RAASi dose. Protocol. 3-wk screening; Baseline randomization; Urine and blood measures at months 1, 2, 4, and Month 6 study completion. Urine interleukin-6 (IL-6) and osteoprotegerin were measured in a subset. Primary outcome. Natural log of urine protein/creatinine (ln U P:Cr) ratio at Month 6 vs Baseline. Results 30 patients completed the study. The 15% decline in U P: Cr in minocycline patients (6 month P:Cr ÷ Baseline P:Cr, 0.85 vs. 0.92) was not significant (p = 0.27). Creatinine clearance did not differ in the 2 groups. Urine IL-6:Cr (p = 0.03) and osteoprotegerin/Cr (p = 0.046) decrements were significant. Minocycline modified the relationship between urine IL-6 and proteinuria, suggesting a protective biological effect. Conclusions Although the decline in U P:Cr in minocycline patients was not statistically significant, the significant differences in urine IL-6 and osteoprotegerin suggest that minocycline may confer cytoprotection in patients with DN, providing a rationale for further study. Trial Registration Clinicaltrials.gov NCT01779089 PMID:27019421

  8. Interleukin-6, A Cytokine Critical to Mediation of Inflammation, Autoimmunity and Allograft Rejection: Therapeutic Implications of IL-6 Receptor Blockade.

    PubMed

    Jordan, Stanley C; Choi, Jua; Kim, Irene; Wu, Gordon; Toyoda, Mieko; Shin, Bonga; Vo, Ashley

    2017-01-01

    The success of kidney transplants is limited by the lack of robust improvements in long-term survival. It is now recognized that alloimmune responses are responsible for the majority of allograft failures. Development of novel therapies to decrease allosensitization is critical. The lack of new drug development in kidney transplantation necessitated repurposing drugs initially developed in oncology and autoimmunity. Among these is tocilizumab (anti-IL-6 receptor [IL-6R]) which holds promise for modulating multiple immune pathways responsible for allograft injury and loss. Interleukin-6 is a cytokine critical to proinflammatory and immune regulatory cascades. Emerging data have identified important roles for IL-6 in innate immune responses and adaptive immunity. Excessive IL-6 production is associated with activation of T-helper 17 cell and inhibition of regulatory T cell with attendant inflammation. Plasmablast production of IL-6 is critical for initiation of T follicular helper cells and production of high-affinity IgG. Tocilizumab is the first-in-class drug developed to treat diseases mediated by IL-6. Data are emerging from animal and human studies indicating a critical role for IL-6 in mediation of cell-mediated rejection, antibody-mediated rejection, and chronic allograft vasculopathy. This suggests that anti-IL-6/IL-6R blockade could be effective in modifying T- and B-cell responses to allografts. Initial data from our group suggest anti-IL-6R therapy is of value in desensitization and prevention and treatment of antibody-mediated rejection. In addition, human trials have shown benefits in treatment of graft versus host disease in matched or mismatched stem cell transplants. Here, we explore the biology of IL-6/IL-6R interactions and the evidence for an important role of IL-6 in mediating allograft rejection.

  9. Breviscapine reduces neuronal injury caused by traumatic brain injury insult: partly associated with suppression of interleukin-6 expression

    PubMed Central

    Jiang, Ling; Hu, Yue; He, Xiang; Lv, Qiang; Wang, Ting-hua; Xia, Qing-jie

    2017-01-01

    Breviscapine, extracted from the herb Erigeron breviscapus, is widely used for the treatment of cardiovascular diseases, cerebral infarct, and stroke, but its mechanism of action remains unclear. This study established a rat model of traumatic brain injury induced by controlled cortical impact, and injected 75 μg breviscapine via the right lateral ventricle. We found that breviscapine significantly improved neurobehavioral dysfunction at 6 and 9 days after injection. Meanwhile, interleukin-6 expression was markedly down-regulated following breviscapine treatment. Our results suggest that breviscapine is effective in promoting neurological behavior after traumatic brain injury and the underlying molecular mechanism may be associated with the suppression of interleukin-6. PMID:28250753

  10. Heat induces interleukin-6 in skeletal muscle cells via TRPV1/PKC/CREB pathways.

    PubMed

    Obi, Syotaro; Nakajima, Toshiaki; Hasegawa, Takaaki; Kikuchi, Hironobu; Oguri, Gaku; Takahashi, Masao; Nakamura, Fumitaka; Yamasoba, Tatsuya; Sakuma, Masashi; Toyoda, Shigeru; Tei, Chuwa; Inoue, Teruo

    2017-03-01

    Interleukin-6 (IL-6) is released from skeletal muscle cells and induced by exercise, heat, catecholamine, glucose, lipopolysaccharide, reactive oxygen species, and inflammation. However, the mechanism that induces release of IL-6 from skeletal muscle cells remains unknown. Thermosensitive transient receptor potential (TRP) proteins such as TRPV1-4 play vital roles in cellular functions. In this study we hypothesized that TRPV1 senses heat, transmits a signal into the nucleus, and produces IL-6. The purpose of the present study is to investigate the underlying mechanisms whereby skeletal muscle cells sense and respond to heat. When mouse myoblast cells were exposed to 37-42°C for 2 h, mRNA expression of IL-6 increased in a temperature-dependent manner. Heat also increased IL-6 secretion in myoblast cells. A fura 2 fluorescence dual-wavelength excitation method showed that heat increased intracellular calcium flux in a temperature-dependent manner. Intracellular calcium flux and IL-6 mRNA expression were increased by the TRPV1 agonists capsaicin and N-arachidonoyldopamine and decreased by the TRPV1 antagonists AMG9810 and SB366791 and siRNA-mediated knockdown of TRPV1. TRPV2, 3, and 4 agonists did not change intracellular calcium flux. Western blotting with inhibitors demonstrated that heat increased phosphorylation levels of TRPV1, followed by PKC and cAMP response element-binding protein (CREB). PKC inhibitors, Gö6983 and staurosporine, CREB inhibitors, curcumin and naphthol AS-E, and knockdown of CREB suppressed the heat-induced increases in IL-6. These results indicate that heat increases IL-6 in skeletal muscle cells through the TRPV1, PKC, and CREB signal transduction pathway.NEW & NOTEWORTHY Heat increases the release of interleukin-6 (IL-6) from skeletal muscle cells. IL-6 has been shown to serve immune responses and metabolic functions in muscle. It can be anti-inflammatory as well as proinflammatory. However, the mechanism that induces release of IL-6

  11. The miR-608 rs4919510 polymorphism may modify cancer susceptibility based on type.

    PubMed

    Wu, Shuangshuang; Yuan, Weiyan; Shen, Yu; Lu, Xiao; Li, Yue; Tian, Tian; Jiang, Liying; Zhuang, Xun; Wu, Jianqing; Chu, Minjie

    2017-06-01

    Previous meta-analysis has not shown different effects of miR-608 rs4919510 polymorphism in specific cancer types and reported no significant association between rs4919510 and cancer risk among Chinese. However, more recent findings have been inconsistent. Therefore, we performed an updated meta-analysis to examine whether this polymorphism is associated with cancer risk based on ethnicity and type. A total of 18 case-control studies, comprising 12,517 cases and 15,624 controls, were included in our study. Surprisingly, in contrast with previous meta-analysis, a significant association between the rs4919510 polymorphism and cancer risk was observed in Chinese (CG vs CC: odds ratio = 1.11; 95% confidence interval = 1.04-1.19). In further stratified analyses based on cancer type, rs4919510 was significantly associated with an increased risk of papillary thyroid cancer (CG vs CC: odds ratio = 1.25; 95% confidence interval = 1.01-1.54) and exhibited borderline significant associations with increased risk of gastric cancer (GG vs CC: odds ratio = 1.27; 95% confidence interval = 1.00-1.62) and lung cancer (CG vs CC: odds ratio = 1.14; 95% confidence interval = 0.99-1.32), but a decreased risk of colorectal cancer (GG vs CC: odds ratio = 0.74; 95% confidence interval = 0.60-0.91). Moreover, the RegulomeDB database indicated that rs4919510 may affect the expression of two nearby genes ( SEMA4G and MRPL43), and the Cancer Genome Atlas database revealed that the expression level of SEMA4G was significantly lower in colorectal cancer and lung cancer tissues than that in adjacent non-tumour tissues, while the expression level of SEMA4G was significantly higher in gastric cancer tissues than that in adjacent non-tumour tissues. These findings provide evidence that the miR-608 rs4919510 polymorphism may modify cancer susceptibility in a type-specific manner. Furthermore, SEMA4G may function as an oncogene or tumour suppressor to regulate

  12. Polymorphisms in Catechol-O-methyltransferase Modify Treatment Effects of Aspirin on Risk of Cardiovascular Disease

    PubMed Central

    Hall, Kathryn T.; Nelson, Christopher P.; Davis, Roger B.; Buring, Julie E.; Kirsch, Irving; Mittleman, Murray A.; Loscalzo, Joseph; Samani, Nilesh J.; Ridker, Paul M; Kaptchuk, Ted J.; Chasman, Daniel I.

    2014-01-01

    Objective Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. Approach and Results We examined COMT polymorphism rs4680 (MAF=0.47), encoding a non-synonymous methionine (met)-to-valine (val) substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E compared with placebo and 10 years follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in CARDIoGRAM/C4D, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/N=5811), the rs4680 val allele was protective against incident CVD relative to the met, (HR[95%CI]=0.66[0.51-0.84], p=0.0007); an association also observed in CARDIoGRAM and C4D (combined p=2.4×10-5). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that val/val women experienced higher CVD rates with aspirin allocation compared to placebo (HR[95%CI]=1.85[1.05-3.25], p=0.033) while met/met women experienced lower rates (HR[95%CI]=0.60[0.39-0.93], p=0.023). Allocation to vitamin E also conferred higher but non-significant CVD rates on val/val (HR[95%CI]=1.50 [0.83-2.70], p=0.180) compared with significantly lower rates on met/met (HR[95%CI]=0.53[0.34-0.84], p=0.006) women. Rs4818 results were similar. Conclusions Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required. PMID:25035343

  13. Serum interleukin-6 is associated with pancreatic ductal adenocarcinoma progression pattern

    PubMed Central

    Kim, Hyoung Woo; Lee, Jong-chan; Paik, Kyu-hyun; Kang, Jingu; Kim, Jaihwan; Hwang, Jin-Hyeok

    2017-01-01

    Abstract Several reports showed that interleukin-6 (IL-6) or -8 (IL-8) might be useful inflammatory biomarkers for pancreatic ductal adenocarcinoma (PDAC), although these clinical impact is still open to debate. The aim of this study was to elucidate whether serum levels of IL-6 and IL-8 at diagnosis could predict the tumor progression pattern of PDAC, especially in extensive hepatic metastasis. According to the tumor burden of hepatic metastasis at the last follow-up, tumor progression pattern was defined as follows: no or limited (unilobar involvement and 5 or less in the within liver, limited group) and extensive hepatic metastasis (bilobar or more than 5, progressed group). Fifty-three PDAC patients with initially no or limited hepatic metastasis were enrolled retrospectively. Around 42 (79.2%) were included in the limited and 11 (20.8%) in the progressed group. The median serum level of IL-6 in the progressed group was elevated significantly compared with the limited group. However, the median serum level of IL-8 was not. Furthermore, multivariate analysis revealed that the elevated serum level of IL-6 was an independent risk factor for progression to extensive hepatic metastasis (odds ratio 1.928, 95% confidence interval 1.131–3.365, P = 0.019), but IL-8 was not. However, higher IL-6 did not predict shorter survival. High serum IL-6 can be an independent risk factor for progression to extensive hepatic metastasis in PDAC patients. PMID:28151872

  14. Clinical anxiety, cortisol and interleukin-6: evidence for specificity in emotion-biology relationships.

    PubMed

    O'Donovan, Aoife; Hughes, Brian M; Slavich, George M; Lynch, Lydia; Cronin, Marie-Therese; O'Farrelly, Cliona; Malone, Kevin M

    2010-10-01

    Anxiety confers increased risk for inflammatory diseases, and elevated inflammatory activity in anxious individuals may contribute to this increased risk. One complication, however, is that anxiety could be associated with inflammatory activity either through a specific anxiety pathway or through a more general negative emotionality pathway. To investigate, we measured levels of the stress hormone cortisol, the pro-inflammatory cytokine interleukin-6 (IL-6), and the systemic inflammatory marker C-reactive protein (CRP), as well as depression and neuroticism, in clinically anxious and non-anxious adults. Compared with non-anxious participants, clinically anxious participants exhibited significantly lower levels of morning cortisol and significantly higher levels of IL-6, independent of age, sex, and depressive symptoms. These group differences were robust when controlling for neuroticism. Conversely, the groups had equivalent levels of CRP in all analyses. Results are indicative of anxiety-specific effects on inflammatory activity, and highlight a pathway by which anxiety may increase risk for inflammatory diseases. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Interleukin-6 gene transfer reverses body weight gain and fatty liver in obese mice.

    PubMed

    Ma, Yongjie; Gao, Mingming; Sun, Hao; Liu, Dexi

    2015-05-01

    Interleukin-6 (IL-6) is a multifunctional protein and has a major influence on energy metabolism. The current study was designed to assess the therapeutic effect of overexpression of Il-6 gene through gene transfer on high fat diet-induced obese mice. Hydrodynamic delivery of 1 μg pLIVE-IL6 plasmid per mouse into C57BL/6 obese mice resulted in peak level at 10 ng/ml of circulating IL-6 1 day after gene transfer and above 1n g/ml thereafter for a period of 6 weeks. Persistent Il-6 gene expression did not affect food intake but induced a significant reduction in body weight and improved obesity-associated hepatic steatosis. Il-6 gene delivery enhanced thermogenic gene expression and elevated protein levels of phosphorylated STAT3, PGC1α and UCP1 in brown adipose tissue. Il-6 overexpression elevated mRNA levels of lipolysis genes, triggered phosphorylation of STAT3, AMPK, and ACC, and increased expression of genes involved in fatty acid oxidation in skeletal muscle. IL-6 did not affect macrophage infiltration but maintained the M2 macrophage population in adipose tissue. Collectively, these results suggest that overexpression of the Il-6 gene by hydrodynamic gene delivery induces weight loss and alleviates obesity-induced fatty liver and insulin resistance, supporting the notion that gene transfer is a valid approach in managing obesity epidemics.

  16. Polychlorinated biphenyls induce proinflammatory cytokine release and dopaminergic dysfunction: protection in interleukin-6 knockout mice.

    PubMed

    Goodwill, Meleik Hebert; Lawrence, David A; Seegal, Richard F

    2007-02-01

    Proinflammatory cytokines are not only important mediators of brain development, but also pose an increased risk for neurodegeneration following exposure to neurotoxicants or trauma. We have used the ubiquitous environmental and occupational neurotoxicant polychlorinated biphenyls (PCBs) to investigate the putative role of inflammatory agents in mediating processes involved in basal ganglia dysfunctions. PCBs induced inflammatory responses in C57BL/6 adult male mice, significantly elevating serum levels of IL-6 (31%), IL-1beta (71%) and TNF-alpha (22%) and significantly reducing striatal dopamine (DA, 21%), tyrosine hydroxylase (TH, 26%), dopamine transporter (DAT, 39%), and synaptophysin (29%) concentrations. We also exposed mice deficient in the proinflammatory cytokine interleukin-6 (IL-6-/-) to PCBs, to explore the role of this specific cytokine in mediating PCB-induced DA neurodegeneration. Not only did the PCB-treated IL-6-/- mice exhibit a decrease in serum levels of IL-1beta and TNF-alpha, but they were also protected from PCB-induced striatal dopaminergic dysfunction, displaying no signs of toxicant-induced reductions in DA levels, or TH, DAT or synaptophysin expression. Taken together, these results suggest that: (1) PCB exposure results in a peripheral inflammatory response associated with striatal terminal degeneration; and (2) the absence of IL-6 prevents PCB-induced dopaminergic losses in the striatum.

  17. Induction of immunoglobulin G1, interleukin-6 and interleukin-10 by Taenia crassiceps metacestode carbohydrates

    PubMed Central

    Dissanayake, Senarath; Khan, Nasir; Shahin, Allen; Wijesinghe, Shanaka; Lukic, Miodrag

    2002-01-01

    T helper type 2 (Th2) -polarized immune responses are characteristically dominant in helminth infections. Two murine models that show a Th1 to Th2 polarization with infection progression are those of Schistosoma mansoni and Taenia crassiceps. In both, an early Th1 response is replaced by a late Th2 response. We report that the nucleic acid-, protein- and lipid-free carbohydrate fraction of T. crassiceps metacestodes (denoted T-CHO) possesses Th2-like immunomodulatory activity. Immunization of two strains of rats (Dark Agouti and Albino Oxford) and BALB/c mice with chicken albumin in the presence of T-CHO resulted in selective enhancement of immunoglobulin G1 (IgG1) antibodies, considered to be associated with Th2 responses in both rats and mice. Interleukin-6 (IL-6) followed by IL-10 were the dominant cytokines detected in in vitro cultures of mouse spleen cells stimulated with T-CHO. IL-4 and IL-5 were not detected in these culture supernates. Furthermore, Taenia carbohydrates were mitogenic to spleen cells, activated serine phosphorylation of proteins and up-regulated the expression of the anti-apoptotic protein, Bcl-2. When mouse spleen cells were cultured in the presence of Taenia carbohydrates, a concentration-dependent down-regulation of IL-2 and an overlapping up-regulation of IL-6 secretion were seen. PMID:12460185

  18. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma

    PubMed Central

    Rosean, Timothy R.; Tompkins, Van S.; Tricot, Guido; Holman, Carol J.; Olivier, Alicia K.; Zhan, Fenghuang; Janz, Siegfried

    2014-01-01

    Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in the bone marrow of patients with myeloma. This knowledge has engendered considerable interest in targeting IL-6 for therapeutic purposes, using a variety of antibody- and small-molecule-based therapies. However, despite the early recognition of the importance of IL-6 for myeloma and the steady progress in our knowledge of IL-6 in normal and malignant development of plasma cells, additional efforts will be required to translate the promise of IL-6 as a target for new myeloma therapies into significant clinical benefits for patients with myeloma. This review summarizes published research on the role of IL-6 in myeloma development and describes ongoing efforts by the University of Iowa Myeloma Multidisciplinary Oncology Group to develop new approaches to the design and testing of IL-6-targeted therapies and preventions of MM. PMID:24845460

  19. Neuromodulatory loop mediated by nerve growth factor and interleukin 6 in thymic stromal cell cultures.

    PubMed Central

    Screpanti, I; Meco, D; Scarpa, S; Morrone, S; Frati, L; Gulino, A; Modesti, A

    1992-01-01

    Neural crest cell derivatives have been suggested to be involved in thymus development. We established nonlymphoid thymic stromal cell cultures capable of supporting T-cell differentiation. In these nonlymphoid cell cultures, we identified cells with phenotypic and biochemical markers specific for neuronal cells. Neurofilament mRNA and 68- and 160-kDa neurofilament proteins, as well as 74-kDa synapsin I isoform, were expressed in many of the cultured cells. For example, neurofilament immunoreactivity was detected in 20-30% of the cells. To see whether thymic neuronal-like cells were involved in a neural differentiation pathway, we investigated the effect of nerve growth factor (NGF) and interleukin 6 (IL-6), two known neurotrophic factors. The expression of the above-described neural markers was enhanced by NGF and IL-6, which we report to be produced in an autocrine way by thymic stromal cell cultures. Finally, we found that IL-6 gene expression in these cell cultures was enhanced by NGF. Evidence is thus offered of a neuromodulatory loop within the thymic stromal cell population supported by local production of NGF and IL-6 and involving neural cell elements. Interestingly, IL-6, which is known to be implicated in thymocyte differentiation, also displays a neuromodulatory activity on thymic stromal cells, suggesting a multivalent role for this cytokine within the thymus. Images PMID:1373490

  20. Interleukin-1 and interleukin-6 gene expression in human monocytes stimulated with Salmonella typhimurium porins.

    PubMed Central

    Galdiero, M; Cipollaro de L'ero, G; Donnarumma, G; Marcatili, A; Galdiero, F

    1995-01-01

    The aim of this study was to verify whether Salmonella typhimurium porins can affect the expression of interleukin-1 (IL-1) and interleukin-6 (IL-6) genes. Human monocytes were treated with porins, and total RNAs were analysed by Northern blotting to evaluate the expression of IL-1 alpha, IL-1 beta and IL-6 in both treated and untreated cell cultures. Porins induced a significant increase in IL-1 and IL-6 transcripts. This increase was related to the dose of porins, and it peaked 5 hr after treatment. The same results were obtained when polymyxin B was added to the porin preparation to eliminate eventual traces of lipopolysaccharide (LPS) associated with porins. The porins-mediated increase in interleukin transcripts did not require de novo protein synthesis, and it was because of the enhanced half-life of IL-1 and IL-6 mRNAs, rather an increased rate of gene transcription. These data suggest that porins may affect inflammatory and immunological responses by enhancing the expression of cytokine genes. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:8567029

  1. Interleukin-6 blockade attenuates lung cancer tissue construction integrated by cancer stem cells.

    PubMed

    Ogawa, Hiroyuki; Koyanagi-Aoi, Michiyo; Otani, Kyoko; Zen, Yoh; Maniwa, Yoshimasa; Aoi, Takashi

    2017-09-26

    In the present study, we successfully generated lung cancer stem cell (CSC)-like cells by introducing a small set of transcription factors into a lung cancer cell line. In addition to properties that are conventionally referred to as CSC properties, the lung induced CSCs exhibited the ability to form lung cancer-like tissues in vitro with vascular cells and mesenchymal stem cells, which showed structures and immunohistological patterns that were similar to human lung cancer tissues. We named them "lung cancer organoids". We found that interleukin-6 (IL-6), which was expressed in the lung induced CSCs, facilitates the formation of lung cancer organoids via the conversion of mesenchymal stem cells into alpha-smooth muscle actin (αSMA)-positive cells. Interestingly, the combination of anti-IL-6 antibody and cisplatin could destroy the lung cancer organoids, while cisplatin alone could not. Furthermore, IL-6 mRNA-positive cancer cells were found in clinical lung cancer samples. These results suggest that IL-6 could be a novel therapeutic target in lung cancer.

  2. Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies.

    PubMed

    Blanchetot, Christophe; De Jonge, Natalie; Desmyter, Aline; Ongenae, Nico; Hofman, Erik; Klarenbeek, Alex; Sadi, Ava; Hultberg, Anna; Kretz-Rommel, Anke; Spinelli, Silvia; Loris, Remy; Cambillau, Christian; de Haard, Hans

    2016-06-24

    Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing antibodies against IL-6 and its receptor have been approved for therapeutic intervention or are in advanced stages of clinical development. Here we describe the crystal structures of the complexes of IL-6 with two Fabs derived from conventional camelid antibodies that antagonize the interaction between the cytokine and its receptor. The x-ray structures of these complexes provide insights into the mechanism of neutralization by the two antibodies and explain the very high potency of one of the antibodies. It effectively competes for binding to the cytokine with IL-6 receptor (IL-6R) by using side chains of two CDR residues filling the site I cavities of IL-6, thus mimicking the interactions of Phe(229) and Phe(279) of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe(279) Mutation of this HCDR3 Trp residue into any other residue except Tyr or Phe significantly weakens binding of the antibody to IL-6, as was also observed for IL-6R mutants of Phe(279) In the second antibody, the side chain of HCDR3 valine ties into site I like IL-6R Phe(279), whereas a LCDR1 tyrosine side chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe(229).

  3. Openness and conscientiousness predict 34-week patterns of Interleukin-6 in older persons.

    PubMed

    Chapman, Benjamin P; van Wijngaarden, Edwin; Seplaki, Christopher L; Talbot, Nancy; Duberstein, Paul; Moynihan, Jan

    2011-05-01

    Studies have indicated that personality may be associated with inflammatory markers such as Interleukin (IL)-6. One pathway between personality and IL-6 may be health behaviors and conditions resulting in inflammation, while an alternate pathway involves activation of stress-response systems. In a clinical trial sample of 200 older adults, we examined associations between personality traits at baseline and three measures of IL-6 spanning 34 weeks of follow-up. Results indicate that IL-6 remained very stable over time, and that higher Conscientiousness and Openness were associated with lower IL-6 across the entire 34 week period. Goal striving was the active subcomponent of Conscientiousness, while aesthetic interests was the active subcomponent of Openness in IL-6 associations. Common health behaviors and chronic illness accounted for only a portion of these effects, suggesting that other behavioral and/or physiological processes may also predispose some persons to inflammation. Personality phenotype may provide useful prognostic information for inflammation. Older adults lower in Conscientiousness and Openness constitute a target population for anti-inflammatory interventions. Openness and Conscientiousness predicts 32-week patterns of Interleukin-6 in older persons.

  4. Synergistic inhibition of interleukin-6 production in adipose stem cells by tart cherry anthocyanins and atorvastatin.

    PubMed

    Zhou, Zhou; Nair, Muraleedharan G; Claycombe, Kate J

    2012-07-15

    Studies have shown positive correlations between inflammatory cytokines such as interleukin-6 (IL-6) and the development of chronic diseases including cardiovascular disease by activating C-reactive protein (CRP). Both atorvastatin calcium (lipitor) as well as flavonoid rich fruit such as tart cherry demonstrate potent anti-inflammatory effects on IL-6 secretion. In this study, we investigated whether tart cherry extract or specific anthocyanins contained in the tart cherry show synergistic anti-inflammatory effects with lipitor. Results showed that LPS-induced adipose stem cell secretion of IL-6 reduced with the addition of tart cherry extract, a mixture of tart cherry anthocyanins, and pure tart cherry cyanidin-3-O-glucoside (C3G) in a dose-dependent manner. Furthermore, lipitor and C3G exhibited synergistic effects in reducing LPS-induced IL-6 secretion from adipose stem cells. In conclusion, these results support potential benefits of using dietary phytochemicals in conjunction with pharmacological therapies to decrease adipose inflammation, drug doses, and ultimately, drug-induced adverse effects.

  5. Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity.

    PubMed

    Zhang, Wenliang; Mottillo, Emilio P; Zhao, Jiawei; Gartung, Allison; VanHecke, Garrett C; Lee, Jen-Fu; Maddipati, Krishna R; Xu, Haiyan; Ahn, Young-Hoon; Proia, Richard L; Granneman, James G; Lee, Menq-Jer

    2014-11-14

    Adipocyte lipolysis can increase the production of inflammatory cytokines such as interleukin-6 (IL-6) that promote insulin resistance. However, the mechanisms that link lipolysis with inflammation remain elusive. Acute activation of β3-adrenergic receptors (ADRB3) triggers lipolysis and up-regulates production of IL-6 in adipocytes, and both of these effects are blocked by pharmacological inhibition of hormone-sensitive lipase. We report that stimulation of ADRB3 induces expression of sphingosine kinase 1 (SphK1) and increases sphingosine 1-phosphate production in adipocytes in a manner that also depends on hormone-sensitive lipase activity. Mechanistically, we found that adipose lipolysis-induced SphK1 up-regulation is mediated by the c-Jun N-terminal kinase (JNK)/activating protein-1 signaling pathway. Inhibition of SphK1 by sphingosine kinase inhibitor 2 diminished the ADRB3-induced IL-6 production both in vitro and in vivo. Induction of IL-6 by ADRB3 activation was suppressed by siRNA knockdown of Sphk1 in cultured adipocytes and was severely attenuated in Sphk1 null mice. Conversely, ectopic expression of SphK1 increased IL-6 expression in adipocytes. Collectively, these data demonstrate that SphK1 is a critical mediator in lipolysis-triggered inflammation in adipocytes. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Glucosyltransferases of viridans streptococci are modulins of interleukin-6 induction in infective endocarditis.

    PubMed

    Shun, Chia-Tung; Lu, Shih-Yu; Yeh, Chiou-Yueh; Chiang, Chung-Pin; Chia, Jean-San; Chen, Jen-Yang

    2005-06-01

    The glucosyltransferases (GTFs) of viridans streptococci, common pathogens of infective endocarditis, are extracellular proteins that convert sucrose into exopolysaccharides and glucans. GTFs B, C, and D of Streptococcus mutans are modulins that induce, in vitro and in vivo, the production of cytokines, in particular interleukin-6 (IL-6), from monocytes. The roles of S. mutans GTFs in infectivity and inflammation in situ were tested in a rat experimental model of endocarditis. No significant differences in infectivity, in terms of 95% infective dose and densities of bacteria inside vegetations, were observed between laboratory strain GS-5 and two clinical isolates or isogenic mutant NHS1DD, defective in the expression of GTFs. In aortic valves and surrounding tissues, IL-6 was detected by Western blots and immunostaining 24 h after GS-5 infection, was maintained over 72 h, and was followed by production of tumor necrosis factor alpha but not IL-1beta. Animals infected with NHS1DD showed markedly lower levels of IL-6 (less than 5% of that of parental GS-5-infected rats), while tumor necrosis factor alpha was unaffected. In contrast, animals infected with NHR1DD, another isogenic mutant expressing only GtfB, showed a much smaller reduction (down to 56%). These results suggest that GTFs are specific modulins that act during acute inflammation, inducing IL-6 from endothelial cells surrounding the infected valves without affecting bacterial colonization in vegetations, and that IL-6 might persist in chronic inflammation in endocarditis.

  7. Glucosyltransferases of Viridans Streptococci Are Modulins of Interleukin-6 Induction in Infective Endocarditis

    PubMed Central

    Shun, Chia-Tung; Lu, Shih-Yu; Yeh, Chiou-Yueh; Chiang, Chung-Pin; Chia, Jean-San; Chen, Jen-Yang

    2005-01-01

    The glucosyltransferases (GTFs) of viridans streptococci, common pathogens of infective endocarditis, are extracellular proteins that convert sucrose into exopolysaccharides and glucans. GTFs B, C, and D of Streptococcus mutans are modulins that induce, in vitro and in vivo, the production of cytokines, in particular interleukin-6 (IL-6), from monocytes. The roles of S. mutans GTFs in infectivity and inflammation in situ were tested in a rat experimental model of endocarditis. No significant differences in infectivity, in terms of 95% infective dose and densities of bacteria inside vegetations, were observed between laboratory strain GS-5 and two clinical isolates or isogenic mutant NHS1DD, defective in the expression of GTFs. In aortic valves and surrounding tissues, IL-6 was detected by Western blots and immunostaining 24 h after GS-5 infection, was maintained over 72 h, and was followed by production of tumor necrosis factor alpha but not IL-1β. Animals infected with NHS1DD showed markedly lower levels of IL-6 (less than 5% of that of parental GS-5-infected rats), while tumor necrosis factor alpha was unaffected. In contrast, animals infected with NHR1DD, another isogenic mutant expressing only GtfB, showed a much smaller reduction (down to 56%). These results suggest that GTFs are specific modulins that act during acute inflammation, inducing IL-6 from endothelial cells surrounding the infected valves without affecting bacterial colonization in vegetations, and that IL-6 might persist in chronic inflammation in endocarditis. PMID:15908350

  8. The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia.

    PubMed

    Contreras-Jurado, Constanza; Alonso-Merino, Elvira; Saiz-Ladera, Cristina; Valiño, Arturo José; Regadera, Javier; Alemany, Susana; Aranda, Ana

    2016-08-03

    Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-κB and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections.

  9. Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery

    PubMed Central

    Görtz, Dieter; Braun, Gerald S.; Maruta, Yuichi; Djudjaj, Sonja; van Roeyen, Claudia R.; Martin, Ina V.; Küster, Andrea; Schmitz-Van de Leur, Hildegard; Scheller, Jürgen; Ostendorf, Tammo; Floege, Jürgen; Müller-Newen, Gerhard

    2015-01-01

    Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases. PMID:26423228

  10. Clinical Roles of Interleukin-6 and STAT3 in Oral Squamous Cell Carcinoma.

    PubMed

    Shinagawa, Kenichi; Yanamoto, Souichi; Naruse, Tomofumi; Kawakita, Akiko; Morishita, Kota; Sakamoto, Yuki; Rokutanda, Satoshi; Umeda, Masahiro

    2017-04-01

    The effect inflammation has on cancer prognosis is marked by the presence of cytokines and chemokines. Interleukin-6 (IL-6) is one a multifunctional cytokine that regulates inflammatory responses. We investigated the roles of IL-6 and STAT3 and examined the relationship between IL-6 signaling and clinicopathological factors in patients with oral squamous cell carcinoma (OSCC). We retrospectively examined 116 patients who underwent radical surgery for OSCC. IL-6 and STAT3 expression were detected by immunohistochemistry. IL-6 and STAT3 positivity were detected by IHC, at 78.4 and 80.2 %, respectively. IL-6 expression was significantly associated with pattern of invasion (P = 0.004), vascular invasion (P = 0.003), and pathological nodal status (P = 0.019). Multivariate logistic regression analysis revealed that IL-6 expression was significantly associated with vascular invasion (P = 0.044). Meanwhile, there was no significant association between STAT3 expression and clinicopathological factors and no significant relationship between IL-6 and STAT3 expression. IL-6 expression was significantly associated with 5-year disease-free survival. These results suggest that IL-6 is involved in lymphangiogenesis and recurrence in OSCC.

  11. Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer.

    PubMed

    Han, Jun; Meng, Qingyang; Xi, Qiulei; Zhang, Yongxian; Zhuang, Qiulin; Han, Yusong; Jiang, Yi; Ding, Qiurong; Wu, Guohao

    2016-01-01

    Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC.

  12. Effects of garlic oil on interleukin-6 mediated cardiac hypertrophy in hypercholesterol-fed hamsters.

    PubMed

    Hsieh, You-Liang; Pai, Peiying; Ho, Tsung-Jung; Chung, Li-Chin; Cheng, Yi-Chang; Wu, Chieh-Hsi; Fan, Ming-Jen; Day, Cecilia Hsuan; Shen, Chia-Yao; Huang, Chih-Yang

    2014-12-31

    Hypercholesterol diets are the major causes of cardiac hypertrophy and various cardiac disorders. The purpose of this study is to evaluate the effects of garlic oil on cardiac hypertrophy induced by hypercholesterol diets. Golden Syrian hamsters were fed with 2% cholesterol or 2% cholesterol plus 1% garlic oil for 2 months. Heart architecture changes were measured by hematoxylin-eosin staining and the molecular mechanism was determined by western blotting. Garlic oil reduced whole-heart weight to bone weight ratio, and left ventricle weight to bone weight ratio in the cholesterol-fed group. Moreover, the garlic oil group showed significantly reduced interleukin-6, phosphorylated (p)-extracellular signal-regulated kinase-5, p-mitogen-activated protein kinase-5, calcineurin, nuclear transcription factor of nuclear factor of activated T-cells-3 and p-GATA binding protein 4 when compared with the cholesterol group. However, no changes were observed in gp-130, signal transducer and activator of transcription-3, p-P38 and p-Jun N-terminal kinases protein levels in all groups. The results show that garlic oil may be useful in the treatment of hypertrophy-associated cardiovascular diseases.

  13. Role of interleukin-6 in the induction of protective T cells during mycobacterial infections in mice.

    PubMed Central

    Appelberg, R; Castro, A G; Pedrosa, J; Minóprio, P

    1994-01-01

    Interleukin-6 (IL-6) has been shown to regulate numerous functions of the immune system including the differentiation of T-cell subpopulations. Here we examined the involvement of this cytokine in the in vivo generation of a population of T cells able to protect mice against mycobacterial infections. BALB/c mice were infected intravenously with Mycobacterium avium 2447 and anti-IL-6 monoclonal antibodies were administered intraperitoneally throughout the course of the infection. Control mice were able to control the mycobacterial proliferation 1 month after inoculation, whereas mice whose IL-6 had been blocked showed progressive bacterial growth. To distinguish a role for IL-6 associated to the induction or expression of immunity mediated by T cells, we immunized mice with M. bovis bacillus Calmette-Guérin (BCG) Pasteur and challenged them 2 months later with M. avium. One group of mice received anti-IL-6 during the BCG vaccination and another during the M. avium challenge. When M. avium proliferation was assessed at day 30 of the challenge, it was found that the administration of anti-IL-6 during vaccination reduced the protection afforded by BCG compared to administration of the isotype control antibody. No difference in bacterial proliferation was observed at day 30 of challenge when antibodies were administered during M. avium challenge. Our results show that protective T cells arise during M. avium infections in mice after differentiating in the presence of IL-6. PMID:7959868

  14. Interleukin-6 amplifies glucagon secretion: coordinated control via the brain and pancreas

    PubMed Central

    Barnes, Tammy M.; Otero, Yolanda F.; Elliott, Amicia D.; Locke, Alicia D.; Malabanan, Carlo M.; Coldren, Anastasia G.; Brissova, Marcela; Piston, David W.

    2014-01-01

    Inappropriate glucagon secretion contributes to hyperglycemia in inflammatory disease. Previous work implicates the proinflammatory cytokine interleukin-6 (IL-6) in glucagon secretion. IL-6-KO mice have a blunted glucagon response to lipopolysaccharide (LPS) that is restored by intravenous replacement of IL-6. Given that IL-6 has previously been demonstrated to have a transcriptional (i.e., slow) effect on glucagon secretion from islets, we hypothesized that the rapid increase in glucagon following LPS occurred by a faster mechanism, such as by action within the brain. Using chronically catheterized conscious mice, we have demonstrated that central IL-6 stimulates glucagon secretion uniquely in the presence of an accompanying stressor (hypoglycemia or LPS). Contrary to our hypothesis, however, we found that IL-6 amplifies glucagon secretion in two ways; IL-6 not only stimulates glucagon secretion via the brain but also by direct action on islets. Interestingly, IL-6 augments glucagon secretion from both sites only in the presence of an accompanying stressor (such as epinephrine). Given that both adrenergic tone and plasma IL-6 are elevated in multiple inflammatory diseases, the interactions of the IL-6 and catecholaminergic signaling pathways in regulating GCG secretion may contribute to our present understanding of these diseases. PMID:25205821

  15. Cleavage Site Localization Differentially Controls Interleukin-6 Receptor Proteolysis by ADAM10 and ADAM17

    PubMed Central

    Riethmueller, Steffen; Ehlers, Johanna C.; Lokau, Juliane; Düsterhöft, Stefan; Knittler, Katharina; Dombrowsky, Gregor; Grötzinger, Joachim; Rabe, Björn; Rose-John, Stefan; Garbers, Christoph

    2016-01-01

    Limited proteolysis of the Interleukin-6 Receptor (IL-6R) leads to the release of the IL-6R ectodomain. Binding of the cytokine IL-6 to the soluble IL-6R (sIL-6R) results in an agonistic IL-6/sIL-6R complex, which activates cells via gp130 irrespective of whether the cells express the IL-6R itself. This signaling pathway has been termed trans-signaling and is thought to mainly account for the pro-inflammatory properties of IL-6. A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 are the major proteases that cleave the IL-6R. We have previously shown that deletion of a ten amino acid long stretch within the stalk region including the cleavage site prevents ADAM17-mediated cleavage, whereas the receptor retained its full biological activity. In the present study, we show that deletion of a triple serine (3S) motif (Ser-359 to Ser-361) adjacent to the cleavage site is sufficient to prevent IL-6R cleavage by ADAM17, but not ADAM10. We find that the impaired shedding is caused by the reduced distance between the cleavage site and the plasma membrane. Positioning of the cleavage site in greater distance towards the plasma membrane abrogates ADAM17-mediated shedding and reveals a novel cleavage site of ADAM10. Our findings underline functional differences in IL-6R proteolysis by ADAM10 and ADAM17. PMID:27151651

  16. Nickel hydroxy carbonate increases tumour necrosis factor alpha and interleukin 6 secretion by alveolar macrophages.

    PubMed

    Arsalane, K; Gosset, P; Hildebrand, H F; Voisin, C; Tonnel, A B; Wallaert, B

    1994-01-01

    The aim of the current study was to assess the in vitro effects of nickel hydroxy carbonate (NiHC) at noncytotoxic concentrations on the production of cytokines such as tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in alveolar macrophages (AMs). The effect of NiHC was evaluated in both unstimulated AMs and cells activated by lipopolysaccharide (LPS). Cytotoxicity was related to lactate dehydrogenase release and ATP cell content. The results confirm that NiHC at concentrations of 0.125, 1.25 and 3.125 micrograms NiHC 10(-6) cells was not cytotoxic. The NiHC exposure of unstimulated AMs significantly increased the release of TNF-alpha at all concentrations and that of IL-6 at 1.25 micrograms NiHC 10(-6) cells. LPS addition significantly increased the secretion of both cytokines. However, NiHC did not cause a significant increase in the release of TNF-alpha and IL-6 in LPS-stimulated cells. In conclusion, the ability of NiHC to activate AMs and to release increased amounts of pro-inflammatory mediators may be responsible, at least partly, for inflammation and pneumotoxicity associated with nickel exposure.

  17. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6

    SciTech Connect

    Miles, S.A.; Rezai, A.R.; Salazar-Gonzalez, J.F.; Meyden, M.V.; Stevens, R.H.; Mitsuyasu, R.T.; Martinez-Maza, O. ); Logan, D.M. ); Taga, Tetsuya; Hirano, Toshio; Kishimoto, Tadamitsu )

    1990-06-01

    Cell lines derived from Kaposi sarcoma lesions of patients with AIDS (AIDS-KS cells) produce several cytokines, including an endothelial cell growth factor, interleukin 1{beta}, and basic fibroblast growth factor. Since exposure to human immunodeficiency virus increases interleukin 6 (IL-6) production in monocytes and endothelial cells produce IL-6, the authors examined IL-6 expression and response in AIDS-KS cell lines and IL-6 expression in AIDS Kaposi sarcoma tissue. The AIDS-KS cell lines (N521J and EKS3) secreted large amounts of immunoreactive and biologically active IL-6. The authors found both IL-6 and IL-6 receptor (IL-6-R) RNA by slot blot hybridization analysis of AIDS-KS cells. The IL-6-R was functional, as ({sup 3}H)thymidine incorporation by AIDS-KS cells increased significantly after exposure to human recombinant IL-6 (hrIL-6) at >10 units/ml. When AIDS-KS cells (EKS3) were exposed to IL-6 antisense oligonucleotide, cellular proliferation decreased by nearly two-thirds, with a corresponding decrease in the production of IL-6. These results show that both IL-6 and IL-6-R are produced by AIDS-KS cells and that IL-6 is required for optimal AIDS-KS cell proliferation, and they suggest that IL-6 is an autocrine growth factor for AIDS-KS cells.

  18. Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

    PubMed Central

    Arnold, Philipp; Boll, Inga; Rothaug, Michelle; Schumacher, Neele; Schmidt, Frederike; Wichert, Rielana; Schneppenheim, Janna; Lokau, Juliane; Pickhinke, Ute; Koudelka, Tomas; Tholey, Andreas; Rabe, Björn; Scheller, Jürgen; Lucius, Ralph; Garbers, Christoph; Rose-John, Stefan; Becker-Pauly, Christoph

    2017-01-01

    Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction. PMID:28276471

  19. The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia

    PubMed Central

    Contreras-Jurado, Constanza; Alonso-Merino, Elvira; Saiz-Ladera, Cristina; Valiño, Arturo José; Regadera, Javier; Alemany, Susana; Aranda, Ana

    2016-01-01

    Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-κB and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections. PMID:27484112

  20. Sex Differences in the Association between Level of Childhood Interleukin-6 and Insulin Resistance in Adolescence

    PubMed Central

    Bugge, Anna; El-Naaman, Bianca; G. McMurray, Robert; Froberg, Karsten; Nielsen, Claus Henrik; Müller, Klaus; Andersen, Lars Bo

    2012-01-01

    The purpose of this study was to determine whether levels of interleukin-6 (IL-6) in childhood are related to insulin resistance in adolescence. Further, to explore how fatness and cardiorespiratory fitness (VO2peak) moderate this relationship. Methods. 292 nine-year-old children (n = 292) were followed for 4 years. Anthropometrics and VO2peak were measured. Fasting blood samples were analyzed for IL-6, insulin, and glucose. Homeostasis model assessment (HOMA-IR) was used as a measure of insulin resistance. Results. For girls but not boys, levels of IL-6 at age 9 yrs correlated with HOMA-IR at age 13 yrs: r = 0.223, P = 0.008. Girls with IL-6 levels within the highest quartile at age 9 yrs had an odds ratio of 3.68 (CI = 1.58–8.57) being in the highest quartile of HOMA-IR four years later. Conclusion. In this cohort, IL-6 levels in childhood were related to insulin resistance in adolescence, but only for girls. PMID:22272193

  1. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees

    PubMed Central

    1994-01-01

    The role of interleukin 6 (IL-6) in the toxic sequelae of sepsis is controversial. To assess the part of IL-6 in inflammatory responses to endotoxin, we investigated eight chimpanzees after either a bolus intravenous injection of Escherichia coli endotoxin (n = 4; 4 ng/kg) or after the same dose of endotoxin with a simultaneous bolus intravenous injection of an anti-IL-6 mAb (30 mg; n = 4). Anti-IL-6 did not affect the induction of the cytokine network (tumor necrosis factor [TNF], soluble TNF receptors types I and II, and IL-8) by endotoxin, nor did it influence the occurrence of a neutrophilic leukocytosis and neutrophil degranulation, as monitored by the measurement of elastase- alpha 1-antitrypsin complexes. In contrast, anti-IL-6 markedly attenuated endotoxin-induced activation of coagulation, monitored with the plasma levels of the prothrombin fragment F1+2 and thrombin- antithrombin III complexes, whereas activation of fibrinolysis, determined with the plasma concentrations of plasmin-alpha 2- antiplasmin complexes, remained unaltered. We conclude that IL-6 does not have a feedback effect on the release of other cytokines after injection of endotoxin, and that it is not involved in endotoxin- induced neutrophilia or neutrophil degranulation. IL-6 is, however, an important intermediate factor in activation of coagulation in low grade endotoxemia in chimpanzees. PMID:8145042

  2. Prenatal expression of interleukin 1beta and interleukin 6 in the rat pituitary gland.

    PubMed

    Moro, J A; Carretero, J; Alonso, M I; Martín, C; Gato, A; Mano, A de la

    2008-12-01

    It is known that interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) are expressed post-natally in normal and tumoral cells in the anterior pituitary, and that they play a role in both the liberation of different hormones and in the growth, proliferation and tumor formation of the pituitary gland. However, their expression and role during embryonic and fetal development remain unknown. We have performed an immunocytochemistry study of prenatal expression and distribution of IL-1beta and IL-6 in isolated embryonic rat Rathke's pouch prior to birth, more specifically between 13.5 and 19.5 days p.c. Western-blot analysis carried out on 19.5-day p.c. embryos showed positive immunolabelling for IL-1beta and IL-6. These interleukins were initially expressed simultaneously in the rostral and ventral portions of Rathke's pouch in 15.5-day p.c. embryos, and this expression progressed caudodorsally in later developmental stages, extending to most of the hypophysis before birth. The number of cells expressing these interleukins increased throughout this period: 48.22% of anterior pituitary cells expressed IL-6 in 19.5-day embryos, whilst IL-1beta was positive in 39.8% of the cells. Moreover, we have demonstrated that some adenohypophyseal cells co-express both interleukins. Such findings represent the first step towards an understanding of the physiological role of these interleukins in anterior pituitary development.

  3. Hepcidin Induction by Pathogens and Pathogen-Derived Molecules Is Strongly Dependent on Interleukin-6

    PubMed Central

    Rodriguez, Richard; Jung, Chun-Ling; Gabayan, Victoria; Deng, Jane C.; Ganz, Tomas; Nemeth, Elizabeta

    2014-01-01

    Hepcidin, the iron-regulatory hormone, is increased during infection or inflammation, causing hypoferremia. This response is thought to be a host defense mechanism that restricts iron availability to invading pathogens. It is not known if hepcidin is differentially induced by bacterial versus viral infections, whether the stimulation of pattern recognition receptors directly regulates hepcidin transcription, or which of the proposed signaling pathways are essential for hepcidin increase during infection. We analyzed hepcidin induction and its dependence on interleukin-6 (IL-6) in response to common bacterial or viral infections in mice or in response to a panel of pathogen-derived molecules (PAMPs) in mice and human primary hepatocytes. In wild-type (WT) mice, hepcidin mRNA was induced several hundred-fold both by a bacterial (Streptococcus pneumoniae) and a viral infection (influenza virus PR8) within 2 to 5 days. Treatment of mice and human primary hepatocytes with most Toll-like receptor ligands increased hepcidin mRNA within 6 h. Hepcidin induction by microbial stimuli was IL-6 dependent. IL-6 knockout mice failed to increase hepcidin in response to S. pneumoniae or influenza infection and had greatly diminished hepcidin response to PAMPs. In vitro, hepcidin induction by PAMPs in primary human hepatocytes was abolished by the addition of neutralizing IL-6 antibodies. Our results support the key role of IL-6 in hepcidin regulation in response to a variety of infectious and inflammatory stimuli. PMID:24478088

  4. Plasma Levels of Tumor Necrosis Factor-Alpha and Interleukin-6 in Obsessive Compulsive Disorder

    PubMed Central

    Konuk, N.; Tekın, I. O.; Ozturk, U.; Atik, L.; Atasoy, N.; Bektas, S.; Erdogan, A.

    2007-01-01

    Aim. Recent research implicated place of an immune mechanism in the pathophysiology of obsessive-compulsive disorder (OCD). Despite increasing evidence involvement of cytokine release in OCD, results of the studies are inconsistent. The aim of this study was to evaluate the plasma levels of the cytokines; tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in OCD patients. Methods. Plasma concentrations of TNF-α and IL-6 were measured in 31 drug-free outpatients with OCD, and 31-year age and sex-matched healthy controls. TNF-α and IL-6 concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA). Results. Both TNF-α and IL-6 levels showed statistically significant increases in OCD patients compared to controls (P < .000, P < .001, resp.). In addition, the age of onset was negatively correlated with TNF-α level (r = −.402, P = .025) and duration of illness was weakly correlated with IL-6 levels (r : .357; P : .048) in patients group. Conclusion. OCD patients showed increases in TNF-α and IL-6 levels compared to the healthy controls. This study provides evidence for alterations in the proinflamatory cytokines which suggest the involvement of the immune system in the pathophysiology of OCD. PMID:17497035

  5. Evaluation of salivary interleukin-6 in children with early childhood caries after treatment

    PubMed Central

    Menon, Medhini Madhavan; Balagopal, R. Varma; Sajitha, Krishnan; Parvathy, Kumaran; Sangeetha, G. Bhat; Arun, X. Mamachan; Sureshkumar, Janardhanan

    2016-01-01

    Background: The role of cytokines as a marker in the oral inflammatory process in ECC has not been fully explored before and after full mouth rehabilitation. Aims: The aim of this study was to assess the level of salivary interleukin-6 (IL-6) in children with ECC and to compare its levels before and after comprehensive full mouth rehabilitation. Methods and Materials: Saliva samples were collected from children with ECC prior to dental treatment and 3-month post treatment. The salivary IL-6 levels were analyzed using the ELISA method. The gingival index was also timely recorded. Oral health awareness sessions were conducted for children and their parents at regular intervals during the 3-month study period. Statistical analysis used: Wilcoxon Signed Rank test compared the levels of salivary IL-6 while, the paired t test compared the values of gingival index before and after treatment. Results: The mean level of salivary IL-6 before and 3 months after treatment had reduced and this reduction was statistically significant (P < 0.000). The gingival index scores had also reduced significantly 3-months post treatment (P < 0.002). Conclusions: Children with ECC when completely rehabilitated and kept under frequent follow up, which includes reinforcement of oral hygiene measures and maintaining a low caries activity state, the level of inflammation (IL-6) can definitely be minimized and thereby improving the quality of life of affected children. PMID:27307667

  6. Interleukin-6 amplifies glucagon secretion: coordinated control via the brain and pancreas.

    PubMed

    Barnes, Tammy M; Otero, Yolanda F; Elliott, Amicia D; Locke, Alicia D; Malabanan, Carlo M; Coldren, Anastasia G; Brissova, Marcela; Piston, David W; McGuinness, Owen P

    2014-11-15

    Inappropriate glucagon secretion contributes to hyperglycemia in inflammatory disease. Previous work implicates the proinflammatory cytokine interleukin-6 (IL-6) in glucagon secretion. IL-6-KO mice have a blunted glucagon response to lipopolysaccharide (LPS) that is restored by intravenous replacement of IL-6. Given that IL-6 has previously been demonstrated to have a transcriptional (i.e., slow) effect on glucagon secretion from islets, we hypothesized that the rapid increase in glucagon following LPS occurred by a faster mechanism, such as by action within the brain. Using chronically catheterized conscious mice, we have demonstrated that central IL-6 stimulates glucagon secretion uniquely in the presence of an accompanying stressor (hypoglycemia or LPS). Contrary to our hypothesis, however, we found that IL-6 amplifies glucagon secretion in two ways; IL-6 not only stimulates glucagon secretion via the brain but also by direct action on islets. Interestingly, IL-6 augments glucagon secretion from both sites only in the presence of an accompanying stressor (such as epinephrine). Given that both adrenergic tone and plasma IL-6 are elevated in multiple inflammatory diseases, the interactions of the IL-6 and catecholaminergic signaling pathways in regulating GCG secretion may contribute to our present understanding of these diseases.

  7. Effect of azithromycin on Prevotella intermedia lipopolysaccharide-induced production of interleukin-6 in murine macrophages.

    PubMed

    Choi, Eun-Young; Jin, Ji-Young; Choi, Jeom-Il; Choi, In Soon; Kim, Sung-Jo

    2014-04-15

    Interleukin-6 (IL-6) is a key proinflammatory cytokine which plays a central role in the pathogenesis of periodontal disease. Host modulatory agents targeting at inhibiting IL-6, therefore, appear to be beneficial in slowing the progression of periodontal disease and potentially reducing destructive aspects of the host response. The present study was designed to investigate the effect of the macrolide antibiotic azithromycin on IL-6 generation in murine macrophages treated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen implicated in inflammatory periodontal disease, and its mechanisms of action. Azithromycin significantly suppressed IL-6 production as well as its mRNA expression in P. intermedia LPS-activated RAW264.7 cells. LPS-induced activation of JNK and p38 was not affected by azithromycin treatment. Azithromycin failed to prevent P. intermedia LPS from degrading IκB-α. Instead, azithromycin significantly diminished nuclear translocation and DNA binding activity of NF-κB p50 subunit induced with LPS. Azithromycin inhibited P. intermedia LPS-induced STAT1 and STAT3 phosphorylation. In addition, azithromycin up-regulated the mRNA level of SOCS1 in cells treated with LPS. In conclusion, azithromycin significantly attenuated P. intermedia LPS-induced production of IL-6 in murine macrophages via inhibition of NF-κB, STAT1 and STAT3 activation, which is possibly related to the activation of SOCS1 signaling. Further in vivo studies are required to better evaluate the potential of azithromycin in the treatment of periodontal disease.

  8. [Effect of paraaminobenzoic acid on interleukine-6 production in patients with herpetic keratitis].

    PubMed

    Akberova, S I; Tazulakhova, E B; Musaev Galbinur, P I; Mamedova, V M

    2006-01-01

    The purpose of the study was to compare the effect of para-aminobenzoic acid (PABA) (actipol) on tear interleukin-6 (IL-6) levels in patients with herpetic keratitis and in peripheral blood cells of volunteers in vitro. Enzyme immunoassay was used to measure lacrimal fluid IL-6 levels in the actipol and acyclovir groups before and 1, 2, 3, 4, and 7-8 days after therapy and after clinical recovery in 30 patients with herpetic keratitis. A control group comprised apparently healthy volunteers (n=13, 26 eyes) who used actipol instillations into the conjunctival sac 4-5 times a day. The spontaneous production of cytokines and their production in response to the induction with different PABA concentrations (0.001, 0.01, 0.1, and 10 microkg/ml) were studied on peripheral blood cells taken from 9 volunteers. In the patients with herpetic, actipol was found to reduce and normalize tear IL-6 levels while acyclovir failed to produce this effect. In the healthy individuals, actipol did not affect IL-6 production in the anterior segment of the eye. All study PABA concentrations exerted a modulating effect on the production of IL-6 in the peripheral blood cells in vitro.

  9. A GALECTIN-3-DEPENDENT PATHWAY UPREGULATES INTERLEUKIN-6 IN THE MICROENVIRONMENT OF HUMAN NEUROBLASTOMA

    PubMed Central

    Silverman, Ayaka M.; Nakata, Rie; Shimada, Hiroyuki; Sposto, Richard; DeClerck, Yves A.

    2013-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine with a broad range of physiological and pathological functions. Because in cancer IL-6 contributes to a microenvironment that promotes tumor cell survival, angiogenesis and inflammation, understanding the mechanism responsible for its production is important. In neuroblastoma, the second most common solid tumor in children, IL-6 is produced not by tumor cells but by stromal cells such as monocytes and bone marrow mesenchymal stem cells (BMMSC). Here we show that the production of IL-6 in BMMSC is in part stimulated by galectin-3 binding protein (Gal-3BP) secreted by neuroblastoma cells. We identified a distal region of the IL-6 promoter that contains 3 CCATT/enhancer binding protein (C/EBP) binding domains involved in the transcriptional upregulation of IL-6 by Gal-3BP.Gal-3BP interacted with Galectin-3 (Gal-3) present in BMMSC, and a Gal-3BP/Gal-3/Ras/MEK/ERK signaling pathway was responsible for the transcriptional upregulation of IL-6 in BMMSC where Gal-3 has a necessary function. In support of the role of this pathway in human neuroblastoma tumors, Gal-3BP was found to be present in tumor cells and in the adjacent extracellular matrix of 96% of 78 primary neuroblastoma tumor samples examined by immunohistochemistry. Considering the protumorigenic function of IL-6 in cancer, this tumor cell-stromal cell interactive pathway could be a target for anticancer therapy. PMID:22389450

  10. Diurnal Variation of Circulating Interleukin-6 in Humans: A Meta-Analysis

    PubMed Central

    Lekander, Mats; Åkerstedt, Torbjörn; Axelsson, John; Ingre, Michael

    2016-01-01

    The pleiotropic cytokine interleukin-6 (IL-6) has been proposed to contribute to circadian regulation of sleepiness by increasing in the blood at night. Earlier studies have reported diurnal variation of IL-6, but phase estimates are conflicting. We have therefore performed a meta-analysis on the diurnal variation of circulating IL-6. Studies were included if they reported IL-6 in plasma or serum recorded at least twice within 24 hours in the same individual. A systematic search resulted in the inclusion of 43 studies with 56 datasets, for a total of 1100 participants. Individual participant data were available from 4 datasets with a total of 56 participants. Mixed-effects meta-regression modelling confirmed that IL-6 varied across the day, the most conspicuous effect being a trough in the morning. These results stand in contrast to earlier findings of a peak in the evening or night, and suggest that diurnal variation should be taken into account in order to avoid confounding by time of day in studies of IL-6 in plasma or serum. PMID:27832117

  11. Influence of fluvoxamine on plasma interleukin-6 or clinical improvement in patients with major depressive disorder

    PubMed Central

    Yoshimura, Reiji; Katsuki, Asuka; Atake, Kiyokazu; Hori, Hikaru; Igata, Ryohei; Konishi, Yuki

    2017-01-01

    Objectives The etiology of depression remains unknown. There is, however, a growing body of evidence that cytokines are involved in the pathophysiology of depression. The aim of this study is to investigate the effects of fluvoxamine on plasma interleukin-6 (IL-6) levels and on clinical improvement of the depressive state. Subjects and methods Thirty patients who met the DSM-IV criteria for major depressive disorder (MDD) were enrolled in the study. Thirteen were male and 17 were female, and their ages ranged from 26 to 70 years (mean ± standard deviation 45.0±14.2). The patients were treated with fluvoxamine for 8 weeks. The dosages of fluvoxamine varied among the patients and, based on ethical considerations, were not fixed. Results The fluvoxamine doses were positively related to plasma fluvoxamine levels (r =0.8798, P<0.001). A significant correlation was observed between the patients’ plasma IL-6 levels and their 17-item Hamilton Rating Scale for Depression (HAMD17) scores (r =0.4555, P=0.0010). A positive correlation was found between the delta plasma IL-6 (week 0–week 8) and the delta HAMD17 (week 0–week 8) (r =0.5226, P=0.002). Conclusion Effect of fluvoxamine on IL-6 is partially associated with its clinical efficacy for MDD. PMID:28243095

  12. Increased serum levels of interleukin 6 are associated with severe intraventricular haemorrhage in extremely premature infants

    PubMed Central

    Heep, A; Behrendt, D; Nitsch, P; Fimmers, R; Bartmann, P; Dembinski, J

    2003-01-01

    Background: Intraventricular haemorrhage (IVH) and periventricular leucomalacia (PVL) in premature infants presumably have many causes. It has been proposed that inflammatory processes in the fetomaternal unit play an important role in the pathogenesis of these lesions. Objective: To study the correlation of postpartum serum interleukin 6 (IL6) concentration as a marker of inflammation and neonatal cerebral morbidity in preterm infants < 28 weeks of gestational age. Methods: A total of 88 infants were grouped according to maximum serum IL6 levels within 12 hours post partum: group A (n = 50), ⩽ 100 pg/ml; group B (n = 38), > 100 pg/ml. Ultrasound studies and clinical assessment were performed routinely. Results: IVH was noted significantly more often in group B (24/38; 63%) than in group A (19/50; 38%) (p = 0.02). In a multiple logistic regression model, raised serum IL6 independently predicted development of severe IVH (odds ratio 8.4; 95% confidence interval 2.85 to 24.9; p = 0.0001). Conclusions: Raised serum IL6 may serve as a marker for severe IVH in infants < 28 weeks of gestational age. Although cerebral morbidity in premature infants is determined by different variables, the identification of systemic inflammation can help to define the need for anti-inflammatory strategies to prevent cerebral morbidity. PMID:14602698

  13. A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy.

    PubMed

    Tanaka, Toshio; Narazaki, Masashi; Ogata, Atsushi; Kishimoto, Tadamitsu

    2014-02-01

    Interleukin-6 (IL-6) is a cytokine with redundant and pleiotropic activities, and its synthesis is tightly regulated by transcriptional and posttranscriptional mechanisms. When infections and tissue injuries occur, IL-6 synthesis is promptly induced and provides an emergent signal that contributes to host defense through the stimulation of acute-phase responses, immune reactions, and hematopoiesis. After the environmental stress is removed from the host, the production of IL-6 is terminated. However, dysregulated continual synthesis of IL-6 is involved in the development of chronic inflammatory autoimmune diseases. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Worldwide clinical trials have demonstrated the outstanding efficacy of tocilizumab in rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman's disease; thus, a new era has come for the treatment of these diseases, which were previously considered intractable. Moreover, favorable results from off-label use of tocilizumab strongly suggest that it will be widely applicable for various refractory inflammatory autoimmune diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated in order to investigate the pathogenesis of specific diseases and to facilitate the development of more specific therapeutic strategies. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Diagnostic Utility of Interleukin-6 Expression by Immunohistochemistry in Differentiating Castleman Disease Subtypes and Reactive Lymphadenopathies.

    PubMed

    Post, Ginell R; Bell, Robert C; Rjoop, Anwar; Lobo, Rodolfo Henrich; Yuan, Youzhong; Post, Steven R

    2016-09-01

    The objective of the study was to evaluate the expression pattern of interleukin-6 (IL-6) to determine its utility in differentiating Castleman Disease subtypes and reactive lymphadenopathies. Paraffin-embedded tissue blocks from 20 cases referred for assessment of Castleman Disease (CD) and 4 cases of reactive hyperplasia were selected for immunohistochemical staining with an IL-6 antibody. Six pathologists evaluated the hematoxylin and eosin stained tissue sections and IL-6 expression pattern. Of 20 CD referral cases, the pathologic diagnosis was CD in 14 cases and included 6 hyaline-vascular (HV-CD), 6 plasma cell (PC-CD) and 2 "mixed type"-CD cases. The remaining 6 referral cases showed morphologic features consistent with reactive lymphadenopathy. Patients with non-CD, reactive lymphadenopathies had clinical and/or laboratory features of systemic lupus erythematosus, Hashimoto's disease, viral infection or chronic cellulitis. The pattern of IL-6 expression differed between CD subtypes and non-CD cases. In PC-CD, IL-6 expression was detected in plasma cells and vascular endothelial cells; whereas IL-6 immunoreactivity was detected primarily in vascular endothelial cells in HV-CD. Interfollicular plasma cells were prominent in PC-CD and reactive lymphadenopathies; however, IL-6 expression was significantly increased in PC-CD compared to reactive lymph nodes. Together with morphologic features, the expression pattern of IL-6 detected by immunohistochemistry is helpful to distinguish CD subtypes and reactive mimics. © 2016 by the Association of Clinical Scientists, Inc.

  15. Biological effects of interleukin-6: Clinical applications in autoimmune diseases and cancers.

    PubMed

    Ho, Ling-Jun; Luo, Shue-Fen; Lai, Jenn-Haung

    2015-09-01

    Interleukin-6 (IL-6) is a pro-inflammatory cytokine involved in the pathogenesis of various autoimmune and chronic inflammatory diseases. Binding of IL-6 to its receptor (IL-6R) initiates both classical- and trans-signaling pathways. A number of autoimmune diseases are characterized by overproduction of IL-6. Tocilizumab, a humanized monoclonal antibody against IL-6R, blocks IL-6-mediated signaling and has been approved for the treatment of rheumatoid arthritis and Castleman's disease. IL-6 levels are also upregulated in various tumors, and the levels of circulating IL-6 are associated with prognosis in cancer patients. The major issues covered in this commentary include (1) how IL-6-mediated biological effects may lead to the pathogenesis of autoimmune diseases and cancers, (2) the rationale of developing anti-IL-6 strategies for therapeutic purposes, (3) recent advances in anti-IL-6 therapeutics (clinical benefits and adverse events), (4) current knowledge about clinical trials evaluating newly emerging anti-IL-6 treatments, (5) strategies to improve anti-IL-6 therapeutics from both basic and clinical aspects. This commentary provides a useful overview of the role of IL-6 in both autoimmune diseases and cancers from the laboratory as well as clinical perspectives.

  16. Big 5 personality traits and interleukin-6: evidence for "healthy Neuroticism" in a US population sample.

    PubMed

    Turiano, Nicholas A; Mroczek, Daniel K; Moynihan, Jan; Chapman, Benjamin P

    2013-02-01

    The current study investigated if the Big 5 personality traits predicted interleukin-6 (IL-6) levels in a national sample over the course of 5years. In addition, interactions among the Big 5 were tested to provide a more accurate understanding of how personality traits may influence an inflammatory biomarker. Data included 1054 participants in the Midlife Development in the U.S. (MIDUS) biomarkers subproject. The Big 5 personality traits were assessed in 2005-2006 as part of the main MIDUS survey. Medication use, comorbid conditions, smoking behavior, alcohol use, body mass index, and serum levels of IL-6 were assessed in 2005-2009 as part of the biomarkers subproject. Linear regression analyses examined personality associations with IL-6. A significant Conscientiousness*Neuroticism interaction revealed that those high in both Conscientiousness and Neuroticism had lower circulating IL-6 levels than people with all other configurations of Conscientiousness and Neuroticism. Adjustment for health behaviors diminished the magnitude of this association but did not eliminate it, suggesting that lower comorbid conditions and obesity may partly explain the lower inflammation of those high in both Conscientiousness and Neuroticism. Our findings suggest, consistent with prior speculation, that average to higher levels of Neuroticism can in some cases be associated with health benefits - in this case when it is accompanied by high Conscientiousness. Using personality to identify those at risk may lead to greater personalization in the prevention and remediation of chronic inflammation.

  17. Interleukin-6 promotes tumor progression in colitis-associated colorectal cancer through HIF-1α regulation

    PubMed Central

    Han, Jun; Xi, Qiulei; Meng, Qingyang; Liu, Jingzheng; Zhang, Yongxian; Han, Yusong; Zhuang, Qiulin; Jiang, Yi; Ding, Qiurong; Wu, Guohao

    2016-01-01

    Interleukin-6 (IL-6) is a well-known etiological factor of colitis-associated colorectal cancer (CAC) and has a significant role in CAC progression. In addition, hypoxia-inducible factor 1α (HIF-1α) serves a primary role in the progression of CAC. However, the association between IL-6 and HIF-1α during the progression of CAC remains unclear. To investigate this association, the present study induced CAC in a mouse model using azoxymethane and dextran sulfate sodium. In addition, an anti-IL-6 receptor antibody was used to inhibit IL-6. In this model, anti-IL-6 receptor antibody treatment significantly inhibited the development of CAC and the expression of HIF-1α, in colorectal adenomas and adenocarcinomas. In patients with CAC, the HIF-1α gene was demonstrated to be overexpressed in tumor tissue compared with adjacent non-malignant tissue. Furthermore, HIF-1α mRNA expression was positively correlated with serum IL-6 concentration. The results of the present study suggest that IL-6 promotes CAC progression, in the early stage of the disease, through HIF-1α regulation. PMID:28105173

  18. Can serum interleukin-6 levels predict the outcome of patients with right iliac fossa pain?

    PubMed Central

    Goodwin, A. T.; Swift, R. I.; Bartlett, M. J.; Fernando, B. S.; Chadwick, S. J.

    1997-01-01

    In patients with right iliac fossa (RIF) pain it can be difficult to distinguish between appendicitis and nonspecific abdominal pain (NSAP). In this study we sought to determine whether serum interleukin-6 (IL-6) levels, an early marker of acute inflammation, taken at the time of admission could predict the outcome of patients admitted with RIF pain. Data were collected in a prospective manner on 53 consecutive patients (23 male, 30 female), mean age 22.1 years (range 10-79 years). Nineteen (36%) patients underwent surgery, of whom 16 had appendicitis (histologically proven). The mean (SEM) IL-6 levels (pg/ml) in patients undergoing operation vs those receiving non-operative management were 270.8 (106.3) vs 265.0 (80.4) (P = NS). The mean white blood cell (WBC) counts (x10(9)/l) in these patients were 14.28 (0.81) vs 9.66 (0.67), respectively (P = 0.0002). When patients with a confirmed diagnosis of appendicitis were compared with patients with a diagnosis of NSAP, the IL-6 levels were 149.4 (69.1) vs 363.6 (113.2), respectively (P = NS). In the same groups of patients, the WBC counts were 14.21 (0.81) vs 9.51 (0.68) (P = 0.004). We conclude that IL-6 levels taken at the time of admission are not useful in predicting the outcome of RIF pain. PMID:9135242

  19. Can serum interleukin-6 levels predict the outcome of patients with right iliac fossa pain?

    PubMed

    Goodwin, A T; Swift, R I; Bartlett, M J; Fernando, B S; Chadwick, S J

    1997-03-01

    In patients with right iliac fossa (RIF) pain it can be difficult to distinguish between appendicitis and nonspecific abdominal pain (NSAP). In this study we sought to determine whether serum interleukin-6 (IL-6) levels, an early marker of acute inflammation, taken at the time of admission could predict the outcome of patients admitted with RIF pain. Data were collected in a prospective manner on 53 consecutive patients (23 male, 30 female), mean age 22.1 years (range 10-79 years). Nineteen (36%) patients underwent surgery, of whom 16 had appendicitis (histologically proven). The mean (SEM) IL-6 levels (pg/ml) in patients undergoing operation vs those receiving non-operative management were 270.8 (106.3) vs 265.0 (80.4) (P = NS). The mean white blood cell (WBC) counts (x10(9)/l) in these patients were 14.28 (0.81) vs 9.66 (0.67), respectively (P = 0.0002). When patients with a confirmed diagnosis of appendicitis were compared with patients with a diagnosis of NSAP, the IL-6 levels were 149.4 (69.1) vs 363.6 (113.2), respectively (P = NS). In the same groups of patients, the WBC counts were 14.21 (0.81) vs 9.51 (0.68) (P = 0.004). We conclude that IL-6 levels taken at the time of admission are not useful in predicting the outcome of RIF pain.

  20. Interleukin-6 increases expression and secretion of cathepsin B by breast tumor-associated monocytes.

    PubMed

    Mohamed, Mona M; Cavallo-Medved, Dora; Rudy, Deborah; Anbalagan, Arulselvi; Moin, Kamiar; Sloane, Bonnie F

    2010-01-01

    In the tumor microenvironment, monocytes respond to paracrine stimuli from breast cancer cells by secreting molecules that participate in breast cancer growth, invasion, intravasation and metastasis. Here we examined the effects of media conditioned by MDA-MB-231 human breast carcinoma cells (231-CM) on expression and secretion of proteases and secretion of cytokines by U937 human monocytes. We found that 231-CM increased U937: 1) proliferation; 2) expression, activity and secretion of the cysteine protease cathepsin B (CTSB); 3) secretion of matrix metalloproteinases (MMP)-2 and -9; and 4) secretion of interleukin-6 (IL-6) and insulin-like growth factor binding protein-1 (IGFBP-1). We further demonstrated by western blotting and enzymatic activity assays that the increases in CTSB secretion and activity induced by 231-CM could be reduced by neutralizing antibodies against IL-6. Our data suggest a role for IL-6 in increased monocyte expression and secretion of CTSB in response to soluble factors secreted by breast cancer cells.

  1. Molecular modeling and SPRi investigations of interleukin 6 (IL6) protein and DNA aptamers.

    PubMed

    Rhinehardt, Kristen L; Vance, Stephen A; Mohan, Ram V; Sandros, Marinella; Srinivas, Goundla

    2017-06-22

    Interleukin 6 (IL6), an inflammatory response protein has major implications in immune-related inflammatory diseases. Identification of aptamers for the IL6 protein aids in diagnostic, therapeutic, and theranostic applications. Three different DNA aptamers and their interactions with IL6 protein were extensively investigated in a phosphate buffed saline (PBS) solution. Molecular-level modeling through molecular dynamics provided insights of structural, conformational changes and specific binding domains of these protein-aptamer complexes. Multiple simulations reveal consistent binding region for all protein-aptamer complexes. Conformational changes coupled with quantitative analysis of center of mass (COM) distance, radius of gyration (Rg), and number of intermolecular hydrogen bonds in each IL6 protein-aptamer complex was used to determine their binding performance strength and obtain molecular configurations with strong binding. A similarity comparison of the molecular configurations with strong binding from molecular-level modeling concurred with Surface Plasmon Resonance imaging (SPRi) for these three aptamer complexes, thus corroborating molecular modeling analysis findings. Insights from the natural progression of IL6 protein-aptamer binding modeled in this work has identified key features such as the orientation and location of the aptamer in the binding event. These key features are not readily feasible from wet lab experiments and impact the efficacy of the aptamers in diagnostic and theranostic applications.

  2. Human Cytomegalovirus IE1 Protein Disrupts Interleukin-6 Signaling by Sequestering STAT3 in the Nucleus

    PubMed Central

    Reitsma, Justin M.; Sato, Hiromi; Nevels, Michael

    2013-01-01

    In the canonical STAT3 signaling pathway, binding of agonist to receptors activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 (Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the expression of genes involved in inflammation, angiogenesis, invasion, and proliferation. Here, we demonstrate that human cytomegalovirus (HCMV) infection rapidly promotes nuclear localization of STAT3 in the absence of robust phosphorylation at Y705. Furthermore, infection disrupts interleukin-6 (IL-6)-induced phosphorylation of STAT3 and expression of a subset of IL-6-induced STAT3-regulated genes, including SOCS3. We show that the HCMV 72-kDa immediate-early 1 (IE1) protein associates with STAT3 and is necessary to localize STAT3 to the nucleus during infection. Furthermore, expression of IE1 is sufficient to disrupt IL-6-induced phosphorylation of STAT3, binding of STAT3 to the SOCS3 promoter, and SOCS3 gene expression. Finally, inhibition of STAT3 nuclear localization or STAT3 expression during infection is linked to diminished HCMV genome replication. Viral gene expression is also disrupted, with the greatest impact seen following viral DNA synthesis. Our study identifies IE1 as a new regulator of STAT3 intracellular localization and IL-6 signaling and points to an unanticipated role of STAT3 in HCMV infection. PMID:23903834

  3. Immunohistochemical detection of interleukin-6 in human skeletal muscle fibers following exercise.

    PubMed

    Penkowa, Milena; Keller, Charlotte; Keller, Pernille; Jauffred, Sune; Pedersen, Bente Klarlund

    2003-11-01

    Interleukin-6 (IL-6) is produced by many different cell types. Human skeletal muscles produce and release high amounts of IL-6 during exercise; however, the cell source of origin in the muscle is not known. Therefore, we studied the protein expression of IL-6 by immunohistochemistry in human muscle tissue from biopsies obtained at time points 0, 3, 4.5, 6, 9, and 24 h in relation to 3 h of bicycle exercise performed by healthy young males (n=12) and in resting controls (n=6). The IL-6 expression was clearly increased after exercise and remained high even by 24 h, relative to pre-exercise or resting individuals. The IL-6 immunostainings of skeletal muscle cells were homogeneous and without difference between muscle fiber types. The IL-6 mRNA peaked immediately after the exercise, and, in accordance, the IL-6 protein expression within muscle cells was most pronounced around 3 h post-exercise. However, the finding that plasma IL-6 concentration peaked in the end of exercise indicates a high turnover of muscle-derived IL-6. In conclusion, the finding of marked IL-6 protein expression exclusively within skeletal muscle fibers following exercise demonstrates that skeletal muscle fibers of all types are the dominant cell source of exercise-induced release of IL-6 from working muscle.

  4. Interleukin-6 causes hypocholesterolemia in middle-aged and old rhesus monkeys.

    PubMed

    Ettinger, W H; Sun, W H; Binkley, N; Kouba, E; Ershler, W

    1995-05-01

    Hypocholesterolemia is a risk factor for morbidity and mortality in older people. We have hypothesized that hypocholesterolemia in older people is due to the chronic effect of proinflammatory cytokines on lipoprotein metabolism. To test the effects of the chronic administration of interleukin-6 (IL-6) on lipoprotein levels in middle-aged and old rhesus monkeys, five middle-aged and five old rhesus monkeys received a subcutaneous injection of recombinant human IL-6 (15 micrograms/kg) for 28 days. Lipid, apolipoprotein, and albumin levels were measured at 0, 28, and 42 days after injection. Total and HDL cholesterol levels fell by 16 and 23%, respectively, after IL-6 injections. The concentrations of apolipoproteins A1 and B also decreased. The changes in lipoprotein levels were accompanied by a decrease in albumin levels and body weight. Levels of lipids and plasma proteins returned toward normal 2 weeks after injections were stopped. There was no difference in response between middle-aged and older animals. Chronic IL-6 injections cause acquired hypocholesterolemia, hypoalbuminemia, and weight loss in nonhuman primates. These changes are similar to those seen in older persons with acquired hypocholesterolemia.

  5. Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia.

    PubMed

    Herrmann, Oliver; Tarabin, Victoria; Suzuki, Shigeaki; Attigah, Nicolas; Coserea, Irinel; Schneider, Armin; Vogel, Johannes; Prinz, Simone; Schwab, Stefan; Monyer, Hannah; Brombacher, Frank; Schwaninger, Markus

    2003-04-01

    Although the function of fever is still unclear, it is now beyond doubt that body temperature influences the outcome of brain damage. An elevated body temperature is often found in stroke patients and denotes a bad prognosis. However, the pathophysiologic basis and treatment options of elevated body temperature after stroke are still unknown. Cerebral ischemia rapidly induced neuronal interleukin-6 (IL-6) expression in mice. In IL-6-deficient mice, body temperature was markedly decreased after middle cerebral artery occlusion (MCAO), but infarct size was comparable to that in control mice. If body temperature was controlled by external warming after MCAO, IL-6-deficient mice had a reduced survival, worse neurologic status, and larger infarcts than control animals. In cell culture, IL-6 exerted an antiapoptotic and neuroprotective effect. These data suggest that IL-6 is a key regulator of body temperature and an endogenous neuroprotectant in cerebral ischemia. Neuroprotective properties apparently compensate for its pyretic action after MCAO and enhance the safety of this endogenous pyrogen.

  6. STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6.

    PubMed

    Zhang, D; Sun, M; Samols, D; Kushner, I

    1996-04-19

    Interleukin-6 (IL-6) is the major cytokine inducing transcription of human C-reactive protein (CRP) during the acute phase response. STAT (signal transducers and activators of transcription) family members, recently shown to be important mediators of the effects of many cytokines including IL-6, generally induce their effects by binding to palindromic sequences with TT(N)5AA motifs. We report an IL-6 responsive element in the proximal region of the human CRP 5'-flanking region that bears a TT(N)4AA motif, which we have termed CRP acute phase response element (CRP-APRE). In Hep3B cells, IL-6 but not interferon-gamma was capable of activating CAT constructs driven by the CRP promoter containing CRP-APRE. Overexpressed STAT3 was able to transactivate CRP-chloramphenicol acetyltransferase constructs through the CRP-APRE and was able to enhance endogenous CRP mRNA accumulation in response to IL-6. STAT3 (or an antigenically related molecule) bound to the CRP-APRE in response to IL-6. Overexpression of STAT3 in the presence of IL-6 was capable of inducing expression of a construct consisting of the CRP-APRE and a minimal thymidine kinase promoter lacking a C/EBP site. Taken together, these findings indicate that STAT3 participates in the transcriptional activation of CRP in response to IL-6.

  7. The Effect of Air Tourniquet on Interleukin-6 Levels in Total Knee Arthroplasty

    PubMed Central

    Tsunoda, Kenji; Sonohata, Motoki; Kugisaki, Hajime; Someya, Shinsuke; Honke, Hidefumi; Komine, Mitsunori; Izumi, Masataka; Ide, Shuya; Mawatari, Masaaki

    2017-01-01

    Background: Air tourniquet-induced skeletal muscle injury increases the concentrations of some cytokines such as interleukin-6 (IL-6) in plasma. However, the effect of an air tourniquet on the IL-6 concentrations after total knee arthroplasty (TKA) is unclear. We therefore investigated the impact of tourniquet-induced ischemia and reperfusion injury in TKA using the IL-6 level as an index. Methods: Ten patients with primary knee osteoarthrosis who underwent unilateral TKA without an air tourniquet were recruited (Non-tourniquet group). We also selected 10 age- and sex-matched control patients who underwent unilateral TKA with an air tourniquet (Tourniquet group). Venous blood samples were obtained at 3 points; before surgery, 24 h after surgery, and 7 days after surgery. The following factors were compared between the two groups; IL-6, C-reactive protein (CRP), creatine phosphokinase (CPK), the mean white blood cell (WBC) counts, and the maximum daily body temperatures. Results: The IL-6 level at 24 h after surgery was significantly higher than that at any other point (p<0.01). No significant differences were observed in the WBC count, the body temperature, or the CRP, CPK, or IL-6 levels of the two groups at any of the time points. Conclusion: The effect of ischemia and reperfusion due to the use of an air tourniquet on increasing the IL-6 level was much smaller than that induced by surgical stress in TKA. PMID:28217217

  8. Increased Exhaled 8-Isoprostane and Interleukin-6 in Patients with Helicobacter pylori Infection.

    PubMed

    Yildirim, Zeki; Bozkurt, Bulent; Ozol, Duygu; Armutcu, Ferah; Akgedik, Recep; Karamanli, Harun; Kizilirmak, Deniz; İkizek, Mustafa

    2016-10-01

    Helicobacter pylori (H. pylori) infection triggers both local inflammation, usually in gastric mucosa, and chronic systemic inflammation. It is assumed that this local and systemic inflammation is caused by extracellular products excreted by H. pylori. The aim of this study was to investigate the possible association between H. pylori infection and a local inflammatory response in the airway by using exhaled breath condensate technique. This study includes 41 H. pylori seropositive patients who have gastric symptoms and 27 healthy control subjects. Pulmonary function tests (PFT), chest X ray, and physical examination were performed in all patients and interleukin-6 (IL-6), 8-isoprostane and nitrotyrosine levels were measured in exhaled breath condensate. Levels of IL-6 and 8-isoprostane in exhaled breath condensate (EBC) were significantly higher in H. pylori positive patients than control subjects (p < 0.05). Nitrotyrosine levels were also higher in H. pylori positive patients but the difference was not statistically significant. Both groups had similar leukocyte counts, C-reactive protein (CRP) levels and PFT parameters. H. pylori infection causes an asymptomatic airway inflammation which can be detected by exhaled breath condensate. The clinical importance of this inflammation remains unclear. © 2016 John Wiley & Sons Ltd.

  9. Cord blood erythropoietin and interleukin-6 for prediction of intraventricular hemorrhage in the preterm neonate

    PubMed Central

    BHANDARI, VINEET; BUHIMSCHI, CATALIN S.; HAN, CHRISTINA S.; LEE, SARAH Y.; PETTKER, CHRISTIAN M.; CAMPBELL, KATHERINE H.; DULAY, ANTONETTE T.; OLIVER, EMILY A.; WERNER, ERIKA F.; BUHIMSCHI, IRINA A.

    2013-01-01

    Objective To evaluate cord blood erythropoietin (EPO) and interleukin-6 (IL-6) levels to predict preterm infants at risk of developing intraventricular hemorrhage (IVH). Methods Levels of umbilical cord EPO, acid–base status and IL-6 were analyzed in 116 consecutive, preterm newborns (GA at delivery: 29 [23–34] weeks) born to mothers who had a clinically indicated amniocentesis to rule out infection. Early-onset neonatal sepsis (EONS) was diagnosed using symptoms, hematological criteria and blood cultures. Results IVH was diagnosed by cranial ultrasounds. The prevalence of IVH in our population was 25% (29/116). There was a direct relationship between cord blood EPO and cord blood IL-6 concentration (r = 0.225, p = 0.014), independent of GA at birth. Elevated cord blood EPO levels (r = 0.182, p = 0.016) and GA birth at birth (r = –0.236, p = 0.004) remained significant independent factors associated with the risk of IVH, when evaluated with stepwise logistic regression analyses. Cord blood IL-6, pH, and EONS were not associated with IVH. These relationships remained following correction for GA at birth (p = 0.027). Conclusions Our results suggest that elevation in cord blood EPO may predict newborns at risk for IVH, independent of fetal inflammatory status. Further studies are warranted to confirm this association. PMID:20937006

  10. MiR-34a inhibits oral cancer progression partially by repression of interleukin-6-receptor.

    PubMed

    Li, Ting; Li, Lichu; Li, Dongshuang; Wang, Shuting; Sun, Jinhu

    2015-01-01

    Previous reports revealed that a significant decrease of miR-34a in oral cancer. But the role of miR-34a in oral cancer needs further research. In the present study, we will investigate the effect of miR-34a on oral cancer cell phenotypes. First, it was verified that miR-34a expression was lower in oral cancer tissues compared with their normal controls, so did the oral cancer cells. Next, it was showed that miR-34a overexpression in oral cancer cells could inhibit cell proliferation, G1 phase arrest, metastasis and epithelial mesenchymal transition. It was predicted that interleukin-6-receptor (IL6R) was a potential target gene of miR-34a by bioinformatics analysis and identified by luciferase assay. It was further showed that miR-34a inhibited oral cancer progression via IL6R. Collectively, our findings suggested that miR-34a may function as a tumor suppressor in oral cancer by targeting IL6R.

  11. Early interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4

    PubMed Central

    Chen, Jianlin; Hartono, John R.; John, Reji; Bennett, Michael; Zhou, Xin Jin; Wang, Yanxia; Wu, Qingqing; Winterberg, Pamela D.; Nagami, Glenn T.; Lu, Christopher Y.

    2012-01-01

    Although leukocytes infiltrate the kidney during ischemic acute kidney injury (AKI) and release interleukin 6 (IL6), their mechanism of activation is unknown. Here, we tested whether Toll-like receptor 4 (TLR4) on leukocytes mediated this activation by interacting with high-mobility group protein B1 (HMGB1) released by renal cells as a consequence of ischemic kidney injury. We constructed radiation-induced bone marrow chimeras using C3H/HeJ and C57BL/10ScNJ strains of TLR4 (−/−) mice and their respective TLR4 (+/+) wild-type counterparts and studied them at 4 h after an ischemic insult. Leukocytes adopted from TLR4 (+/+) mice infiltrated the kidneys of TLR4 (−/−) mice, and TLR4 (−/−) leukocytes infiltrated the kidneys of TLR4 (+/+) mice but caused little functional renal impairment in each case. Maximal ischemic AKI required both radiosensitive leukocytes and radioresistant renal parenchymal and endothelial cells from TLR4 (+/+) mice. Only TLR4 (−/−) leukocytes produced IL6 in vivo and in response to HMGB1 in vitro. Thus, following infiltration of the injured kidney, leukocytes produce IL6 when their TLR4 receptors interact with HMGB1 released by injured renal cells. This underscores the importance of TLR4 in the pathogenesis of ischemic AKI. PMID:21633411

  12. Interleukin-1 beta, interleukin-6 and TGF-beta in follicular tissue of impacted third molars.

    PubMed

    Mesgarzadeh, Ali Hossein; Abolfathi, Ali Akbar; Dastgiri, Saeed; Shaaker, Maghsod; Vatankhah, Amir Mansour; Solehakahnamoiee, Shiva; Darabi, Masoud

    2011-06-01

    The clinical evaluation and management of impacted third molars remain challenging. The aim of the present study was to investigate possible associations between follicular tissue cytokines and radiographic manifestations of impacted third molar. The population included 72 patients who underwent surgical extraction of impacted third molars. All these patients underwent a preliminary panoramic radiograph. Levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and transforming growth factor beta (TGF-β) in tissue extracts were determined using ELISA. There were no significant differences between bony and tissue impaction as regards IL-1β, IL-6 and TGF-β levels. Moreover, the same results were obtained as far as the amount of pericoronal space and the presence or absence of a history of pericoronitis are concerned. These results suggest that radiographic findings or a history of pericoronitis are not associated with levels of expression of pro-inflammatory cytokines in patients undergoing surgical removal of impacted third molars. However, further studies are needed to address the possibility of variability during disease progression.

  13. Interleukin-6 prevents the initiation but enhances the progression of lung cancer

    PubMed Central

    Qu, Zhaoxia; Sun, Fan; Zhou, Jingjiao; Li, Liwen; Shapiro, Steven D.; Xiao, Gutian

    2015-01-01

    Recent studies suggest that high expression of the pro-inflammatory cytokine interleukin-6 (IL-6) is associated with poor survival of lung cancer patients. Accordingly, IL-6 has been a target of great interest for lung cancer therapy. However, the role of IL-6 in lung cancer has not been determined yet. Here, we demonstrate that IL-6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared to wild type mice, IL-6 deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL-6 deficient mice were significantly smaller. Notably, both the lung tumor-suppressing and -promoting functions of IL-6 involve its ability in activating the transcription factor STAT3. IL-6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator Cyclin D1. These studies reveal a previously unexplored role of IL-6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL-6/STAT3-targeted therapies for this deadliest human cancer. PMID:26122841

  14. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells.

    PubMed

    Qiu, Y; Ravi, L; Kung, H J

    1998-05-07

    Interleukin-6 (IL-6) is a cytokine that was initially recognized as a regulator of immune and inflammatory responses, but it also regulates the growth of many tumour cells, including prostrate carcinoma. Overexpression of the growth-factor receptors ErbB2/neu and ErbB3 has been implicated in the neoplastic transformation of prostate carcinoma. Here we show that treatment of the prostate cancer cell line LNCaP with IL-6 induces tyrosine phosphorylation of ErbB2 and ErbB3, but not ErbB1/EGFR. We also show that ErbB2 forms a complex with the gp130 subunit of the IL-6 receptor in an IL-6-dependent manner. This association is important because the inhibition of ErbB2 activity results in abrogation of IL-6-induced MAPK activation. Thus ErbB2 is a critical component of IL-6 signalling through the MAP kinase pathway. These data show how a cytokine receptor can diversify its signalling pathways by engaging with a growth-factor receptor kinase.

  15. Elevated interleukin-6 expression levels are associated with intervertebral disc degeneration

    PubMed Central

    DENG, XIAO; ZHAO, FENG; KANG, BAOLIN; ZHANG, XIN

    2016-01-01

    The present study aimed to investigate whether serum interleukin-6 (IL-6) expression levels were associated with the onset and progression of intervertebral disc degeneration (IDD). A comprehensive meta-analysis of the scientific literature from numerous electronic databases was performed, in order to obtain published studies associated with the topic of interest. Relevant case-control studies that had previously assessed a correlation between IL-6 expression levels and IDD were identified using predetermined inclusion and exclusion criteria. The STATA version 12.0 software was used for statistical analysis of the extracted data. A total of 112 studies were initially retrieved, with eight studies meeting the inclusion criteria. These contained a total of 392 subjects, of which 263 were patients with IDD and 129 were healthy controls. A meta-analysis of the eight studies demonstrated that serum IL-6 protein expression levels may be associated with IDD, and this was irrespective of IDD subtype (bulging, protrusion, or sequestration). Notably, serum expression levels of the IL-6 protein were upregulated in intervertebral disc (IVD) protrusion tissue, as compared with normal IVD tissue; thus suggesting that IL-6 may have an important role in the pathophysiological process of IDD. PMID:27073460

  16. Immunoexpression of interleukin-6 in drug-induced gingival overgrowth patients

    PubMed Central

    Ganesh, P. R.

    2016-01-01

    Background: To analyze the role of proinflammatory cytokines in drug-induced gingival enlargement in Indian population. Aim: To evaluate for the presence of interleukin-6 (IL-6) in drug-induced gingival enlargement and to compare it with healthy control in the absence of enlargement. Materials and Methods: Thirty-five patients selected for the study and divided into control group (10) and study group (25) consisting of phenytoin (10); cyclosporin (10) and nifedipine (5) induced gingival enlargement. Gingival overgrowth index of Seymour was used to assess overgrowth and allot groups. Under LA, incisional biopsy done, tissue sample fixed in 10% formalin and immunohistochemically evaluated for the presence of IL-6 using LAB-SA method, Labeled- Streptavidin-Biotin Method (LAB-SA kit from Zymed- 2nd generation LAB-SA detection system, Zymed Laboratories, CA). The results of immunohistochemistry were statistically analyzed using Kruskaal–Wallis and Mann–Whitney test. Results: The data obtained from immunohistochemistry assessment shows that drug-induced gingival overgrowth (DIGO) samples express more IL-6 than control group and cyclosporin expresses more IL-6 followed by phenytoin and nifedipine. Conclusion: Increased IL-6 expression was noticed in all three DIGO groups in comparison with control group. Among the study group, cyclosporin expressed maximum IL-6 expression followed by phenytoin and nifedipine. PMID:27307657

  17. Clinical anxiety, cortisol and interleukin-6: Evidence for specificity in emotion–biology relationships

    PubMed Central

    O'Donovan, Aoife; Hughes, Brian M.; Slavich, George M.; Lynch, Lydia; Cronin, Marie-Therese; O'Farrelly, Cliona; Malone, Kevin M.

    2015-01-01

    Anxiety confers increased risk for inflammatory diseases, and elevated inflammatory activity in anxious individuals may contribute to this increased risk. One complication, however, is that anxiety could be associated with inflammatory activity either through a specific anxiety pathway or through a more general negative emotionality pathway. To investigate, we measured levels of the stress hormone cortisol, the pro-inflammatory cytokine interleukin-6 (IL-6), and the systemic inflammatory marker C-reactive protein (CRP), as well as depression and neuroticism, in clinically anxious and non-anxious adults. Compared with non-anxious participants, clinically anxious participants exhibited significantly lower levels of morning cortisol and significantly higher levels of IL-6, independent of age, sex, and depressive symptoms. These group differences were robust when controlling for neuroticism. Conversely, the groups had equivalent levels of CRP in all analyses. Results are indicative of anxiety-specific effects on inflammatory activity, and highlight a pathway by which anxiety may increase risk for inflammatory diseases. PMID:20227485

  18. Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice.

    PubMed

    Pelosi, Laura; Berardinelli, Maria Grazia; Forcina, Laura; Spelta, Elisa; Rizzuto, Emanuele; Nicoletti, Carmine; Camilli, Carlotta; Testa, Erika; Catizone, Angela; De Benedetti, Fabrizio; Musarò, Antonio

    2015-11-01

    Duchenne muscular dystrophy (DMD) is characterized by progressive lethal muscle degeneration and chronic inflammatory response. The mdx mouse strain has served as the animal model for human DMD. However, while DMD patients undergo extensive necrosis, the affected muscles of adult mdx mice rapidly regenerates and regains structural and functional integrity. The basis for the mild effects observed in mice compared with the lethal consequences in humans remains unknown. In this study, we provide evidence that interleukin-6 (IL-6) is causally linked to the pathogenesis of muscular dystrophy. We report that forced expression of IL-6, in the adult mdx mice, recapitulates the severe phenotypic characteristics of DMD in humans. Increased levels of IL-6 exacerbate the dystrophic muscle phenotype, sustaining inflammatory response and repeated cycles of muscle degeneration and regeneration, leading to exhaustion of satellite cells. The mdx/IL6 mouse closely approximates the human disease and more faithfully recapitulates the disease progression in humans. This study promises to significantly advance our understanding of the pathogenic mechanisms that lead to DMD. © The Author 2015. Published by Oxford University Press.

  19. Inhibition of the interleukin-6 signaling pathway: a strategy to induce immune tolerance.

    PubMed

    Zhang, Cheng; Zhang, Xi; Chen, Xing-Hua

    2014-10-01

    Interleukin-6 (IL-6) is a proinflammatory cytokine that is multifunctional, with multifaceted effects. IL-6 signaling plays a vital role in the control of the differentiation and activation of T lymphocytes by inducing different pathways. In particular, IL-6 controls the balance between Th17 cells and regulatory T (Treg) cells. An imbalance between Treg and Th17 cells is thought to play a pathological role in various immune-mediated diseases. Deregulated IL-6 production and signaling are associated with immune tolerance. Therefore, methods of inhibiting IL-6 production, receptors, and signaling pathways are strategies that are currently being widely pursued to develop novel therapies that induce immune tolerance. This survey aims to provide an updated account of why IL-6 inhibitors are becoming a vital class of drugs that are potentially useful for inducing immune tolerance as a treatment for autoimmune diseases and transplant rejection. In addition, we discuss the effect of targeting IL-6 in recent experimental and clinical studies on autoimmune diseases and transplant rejection.

  20. Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6?

    PubMed

    Stenvinkel, Peter; Barany, Peter; Heimbürger, Olof; Pecoits-Filho, Roberto; Lindholm, Bengt

    2002-05-01

    There is growing evidence that increased plasma concentrations of CRP strongly predict cardiovascular death in both non-renal and renal patient populations. The interleukin-6 (IL-6) system activity, which is the major mediator of the acute phase response, is often markedly up-regulated in uremic patients and has also been shown to predict outcome. This raises the issue of whether or not IL-6 per se may contribute to increased mortality from malnutrition and atherosclerotic cardiovascular disease in uremic patients. The causes of elevated IL-6 levels in the uremic circulation are not fully understood, although a number of factors prevalent in uremic patients, such as hypertension, adiposity, infections, and chronic heart failure may all contribute. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysate, may stimulate IL-6 production. Furthermore, available evidence suggests that genetic factors may also have an impact on circulating plasma IL-6 levels. We advance the hypothesis that IL-6 may play a central role in the genesis of inflammatory-driven malnutrition and that it may be regarded as a significant proatherogenic cytokine. This hypothesis may provide a rationale to test if targeted anti-cytokine therapy may be one way to combat the unacceptable high cardiovascular mortality rate among dialysis patients.

  1. Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants

    PubMed Central

    Denson, Lee A.; McDonald, Scott A.; Das, Abhik; Schendel, Diana E.; Skogstrand, Kristin; Hougaard, David M.; Shankaran, Seetha; Higgins, Rosemary D.; Carlo, Waldemar A.; Ehrenkranz, Richard A.

    2017-01-01

    Objective To determine whether reduced growth velocity (GV) in extremely low birth weight (ELBW) infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks post-menstrual age (PMA) in 768 infants 401-1000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small-for-gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks PMA (p<0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p=0.12) when controlling for BW and energy intake. Both BW (p=0.02) and energy intake (p=0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusions IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks PMA and may have a direct effect upon energy balance and postnatal growth. PMID:27455401

  2. Magnetic colorimetric immunoassay for human interleukin-6 based on the oxidase activity of ceria spheres.

    PubMed

    Peng, Juan; Guan, Jufang; Yao, Huiqin; Jin, Xiaoyong

    2016-01-01

    A novel magnetic colorimetric immunoassay strategy was designed for sensitive detection of human interleukin-6 (IL-6) using ceria spheres as labels. Ceria spheres showed excellent oxidase activity, which can directly catalyze the oxidation of substrate o-phenylenediamine (OPD) to a stable yellow product, 2,3-diaminophenazine (oxOPD). The absorbance of oxOPD was recorded to reflect the level of IL-6. The relatively mild conditions made the immunoassay strategy more robust, reliable, and easy. A linear relationship between absorbance intensity and the logarithm of IL-6 concentrations was obtained in the range of 0.0001-10 ng mL(-1) with a detection limit of 0.04 pg mL(-1) (S/N = 3). The colorimetric immunoassay exhibited high sensitivity and specificity for the detection of IL-6. This immunoassay has been successfully applied in the detection of IL-6 in serum samples and can be readily extended toward the on-site monitoring of cancer biomarkers in serum samples.

  3. Interleukin-6 Enhances Production of Anti-OspC Immunoglobulin G2b Borreliacidal Antibody

    PubMed Central

    Remington, Monica C.; Munson, Erik L.; Callister, Steven M.; Molitor, Melanie L.; Christopherson, John A.; DeCoster, David J.; Lovrich, Steven D.; Schell, Ronald F.

    2001-01-01

    Protection against infection with Borrelia burgdorferi is dependent primarily on induction of complement-dependent antibody that can kill the spirochete. Measuring the production of sustained high levels of borreliacidal antibody is thus paramount for determining potential vaccine efficacy. We investigated the borreliacidal antibody response in sera and the amount of antibody produced by cultured lymph node cells of C3H/HeJ mice vaccinated with outer surface protein C (OspC). We showed that recombinant OspC was a weak stimulant of borreliacidal antibody production compared to whole cells of OspC-expressing B. burgdorferi. Mice vaccinated with B. burgdorferi in adjuvant produced a high level (titer, 5,120) of anti-OspC borreliacidal antibody, which waned rapidly. Similarly, borreliacidal antibody production by cultured lymph node cells from vaccinated mice peaked soon after vaccination and then decreased. Treatment of lymph node cells with interleukin-6 (IL-6) augmented borreliacidal antibody production, particularly immunoglobulin G2b, whereas treatment with anti-IL-6 inhibited the borreliacidal response. These findings demonstrate a previously unrecognized role for IL-6 in borreliacidal antibody production that may have important implications for vaccine development. PMID:11401963

  4. Interleukin-6 and tumor necrosis factor-alpha values in elk neonates

    USGS Publications Warehouse

    Barber-Meyer, S. M.; Johnson, C.R.; Murtaugh, M.P.; Mech, L.D.; White, P.J.

    2007-01-01

    Serological indicators of general condition would be helpful for monitoring or assessing ungulate wildlife. Toward that end, we report the 1st reference values for 2 cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-??), in neonatal elk (Cervus elaphus). We obtained blood samples from 140 calves ??? 6 days old in Yellowstone National Park during summer 2003-2005. TL-6 values ranged from 0 to 1.21 pg/ml with a median of 0.03 pg/ml. TNF-?? values ranged from 0 to 225.43 pg/ml with a median of 1.85 pg/ml. IL-6 and TNF-?? concentrations were not significant predictors of elk calf survival through 21 days. Development of ungulate-based IL-6 and TNF-?? assays that provide greater sensitivity than cross-reacting human-based assays could be helpful in monitoring ungulate condition and health status comparisons among herds. Such information could provide indirect assessments of range quality or environmental influences among herds. 

  5. Changes in interleukin-6 levels during electroconvulsive therapy may reflect the therapeutic response in major depression.

    PubMed

    Järventausta, K; Sorri, A; Kampman, O; Björkqvist, M; Tuohimaa, K; Hämäläinen, M; Moilanen, E; Leinonen, E; Peltola, J; Lehtimäki, K

    2017-01-01

    Interleukin-6 (IL-6) has been reported to be elevated in major depressive disorder (MDD) but decreased by antidepressive medication. IL-6 levels are markedly elevated both after epileptic seizures and single electroconvulsive therapy (ECT) session, but long-term changes in IL-6 levels after ECT have not been studied. The correlation between immediate and long-term changes in proinflammatory cytokines and outcome after ECT was investigated. Thirty patients suffering from MDD participated in the study. IL-6, interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1RA) levels were examined at baseline and at 2 and 4 h after the first, fifth and the last ECT sessions. The response to ECT was measured with Montgomery-Åsberg Depression Rating Scale (MADRS). ECT repeatedly caused an increase in IL-6 levels at the 4-h time point. However, the baseline IL-6 levels decreased among remitters, but not among non-remitters, towards the end of ECT. IL-1β levels were mostly below detectable level, and IL-1Ra levels did not change during and after ECT. ECT has distinct acute and long-term effects on IL-6 levels. Interestingly, the long-term effect of ECT on IL-6 seems to correlate with outcome, providing further evidence of the mechanism of action of ECT and supporting the inflammation theory in MDD. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. The regulation of interleukin-6 implicates skeletal muscle as an integrative stress sensor and endocrine organ

    PubMed Central

    Welc, Steven S.; Clanton, Thomas L.

    2017-01-01

    Skeletal muscle has been identified as an endocrine organ owing to its capacity to produce and secrete a variety of cytokines (myokines) and other proteins. To date, myokines have primarily been studied in response to exercise or metabolic challenges; however, numerous observations suggest that skeletal muscle may also release myokines in response to certain categories of internal or external stress exposure. Internal stress signals include oxidative or nitrosative stress, damaged or unfolded proteins, hyperthermia or energy imbalance. External stress signals, which act as indicators of organismal stress or injury in other cells, employ mediators such as catecholamines, endotoxin, alarmins, ATP and pro-inflammatory cytokines, such as tumour necrosis factor-α and interleukin-1β. External stress signals generally induce cellular responses through membrane receptor systems. In this review, we focus on the regulation of interleukin-6 (IL-6) as a prototypical stress response myokine and highlight evidence that IL-6 gene regulation in muscle is inherently organized to respond to a wide variety of internal and external stressors. Given that IL-6 can initiate protective, anti-inflammatory or restorative processes throughout the organism during life-threatening conditions, we present the argument that skeletal muscle has a physiological function as a sensor and responder to stress. Furthermore, we hypothesize that it may comprise a fundamental component of the organism’s acute stress response. PMID:22941979

  7. Negative Emotions Predict Elevated Interleukin-6 in the United States but not in Japan

    PubMed Central

    Miyamoto, Yuri; Boylan, Jennifer Morozink; Coe, Christopher L.; Curhan, Katherine B.; Levine, Cynthia S.; Markus, Hazel Rose; Park, Jiyoung; Kitayama, Shinobu; Kawakami, Norito; Karasawa, Mayumi; Love, Gayle D.; Ryff, Carol D.

    2013-01-01

    Previous studies conducted in Western cultures have shown that negative emotions predict higher levels of pro-inflammatory biomarkers, specifically interleukin-6 (IL-6). This link between negative emotions and IL-6 may be specific to Western cultures where negative emotions are perceived to be problematic and thus may not extend to Eastern cultures where negative emotions are seen as acceptable and normal. Using samples of 1044 American and 382 Japanese middle-aged and older adults, we investigated whether the relationship between negative emotions and IL-6 varies by cultural context. Negative emotions predicted higher IL-6 among American adults, whereas no association was evident among Japanese adults. Furthermore, the interaction between culture and negative emotions remained even after controlling for demographic variables, psychological factors (positive emotions, neuroticism, extraversion), health behaviors (smoking status, alcohol consumption), and health status (chronic conditions, BMI). These findings highlight the role of cultural context in shaping how negative emotions affect inflammatory physiology and underscore the importance of cultural ideas and practices relevant to negative emotions for understanding of the interplay between psychology, physiology, and health. PMID:23911591

  8. Socioeconomic and Psychosocial Predictors of Interleukin-6 in the MIDUS National Sample

    PubMed Central

    Morozink, Jennifer A.; Friedman, Elliot M.; Coe, Christopher L.; Ryff, Carol D.

    2010-01-01

    Objective To investigate whether psychosocial factors (i.e., depression, anxiety, and well-being) moderate educational gradients in interleukin-6 (IL-6) levels using data from the Survey of Mid-life Development in the U.S. (MIDUS). The influences of educational attainment and psychosocial factors on IL-6 in middle aged and older adults were also examined. Design Telephone interviews and mail surveys were utilized to collect educational attainment and psychosocial information from participants (N = 1028). Respondents also participated in an overnight clinic visit, during which health information and a fasting blood sample was obtained. Main Outcome Measures Serum levels of IL-6. Results . Greater educational attainment predicted lower levels of IL-6 independent of age and gender, although this effect was attenuated after taking health behaviors, body mass index, waist-to-hip ratio, and chronic illnesses into account. Psychological well-being interacted with education to predict IL-6, such that for those with less education, higher well-being was associated with lower levels of IL-6. Conclusion The findings indicate a strong association between education and inflammation, which can be further moderated by psychosocial factors. The health benefits associated with psychological well-being were particularly evident for individuals with low educational attainment. PMID:20954777

  9. Negative emotions predict elevated interleukin-6 in the United States but not in Japan.

    PubMed

    Miyamoto, Yuri; Boylan, Jennifer Morozink; Coe, Christopher L; Curhan, Katherine B; Levine, Cynthia S; Markus, Hazel Rose; Park, Jiyoung; Kitayama, Shinobu; Kawakami, Norito; Karasawa, Mayumi; Love, Gayle D; Ryff, Carol D

    2013-11-01

    Previous studies conducted in Western cultures have shown that negative emotions predict higher levels of pro-inflammatory biomarkers, specifically interleukin-6 (IL-6). This link between negative emotions and IL-6 may be specific to Western cultures where negative emotions are perceived to be problematic and thus may not extend to Eastern cultures where negative emotions are seen as acceptable and normal. Using samples of 1044 American and 382 Japanese middle-aged and older adults, we investigated whether the relationship between negative emotions and IL-6 varies by cultural context. Negative emotions predicted higher IL-6 among American adults, whereas no association was evident among Japanese adults. Furthermore, the interaction between culture and negative emotions remained even after controlling for demographic variables, psychological factors (positive emotions, neuroticism, extraversion), health behaviors (smoking status, alcohol consumption), and health status (chronic conditions, BMI). These findings highlight the role of cultural context in shaping how negative emotions affect inflammatory physiology and underscore the importance of cultural ideas and practices relevant to negative emotions for understanding of the interplay between psychology, physiology, and health. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Socioeconomic and psychosocial predictors of interleukin-6 in the MIDUS national sample.

    PubMed

    Morozink, Jennifer A; Friedman, Elliot M; Coe, Christopher L; Ryff, Carol D

    2010-11-01

    To investigate whether psychosocial factors (i.e., depression, anxiety, and well-being) moderated educational gradients in interleukin-6 (IL-6) levels using data from the Survey of Midlife Development in the U.S. (MIDUS). The influences of educational attainment and psychosocial factors on IL-6 in middle aged and older adults were also examined. Telephone interviews and mail surveys were utilized to collect educational attainment and psychosocial information from respondents (N = 1028). Respondents also participated in an overnight clinic visit, during which health information and a fasting blood sample were obtained. Serum levels of IL-6. Greater educational attainment predicted lower levels of IL-6 independent of age and gender, although this effect was attenuated after taking health behaviors, body mass index, waist-to-hip ratio, and chronic illnesses into account. Psychological well-being interacted with education to predict IL-6, such that for those with less education, higher well-being was associated with lower levels of IL-6. The findings indicate a strong association between education and inflammation, which can be further moderated by psychosocial factors. The health benefits associated with psychological well-being were particularly evident for individuals with low educational attainment. © 2010 APA, all rights reserved.

  11. Interleukin-6 Kinetics can be Useful for Early Treatment Monitoring of Severe Bacterial Sepsis and Septic Shock

    PubMed Central

    Cantara, Giulio; Sechtem, Udo; Athanasiadis, Anastasios

    2016-01-01

    Early appropriate anti-microbial therapy is necessary to improve outcomes of septic patients. We describe 20 case histories of patients with severe bacterial sepsis regarding kinetics of several biomarkers. We found that interleukin-6 is able to predict survival and might be able to evaluate appropriateness of anti-microbial therapy. PMID:27103972

  12. The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

    PubMed Central

    Omoigui, Sota

    2007-01-01

    We describe the inflammation pathway from Cholesterol to Aging. Interleukin 6 mediated inflammation is implicated in age-related disorders including Atherosclerosis, Peripheral Vascular Disease, Coronary Artery Disease, Osteoporosis, Type 2 Diabetes, Dementia and Alzheimer's disease and some forms of Arthritis and Cancer. Statins and Bisphosphonates inhibit Interleukin 6 mediated inflammation indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion. Polyphenolic compounds found in plants, fruits and vegetables inhibit Interleukin 6 mediated inflammation by direct inhibition of the signal transduction pathway. Therapeutic targets for the control of all the above diseases should include inhibition of Interleukin-6 mediated inflammation. PMID:17374166

  13. Interleukin-6 and C-reactive protein as early markers of sepsis in patients with diabetic ketoacidosis or hyperosmosis.

    PubMed

    Gogos, C A; Giali, S; Paliogianni, F; Dimitracopoulos, G; Bassaris, H P; Vagenakis, A G

    2001-08-01

    An early diagnosis of sepsis in patients with diabetic ketoacidosis and hyperosmolar non-ketotic coma is crucial and could save lives. We studied serum C-reactive protein and interleukin-6 to find out how useful these might be for identifying sepsis. Sixty one diabetic patients with ketoacidosis or hyperosmolar non-ketotic coma were enrolled. Patients with signs and symptoms of systemic inflammatory response syndrome were identified. Acute-phase reactants, including C-reactive protein and interleukin-6, the main cytokine responsible for the induction of acute-phase proteins, were measured on admission and when patients had clinically improved and were euglycaemic. A total of 49 out of 61 patients with diabetic ketoacidosis or hyperosmosis had signs of systemic inflammatory response syndrome. Another 27 patients had systemic inflammatory response syndrome and no signs of infection and 22 patients had systemic inflammatory response syndrome due to proven infection. We detected a significant increase in serum C-reactive protein and interleukin-6 values in patients infected compared with patients not infected with systemic inflammatory response syndrome SIRS. Patients who finally died had much higher levels of these proteins, while there was a prompt reduction of serum C-reactive protein and interleukin-6 early during remission. Diabetic ketoacidosis and hyperosmolar non-ketotic coma can often cause a clinical syndrome resembling systemic inflammatory response syndrome. Determination of serum C-reactive protein and interleukin-6 levels is a useful way of excluding an underlying infection early on as well as confirming and monitoring sepsis.

  14. The human rs1050286 polymorphism alters LOX-1 expression through modifying miR-24 binding.

    PubMed

    Morini, Elena; Rizzacasa, Barbara; Pucci, Sabina; Polidoro, Chiara; Ferrè, Fabrizio; Caporossi, Daniela; Helmer Citterich, Manuela; Novelli, Giuseppe; Amati, Francesca

    2016-01-01

    The up-regulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, plays a fundamental role in the pathogenesis of atherosclerosis. Moreover, OLR1 polymorphisms were associated with increased susceptibility to acute myocardial infarction (AMI) and coronary artery diseases (CAD). In these pathologies, the identification of therapeutic approaches that can inhibit or reduce LOX-1 overexpression is crucial. Predictive analysis showed a putative hsa-miR-24 binding site in the 3'UTR of OLR1, 'naturally' mutated by the presence of the rs1050286 single nucleotide polymorphism (SNP). Luciferase assays revealed that miR-24 targets OLR1 3'UTR-G, but not 3'UTR-A (P < 0.0005). The functional relevance of miR-24 in regulating the expression of OLR1 was established by overexpressing miR-24 in human cell lines heterozygous (A/G, HeLa) and homozygous (A/A, HepG2) for rs1050286 SNP. Accordingly, HeLa (A/G), but not HepG2 (A/A), showed a significant down-regulation of OLR1 both at RNA and protein level. Our results indicate that rs1050286 SNP significantly affects miR-24 binding affinity to the 3'UTR of OLR1, causing a more efficient post-transcriptional gene repression in the presence of the G allele. On this basis, we considered that OLR1 rs1050286 SNP may contribute to modify OLR1 susceptibility to AMI and CAD, so ORL1 SNPs screening could help to stratify patients risk. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  15. Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology.

    PubMed

    Buyalos, R P; Funari, V A; Azziz, R; Watson, J M; Martinez-Maza, O

    1992-08-01

    To determine if interleukin 6 (IL-6) is a normal constituent of peritoneal fluid (PF), and if various types of pelvic pathology influence its presence within the PF microenvironment. Peritoneal fluid from 73 women obtained at the time of laparoscopy was examined for the presence of IL-6 using an IL-6 specific sandwich enzyme-linked immunosorbent assay. Thirty-nine patients had pelvic endometriosis, 17 had nonendometriotic pelvic adhesive disease, and 17 subjects undergoing tubal sterilization without evidence of pelvic pathology served as controls. Immunoreactive IL-6 was observed in the PF of all 73 subjects (range 0.26 to 11.16 ng/mL). The mean concentration of IL-6 was higher in women with nonendometriotic pelvic adhesions as compared with control subjects (1.28 +/- 0.16 versus 0.80 +/- 0.06 ng/mL, P less than 0.03). There was no difference in the mean peritoneal concentrations of IL-6 between women with endometriosis (1.16 +/- 0.28 ng/mL) and controls, P = 0.38. Twenty-seven of 73 patients (37%) demonstrated elevated levels (greater than 1.0 ng/mL) of IL-6. Patients with pelvic adhesions were significantly more likely to have elevated concentrations of IL-6 than controls (10/17 [59%] versus 3/17 [18%], P less than 0.02). Alternatively, the percentage of patients with elevated IL-6 concentrations did not differ between patients with endometriosis or controls (14/39 [36%] versus 3/17 [18%], P greater than 0.10). These findings demonstrate that IL-6 is a normal constituent of PF and that elevated levels are found in many patients with pelvic adhesions.

  16. Peripheral and central blockade of interleukin-6 trans-signaling differentially affects sleep architecture.

    PubMed

    Oyanedel, Carlos N; Kelemen, Eduard; Scheller, Jürgen; Born, Jan; Rose-John, Stefan

    2015-11-01

    The immune system is known to essentially contribute to the regulation of sleep. Whereas research in this regard focused on the pro-inflammatory cytokines interleukin-1 and tumor necrosis factor, the role of interleukin-6 (IL-6) in sleep regulation has been less intensely studied, probably due to the so far seemingly ambiguous results. Yet, this picture might simply reflect that the effects of IL-6 are conveyed via two different pathways (with possibly different actions), i.e., in addition to the 'classical' signaling pathway via the membrane bound IL-6 receptor (IL-6R), IL-6 stimulates cells through the alternative 'trans-signaling' pathway via the soluble IL-6R. Here, we concentrated on the contributions of the trans-signaling pathway to sleep regulation. To characterize this contribution, we compared the effect of blocking IL-6 trans-signaling (by the soluble gp130Fc fusion protein) in the brain versus body periphery. Thus, we compared sleep in transgenic mice expressing the soluble gp130Fc protein only in the brain (GFAP mice) or in the body periphery (PEPCK mice), and in wild type mice (WT) during a 24-h period of undisturbed conditions and during 18 h following a 6-h period of sleep deprivation. Compared with WT mice, PEPCK mice displayed less sleep, particularly during the late light phase, and this was accompanied by decreases in slow wave sleep (SWS) and rapid eye movement (REM) sleep. Following sleep deprivation PEPCK mice primarily recovered REM sleep rather than SWS. GFAP mice showed a slight decrease in REM sleep in combination with a profound and persistent increase in EEG theta activity. In conclusion, peripheral and central nervous IL-6 trans-signaling differentially influences brain activity. Peripheral IL-6 trans-signaling appears to more profoundly contribute to sleep regulation, mainly by supporting SWS.

  17. Interleukin 6 Receptor Is an Independent Prognostic Factor and a Potential Therapeutic Target of Ovarian Cancer

    PubMed Central

    Isobe, Aki; Sawada, Kenjiro; Kinose, Yasuto; Ohyagi-Hara, Chifumi; Nakatsuka, Erika; Makino, Hiroshi; Ogura, Tomonori; Mizuno, Tomoko; Suzuki, Noriko; Morii, Eiichi; Nakamura, Koji; Sawada, Ikuko; Toda, Aska; Hashimoto, Kae; Mabuchi, Seiji; Ohta, Tsuyoshi; Morishige, Ken-ichirou; Kurachi, Hirohisa; Kimura, Tadashi

    2015-01-01

    Ovarian cancer remains the most lethal gynecologic cancer and new targeted molecular therapies against this miserable disease continue to be challenging. In this study, we analyzed the expressional patterns of Interleukin-6 (IL-6) and its receptor (IL-6R) expression in ovarian cancer tissues, evaluated the impact of these expressions on clinical outcomes of patients, and found that a high-level of IL-6R expression but not IL-6 expression in cancer cells is an independent prognostic factor. In in vitro analyses using ovarian cell lines, while six (RMUG-S, RMG-1, OVISE, A2780, SKOV3ip1 and OVCAR-3) of seven overexpressed IL-6R compared with a primary normal ovarian surface epithelium, only two (RMG-1, OVISE) of seven cell lines overexpressed IL-6, suggesting that IL-6/IL-6R signaling exerts in a paracrine manner in certain types of ovarian cancer cells. Ovarian cancer ascites were collected from patients, and we found that primary CD11b+CD14+ cells, which were predominantly M2-polarized macrophages, are the major source of IL-6 production in an ovarian cancer microenvironment. When CD11b+CD14+ cells were co-cultured with cancer cells, both the invasion and the proliferation of cancer cells were robustly promoted and these promotions were almost completely inhibited by pretreatment with anti-IL-6R antibody (tocilizumab). The data presented herein suggest a rationale for anti-IL-6/IL-6R therapy to suppress the peritoneal spread of ovarian cancer, and represent evidence of the therapeutic potential of anti-IL-6R therapy for ovarian cancer treatment. PMID:25658637

  18. Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis.

    PubMed

    Dong, Hongmei; Xu, Jinjin; Li, Weiwei; Gan, Jinfeng; Lin, Wan; Ke, Jierong; Jiang, Jiali; Du, Liang; Chen, Yuping; Zhong, Xueyun; Zhang, Dianzheng; Yeung, Sai-Ching Jim; Li, Xiaotao; Zhang, Hao

    2017-03-01

    Oesophageal squamous cell carcinoma (ESCC), a leading lethal malignancy of the digestive tract, is characterized by marked gender disparity. Clarifying the roles of the function and regulatory pathway of the androgen receptor (AR) will improve our understanding of oesophageal cancer progression, thereby facilitating the personalized management of ESCC. Here we report evidence to show that AR is a key mediator of inflammatory signals in ESCC cancer progression. High AR expression was associated with poor overall survival in tobacco-using ESCC patients but not in ESCC patients not using tobacco. A gain and loss of AR function enhanced and repressed ESCC cell growth, respectively, by altering cell cycle progression. In mice bearing human ESCC xenografts, silencing AR expression attenuated tumour growth, whereas AR overexpression promoted tumour growth in mice of different androgen statuses (male, female, and castrated male). Array assays revealed that the inflammatory cytokine interleukin-6 (IL6) is a prominent AR target gene in ESCC. By directly binding to the IL6 promoter, AR enhances IL6 transcription, and IL6 can in turn activate AR expression, thus forming a reciprocal regulatory circuit to sustain STAT3 oncogenic signalling in ESCC. Moreover, high expression levels of both AR and IL6 in human ESCC predict poor clinical outcome in tobacco users. Together, these data establish that AR promotes ESCC growth and is associated with poor patient prognosis. The discovery of a positive feedback loop between IL6 and AR bridges the knowledge gaps among lifestyle factor-associated inflammation, gender disparity, and oesophageal carcinoma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  19. First case report of exacerbated ulcerative colitis after anti-interleukin-6R salvage therapy

    PubMed Central

    Atreya, Raja; Billmeier, Ulrike; Rath, Timo; Mudter, Jonas; Vieth, Michael; Neumann, Helmut; Neurath, Markus F

    2015-01-01

    We present the case of a 53-year-old woman with long-standing ulcerative colitis and severe, steroid-dependent disease course unresponsive to treatment with azathioprine, methotrexate, anti-TNF antibodies (infliximab, adalimumab) and tacrolimus, who refused colectomy as a therapeutic option. As the pro-inflammatory cytokine interleukin-6 (IL-6) had been identified as a crucial regulator in the immunopathogenesis of inflammatory bowel diseases, we treated the patient with biweekly intravenous infusions of an anti-IL-6R antibody (tocilizumab) for 12 wk. However, no clinical improvement of disease activity was noted. In fact, endoscopic, histological and endomicroscopic assessment demonstrated exacerbation of mucosal inflammation and ulcer formation upon anti-IL-6R therapy. Mechanistic studies revealed that tocilizumab treatment failed to suppress intestinal IL-6 production, impaired epithelial barrier function and induced production of pro-inflammatory cytokines such as TNF, IL-21 and IFN-γ. Inhibition of IL-6 by tocilizumab had no clinical benefit in this patient with intractable ulcerative colitis and even led to exacerbation of mucosal inflammation. Our findings suggest that anti-IL-6R antibody therapy may lead to aggravation of anti-TNF resistant ulcerative colitis. When targeting IL-6, the differential responsiveness of target cells has to be taken into account, as IL-6 on the one side promotes acute and chronic mucosal inflammation via soluble IL-6R signaling but on the other side also strongly contributes to epithelial cell survival via membrane bound IL-6R signaling. PMID:26668517

  20. Interleukin-6 as inflammatory marker referring to multiple organ dysfunction syndrome in severely injured children

    PubMed Central

    2014-01-01

    Background Despite the suggestion that the inflammatory response in traumatized children is functionally unique, prognostic markers predicting pediatric multiple organ failure are lacking. We intended to verify whether Interleukin-6 (IL-6) displays a pivotal role in pediatric trauma similar to adults. Methods Traumatized children less than 18 years of age with an Injury Severity Score >9 points and consecutive admission to the hospital’s pediatric intensive care unit were included. Organ function was evaluated according to the score by Marshall et al. while IL-6 levels were measured repetitively every morning. Results 59 traumatized children were included (8.4 ± 4.4 years; 57.6% male gender). Incidence of MODS was 11.9%. No differences were found referring to age, gender, injury distribution or overall injury severity between children with and without MODS. Increased IL-6 levels during hospital admission were associated with injury severity (Spearman correlation: r = 0.522, p < 0.001), while an inconsistent association towards the development of MODS was proven at that time point (Spearman correlation: r = 0.180, p = 0.231; Pearson's correlation: r = 0.297, p = 0.045). However, increased IL-6 levels during the first two days were no longer associated with the injury severity but a significant correlation to MODS was measured. Conclusions The presented prospective study is the first providing evidence for a correlation of IL-6 levels with injury severity and the incidence of MODS in traumatized children. PMID:24589345

  1. Engineering human interleukin-6 to obtain variants with strongly enhanced bioactivity.

    PubMed Central

    Toniatti, C; Cabibbo, A; Sporena, E; Salvati, A L; Cerretani, M; Serafini, S; Lahm, A; Cortese, R; Ciliberto, G

    1996-01-01

    Interleukin-6 (IL-6) triggers the formation of a high affinity receptor complex with the ligand binding subunit IL-6Ralpha and the signal transducing chain gp130. Since the intracytoplasmic region of the IL-6Ralpha does not contribute to signaling, soluble forms of the extracytoplasmic domain (sIL-6Ralpha), potentiate IL-6 bioactivity and induce a cytokine-responsive status in cells expressing gp130 only. This observation, together with the detection of high levels of circulating soluble human IL-6Ralpha (shIL-6Ralpha) in sera, suggests that the hIL-6-shIL-6Ralpha complex is an alternative form of the cytokine. Here we describe the generation of human IL-6 (hIL-6) variants with strongly enhanced shIL-6Ralpha binding activity and bioactivity. Homology modeling and site-directed mutagenesis of hIL-6 suggested that the binding interface for hIL-6Ralpha is constituted by the C-terminal portion of the D-helix and residues contained in the AB loop. Four libraries of hIL-6 mutants were generated by each time fully randomizing four different amino acids in the predicted AB loop. These libraries were displayed monovalently on filamentous phage surface and sorted separately for binding to immobilized shIL-6Ralpha. Mutants were selected which, when expressed as soluble proteins, showed a 10- to 40-fold improvement in shIL-6Ralpha binding; a further increase (up to 70-fold) was achieved by combining variants isolated from different libraries. Interestingly, high affinity hIL-6 variants show strongly enhanced bioactivity on cells expressing gp13O in the presence of shIL-6Ralpha at concentrations similar to those normally found in human sera. Images PMID:8654370

  2. Distribution of mast cells and macrophages and expression of interleukin-6 in periapical cysts.

    PubMed

    Bracks, Igor Vieira; Armada, Luciana; Gonçalves, Lúcio Souza; Pires, Fábio Ramôa

    2014-01-01

    Mast cells and macrophages are important components of the inflammatory infiltrate found in inflammatory periapical diseases. Several cytokines participate in the mechanisms of inflammation, tissue repair, and bone resorption associated with periapical cysts. The aim of the present study was to evaluate the distribution of mast cells and macrophages and the expression of interleukin-6 (IL-6) in periapical cysts. Thirty periapical cysts were selected for the study, and clinical, demographic, and gross information from the cases was obtained from the laboratory records. Five-micrometer sections stained with hematoxylin-eosin were reviewed for analysis of the microscopic features of the cysts, and 3-μm sections on silanized slides were used for immunohistochemical reactions with anti-tryptase, anti-CD68, and anti-IL-6. There was no statistically significant difference in the mean number of mast cells and macrophages when comparing superficial and deep regions of the fibrous capsule of the cysts. Mean number of mast cells on the superficial region of the fibrous capsule was higher in cysts showing intense superficial inflammation and exocytosis. Macrophages were more commonly found in areas showing IL-6 expression, and IL-6 was less expressed in deep regions of the fibrous capsule in cysts showing greater gross volume. The results reinforced the participation of mast cells and macrophages in the pathogenesis of periapical cysts and suggested that IL-6 is not the major bone resorption mediator in larger periapical cysts. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  3. The effect of sunlight exposure on interleukin-6 levels in depressive and non-depressive subjects.

    PubMed

    Levandovski, Rosa; Pfaffenseller, Bianca; Carissimi, Alicia; Gama, Clarissa S; Hidalgo, Maria Paz Loayza

    2013-03-05

    The objective of this epidemiological study was to evaluate the effect of length of sunlight exposure on interleukin 6 (IL-6) levels in depressive and non-depressive subjects. This was a cross-sectional study with 154 subjects (54 males, mean age: 43.5 ± 12.8 years) who were living in a rural area in south Brazil. Chronobiological and light parameters were assessed using the Munich Chronotype Questionnaire. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Depressive symptoms were assessed with the Beck Depression Inventory. Plasma levels of inflammatory cytokines (IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, and interferon) were collected during the daytime and measured. IL-6 levels showed a positive correlation with light exposure (r = 0.257; p < 0.001) and a negative correlation with the mid-sleep phase on work-free days (r = -0.177; p = 0.028). Multiple linear regression analysis showed that only the length of light exposure was an independent factor for predicting IL-6 levels (ß = 0.26; p = 0.002). In non-depressed subjects, exposure to a different intensity of light did not affect IL-6 levels (t = -1.6; p = 0.1). However, when the two depressive groups with low and high light exposure were compared, the low light exposure group had lower levels of IL-6 compared with the high light exposure group (t = -2.19 and p = 0.0037). The amount of time that participants are exposed to sunlight is directly related to their IL-6 levels. Additionally, depressed subjects differ in their IL-6 levels if they are exposed to light for differing amounts of time.

  4. Preoperative interleukin-6 production by mononuclear blood cells predicts survival after radical surgery for colorectal carcinoma.

    PubMed

    Clinchy, Birgitta; Fransson, Annelie; Druvefors, Bengt; Hellsten, Anna; Håkansson, Annika; Gustafsson, Bertil; Sjödahl, Rune; Håkansson, Leif

    2007-05-01

    Colorectal cancer is one of the most common forms of cancer in the Western world. Staging based on histopathology is currently the most accurate predictor of outcome after surgery. Colorectal cancer is curable if treated at an early stage (stage I-III). However, for tumors in stages II and III there is a great need for tests giving more accurate prognostic information defining the patient population in need of closer follow-up and/or adjuvant therapy. Furthermore, tests that provide prognostic information preoperatively could provide a guide both for preoperative oncologic treatment and the surgical procedure. Peripheral blood mononuclear cells (PBMCs) were isolated preoperatively, within a week before primary surgery, from 39 patients undergoing surgery for colorectal cancer. The PBMCs were cultured in vitro for 24 hours in the presence of autologous serum and lipopolysaccharide (LPS). Interleukin-6 (IL-6) production was measured with enzyme-linked immunosorbent assay (ELISA). Staging based on histopathology was performed in all patients. Patients were followed for at least 54 months. A production of >5000 pg/mL of IL-6 identified colorectal cancer patients with a poor prognosis. Eight out of 13 patients with >5000 pg/mL IL-6 died from cancer within the follow-up period, whereas no cancer-related deaths were recorded among 21 patients with 5000 pg/mL IL-6 or less. A multivariate Cox regression analysis, stratified for T- and N-stage, identified IL-6 production as an independent prognostic factor. IL-6 production in vitro by PBMC can predict survival after radical surgery for colorectal cancer. Copyright (c) 2007 American Cancer Society

  5. The Pro-Inflammatory Cytokine, Interleukin-6, Enhances the Polarization of Alternatively Activated Macrophages

    PubMed Central

    Fernando, Maria Ruweka; Reyes, Jose Luis; Iannuzzi, Jordan; Leung, Gabriella; McKay, Derek Mark

    2014-01-01

    Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated) subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM)) subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells – immunoregulatory features not observed in the ‘parent’ IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT)-3, was partially dependent on up-regulation of the IL4Rα chain, and was independent of autocrine IL-10. In the presence of IFNγ, IL-6 promoted the production of IL-1β and TNFα suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its’ anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6. PMID:24736635

  6. Interleukin-6 impairs chronotropic responsiveness to cholinergic stimulation and decreases heart rate variability in mice.

    PubMed

    Hajiasgharzadeh, Khalil; Mirnajafi-Zadeh, Javad; Mani, Ali R

    2011-12-30

    Heart rate variability is reduced in several clinical settings associated with systemic inflammation. The underlying mechanism of decreased heart rate variability during systemic inflammation is unknown. It appears that the inflammatory cytokines might play a role, since epidemiologic studies has shown that circulating levels of interleukine-6 (IL-6) correlate significantly with indexes of depressed heart rate variability in various clinical conditions. The present investigation was carried out to study the peripheral and central effects of IL-6 on heart rate dynamic in mice. Adult male BALB/c mice were used in the study. RT-PCR was performed to study the expression of IL-6 receptor in mouse atrial and the results showed that gp130 mRNA was detectable in the atrium. The effect of IL-6 was also studies on chronotropic responsiveness of isolated atria to adrenergic and cholinergic stimulations. Incubation of isolated atria with 10 ng/ml of IL-6 was associated with a significant hypo-responsiveness to cholinergic stimulation (log IC₅₀ of carbacholine changed from -6.26±0.10 in controls to -5.59±0.19 following incubation with IL-6, P<0.05). The chronotropic responsiveness to adrenergic stimulation was identical with or without incubation with IL-6. Intraperitoneal injection of IL-6 (200 ng/mouse) was associated with a significant decrease in heart rate variability parameters (SDNN, SD1, and SD2). While intracerebroventricular injection of IL-6 (50 ng/mouse) had no significant effect on heart rate variability parameters. These data are in line with a peripheral role for IL-6 in the genesis of decreased heart rate variability during systemic inflammation.

  7. Cervical interleukin-6 as a predictive test for preterm delivery in symptomatic women: preliminary results.

    PubMed

    Brik, Maia; Antonio, Pilar; Perales-Puchalt, Alfredo; Diago, Vicente; Perales, Alfredo

    2011-03-01

    The aim of this study is to assess the efficacy of cervical interleukin-6 (IL-6) compared with cervical length and its association in the prediction of preterm delivery in symptomatic women. Observational prospective study was performed at Hospital Universitario La Fe, Valencia (Spain). 100 women between 24 and 34 weeks gestational age, with threatened preterm delivery and intact membranes during the period 2006-2008. Transvaginal scan to assess cervical length was performed and cervical swab for IL-6 detection was taken. Statistical analysis included Chi-square test, receiver operating characteristic (ROC) curve analysis, COX regression, logistic regression, and Kaplan-Meier survival analysis. The prevalence of preterm delivery at <37 weeks was 35% and at <32 weeks was 5%. Cervical length was <15 mm in 12% and <30 mm in 62% of the cases. Cervical length and IL-6 were useful for prediction of delivery at 48 h, 7 days, <32, and <34 weeks. Using ROC curves, the IL-6 value that showed best accuracy for prediction of preterm delivery was >210 pg/ml. No differences were observed between the area under the curve (AUC) of IL-6 and cervical length for the prediction of preterm delivery. The association of IL-6 (>210 pg/ml) and cervical length (<30 mm) increases the prediction of either alone. Cervical IL-6 can predict preterm delivery similarly to cervical length; when combined, it adds prognostic information to that provided by sonographic measurement of the cervical length. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  8. Analysis of YKL-40 acute-phase protein and interleukin-6 levels in periodontal disease.

    PubMed

    Keles, Zeynep Pinar; Keles, Gonca Cayir; Avci, Bahattin; Cetinkaya, Burcu Ozkan; Emingil, Gulnur

    2014-09-01

    YKL-40, a new acute-phase protein, is shown to be elevated in inflammatory diseases, such as rheumatoid arthritis, type 2 diabetes mellitus, and coronary artery diseases. However, there is no data indicating a relationship between YKL-40 and periodontal disease. Interleukin-6 (IL-6) is the major regulator of acute-phase protein synthesis and one of the most studied inflammatory markers in periodontal disease. The purpose of the present study is to evaluate YKL-40 and IL-6 levels in gingival crevicular fluid (GCF) and serum of patients with periodontal disease and healthy individuals. Periodontally healthy individuals (n = 15), patients with gingivitis (n = 15), and patients with severe chronic periodontitis (CP) (n = 15) without any systemic disease were included in the study. Clinical measurements were recorded; GCF and blood samples were obtained from each participant. GCF and serum YKL-40 and IL-6 levels were analyzed by enzyme-linked immunosorbent assay. Statistical analysis was performed by parametric and non-parametric tests. Total amounts of YKL-40 and IL-6 in GCF as well as serum YKL-40 and IL-6 levels were significantly higher in patients with gingivitis and CP compared with healthy controls (P <0.01). YKL-40 levels in GCF and serum as well as serum IL-6 levels were significantly higher in patients with CP compared with patients with gingivitis (P <0.01). YKL-40 levels in GCF as well as serum YKL-40 and IL-6 levels increased from gingivitis to periodontitis. Within the limits of the present study, the YKL-40 molecule might be a potential novel inflammatory marker of periodontal disease.

  9. Interleukin-6 inhibits neurotransmitter release and the spread of excitation in the rat cerebral cortex.

    PubMed

    D'Arcangelo, G; Tancredi, V; Onofri, F; D'Antuono, M; Giovedì, S; Benfenati, F

    2000-04-01

    Cytokines are extracellular mediators that have been reported to affect neurotransmitter release and synaptic plasticity phenomena when applied in vitro. Most of these effects occur rapidly after the application of the cytokines and are presumably mediated through the activation of protein phosphorylation processes. While many cytokines have an inflammatory action, interleukin-6 (IL-6) has been found to have a neuroprotective effect against ischaemia lesions and glutamate excitotoxicity, and to increase neuronal survival in a variety of experimental conditions. In this paper, the functional effects of IL-6 on the spread of excitation visualized by dark-field/infrared videomicroscopy in rat cortical slices and on glutamate release from cortical synaptosomes were analysed and correlated with the activation of the STAT3, mitogen-activated protein kinase ERK (MAPK/ERK) and stress-activated protein kinase/cJun NH2-terminal kinase (SAPK/JNK) pathways. We have found that IL-6 depresses the spread of excitation and evoked glutamate release in the cerebral cortex, and that these effects are accompanied by a stimulation of STAT3 tyrosine phosphorylation, an inhibition of MAPK/ERK activity, a decreased phosphorylation of the presynaptic MAPK/ERK substrate synapsin I and no detectable effects on SAPK/JNK. The effects of IL-6 were effectively counteracted by treatment of the cortical slices with the tyrosine kinase inhibitor lavendustin A. The inhibitory effects of IL-6 on glutamate release and on the spread of excitation in the rat cerebral cortex indicate that the protective effect of IL-6 on neuronal survival could be mediated by a downregulation of neuronal activity, release of excitatory neurotransmitters and MAPK/ERK activity.

  10. Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2

    PubMed Central

    Feng, Siting; Tang, Qizhu; Sun, Meng; Chun, Jae Yeon; Evans, Christopher P.; Gao, Allen C.

    2011-01-01

    The standard treatment for advanced, androgen-responsive prostate cancer is androgen deprivation therapy with or without a nonsteroidal antiandrogen, such as bicalutamide. Although maximal androgen blockade exhibits favorable responses in the majority of patients, prostate cancer eventually progresses to an androgen-refractory stage. The mechanism underlying bicalutamide resistance in the course of prostate cancer progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of CRPC. Herein, we explored an association between IL-6 and bicalutamide resistance. To study this, series of lower and higher passages of LNCaP cell sublines generated by long-term exposure to IL-6 were used. The cells from higher passages of LNCaP treated with IL-6 developed resistance to bicalutamide treatment compared with parental LNCaP cells. The levels of transcriptional intermediary factor 2 (TIF2) in IL-6-treated LNCaP cells were found to be significantly higher than parental LNCaP cells. Down-regulation of TIF2 expression via short hairpin RNA in IL-6-treated LNCaP cells sensitized these cells to bicalutamide treatment, whereas overexpression of TIF2 in the parental LNCaP cells increased resistance to bicalutamide. Furthermore, overexpression of IL-6 attenuated bicalutamide-mediated blockage of androgen-induced androgen receptor nuclear translocation and recruitment. These results show that overexpression of IL-6 increases the resistance of prostate cancer cells to bicalutamide via TIF2. Overexpression of IL-6 not only plays an important role in prostate cancer progression but also contributes to bicalutamide resistance. Our studies suggest that bicalutamide-IL-6-targeted adjunctive therapy may lead to a more effective intervention than bicalutamide alone. PMID:19240160

  11. Interleukin-6 increases prostate cancer cells resistance to bicalutamide via TIF2.

    PubMed

    Feng, Siting; Tang, Qizhu; Sun, Meng; Chun, Jae Yeon; Evans, Christopher P; Gao, Allen C

    2009-03-01

    The standard treatment for advanced, androgen-responsive prostate cancer is androgen deprivation therapy with or without a nonsteroidal antiandrogen, such as bicalutamide. Although maximal androgen blockade exhibits favorable responses in the majority of patients, prostate cancer eventually progresses to an androgen-refractory stage. The mechanism underlying bicalutamide resistance in the course of prostate cancer progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of CRPC. Herein, we explored an association between IL-6 and bicalutamide resistance. To study this, series of lower and higher passages of LNCaP cell sublines generated by long-term exposure to IL-6 were used. The cells from higher passages of LNCaP treated with IL-6 developed resistance to bicalutamide treatment compared with parental LNCaP cells. The levels of transcriptional intermediary factor 2 (TIF2) in IL-6-treated LNCaP cells were found to be significantly higher than parental LNCaP cells. Down-regulation of TIF2 expression via short hairpin RNA in IL-6-treated LNCaP cells sensitized these cells to bicalutamide treatment, whereas overexpression of TIF2 in the parental LNCaP cells increased resistance to bicalutamide. Furthermore, overexpression of IL-6 attenuated bicalutamide-mediated blockage of androgen-induced androgen receptor nuclear translocation and recruitment. These results show that overexpression of IL-6 increases the resistance of prostate cancer cells to bicalutamide via TIF2. Overexpression of IL-6 not only plays an important role in prostate cancer progression but also contributes to bicalutamide resistance. Our studies suggest that bicalutamide-IL-6-targeted adjunctive therapy may lead to a more effective intervention than bicalutamide alone.

  12. Oral contraceptives moderately effect bone resorption markers and serum-soluble interleukin-6 receptor concentrations.

    PubMed

    Zittermann, A; Rühl, J; Berthold, H K; Sudhop, T; van der Ven, H; Reinsberg, J; Stehle, P

    2002-01-01

    This study investigated the effect of ethinylestradiol(EE2)-containing oral contraceptives on mineral and bone metabolism and on serum soluble-interleukin-6-receptor (sIL-6R) during the menstrual cycle. Twelve women, aged 24.3 +/- 2.9 years, were examined. Blood and 24-hour and fasting urine samples were obtained during one menstrual cycle between cycle day 3-5 (t(1)), cycle day 10-12 (t(2)), cycle day 24-26 (t(3)), and again on day 3-5 of the next cycle (t(4)). EE2 intake was 0 mg at t(1), 30 mg at t(2), 30 mg at t(3) and 0 mg at t(4). Fasting renal phosphorus and calcium excretions were slightly reduced at t(2) and t(3) compared with t(1) and t(4) (P < 0.05-0.001). Moreover, renal excretion of the bone resorption marker C-Teleopeptide was at t(3) reduced by 26% compared with t(1)(P < 0.01) and by 13% compared with t(4)(P > 0.05). Fasting sIL-6R levels were 16.5% lower at t(2) and 12% lower at t(3) than at t(4) (P < 0.01 and P < 0.05). sIL-6R was correlated with total deoxypyridinoline excretion (r = +0.35; P < 0.05) and with fasting renal excretions of calcium (r = +0.36; P < 0.05) and phosphorus (r = +0.29; P < 0.05). In summary, our data suggest that in young women, cyclic monthly oral contraceptive intake is associated with small, but significant variations in bone resorption processes and in serum sIL-6R levels. Results are a further indication that monthly fluctuations of bone resorption in young women are mediated by sex hormones and that osteoclastic activity is stimulated by cytokines in vivo.

  13. Disrupted Ultradian Activity Rhythms and Differential Expression of Several Clock Genes in Interleukin-6-Deficient Mice

    PubMed Central

    Monje, Francisco J.; Cicvaric, Ana; Acevedo Aguilar, Juan Pablo; Elbau, Immanuel; Horvath, Orsolya; Diao, Weifei; Glat, Micaela; Pollak, Daniela D.

    2017-01-01

    The characteristics of the cycles of activity and rest stand out among the most intensively investigated aspects of circadian rhythmicity in humans and experimental animals. Alterations in the circadian patterns of activity and rest are strongly linked to cognitive and emotional dysfunctions in severe mental illnesses such as Alzheimer’s disease (AD) and major depression (MDD). The proinflammatory cytokine interleukin 6 (IL-6) has been prominently associated with the pathogenesis of AD and MDD. However, the potential involvement of IL-6 in the modulation of the diurnal rhythms of activity and rest has not been investigated. Here, we set out to study the role of IL-6 in circadian rhythmicity through the characterization of patterns of behavioral locomotor activity in IL-6 knockout (IL-6 KO) mice and wild-type littermate controls. Deletion of IL-6 did not alter the length of the circadian period or the amount of locomotor activity under either light-entrained or free-running conditions. IL-6 KO mice also presented a normal phase shift in response to light exposure at night. However, the temporal architecture of the behavioral rhythmicity throughout the day, as characterized by the quantity of ultradian activity bouts, was significantly impaired under light-entrained and free-running conditions in IL-6 KO. Moreover, the assessment of clock gene expression in the hippocampus, a brain region involved in AD and depression, revealed altered levels of cry1, dec2, and rev-erb-beta in IL-6 KO mice. These data propose that IL-6 participates in the regulation of ultradian activity/rest rhythmicity and clock gene expression in the mammalian brain. Furthermore, we propose IL-6-dependent circadian misalignment as a common pathogenetic principle in some neurodegenerative and neuropsychiatric disorders. PMID:28382017

  14. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation

    PubMed Central

    Tawara, Isao; Koyama, Motoko; Liu, Chen; Toubai, Tomomi; Thomas, Dafydd; Evers, Rebecca; Chockley, Peter; Nieves, Evelyn; Sun, Yaping; Lowler, Kathleen P.; Malter, Chelsea; Nishimoto, Norihiro; Hill, Geoffrey R.; Reddy, Pavan

    2010-01-01

    Purpose The graft-versus-tumor (GVT) effect is a potent form of immunotherapy against many hematological malignancies and some solid tumors. The beneficial GVT effect after allogeneic bone marrow transplantation (BMT) is tightly linked to its most significant complication, graft-versus-host disease (GVHD). The role of interleukin-6 (IL-6) after allogeneic BMT is not well-understood. This study used a series of complementary knock-out and antibody blockade strategies to analyze the impact of IL-6 in multiple clinically relevant murine models of GVHD and GVT. Experimental Design We examined the effect of the source of IL-6 by analyzing the role IL-6 deficiency in donor T cells, donor bone marrow or in host tissues. We confirmed and extended the relevance of IL-6 deficiency on GVHD and GVT by treating BMT recipients with anti-mouse IL-6 receptor (IL-6R), MR16-1. Results Deficiency of IL-6 in donor T cells led to prolongation of survival. Total inhibition of IL-6 with MR16-1 caused an even greater reduction in GVHD-induced mortality. The reduction in GVHD was independent of the direct effects on T effector cell expansion or donor regulatory T cells. GVT responses were preserved after treatment with MR16-1. Conclusion MR16-1 treatment reduced GVHD and preserved sufficient GVT. Tocilizumab, a humanized anti-IL-6R mAb, is approved in several countries including the United States and European Union for the treatment of rheumatoid arthritis and other inflammatory diseases. Blockade of IL-6 with anti-IL-6R mAb therapy may be testable in clinical trials as an adjunct to prevent GVHD in BMT patients without a significant loss of GVT. PMID:21047980

  15. High-Level Transient Expression of ER-Targeted Human Interleukin 6 in Nicotiana benthamiana

    PubMed Central

    Nausch, Henrik; Mikschofsky, Heike; Koslowski, Roswitha; Meyer, Udo; Broer, Inge; Huckauf, Jana

    2012-01-01

    Tobacco plants can be used to express recombinant proteins that cannot be produced in a soluble and active form using traditional platforms such as Escherichia coli. We therefore expressed the human glycoprotein interleukin 6 (IL6) in two commercial tobacco cultivars (Nicotiana tabacum cv. Virginia and cv. Geudertheimer) as well as the model host N. benthamiana to compare different transformation strategies (stable vs. transient expression) and subcellular targeting (apoplast, endoplasmic reticulum (ER) and vacuole). In T0 transgenic plants, the highest expression levels were achieved by ER targeting but the overall yields of IL6 were still low in the leaves (0.005% TSP in the ER, 0.0008% in the vacuole and 0.0005% in the apoplast). The apoplast variant accumulated to similar levels in leaves and seeds, whereas the ER-targeted variant was 1.2-fold more abundant in seeds and the vacuolar variant was 6-fold more abundant in seeds. The yields improved in subsequent generations, with the best-performing T2 plants producing the ER-targeted IL6 at 0.14% TSP in both leaves and seeds. Transient expression of ER-targeted IL6 in leaves using the MagnICON system resulted in yields of up to 7% TSP in N. benthamiana, but only 1% in N. tabacum cv. Virginia and 0.5% in cv. Geudertheimer. Although the commercial tobacco cultivars produced up to threefold more biomass than N. benthamiana, this was not enough to compensate for the lower overall yields. The recombinant IL6 produced by transient and stable expression in plants was biologically active and presented as two alternative bands matching the corresponding native protein. PMID:23152824

  16. PARK2 Mediates Interleukin 6 and Monocyte Chemoattractant Protein 1 Production by Human Macrophages

    PubMed Central

    de Léséleuc, Louis; Girard, Manon; Huong, Nguyen Thu; Ba, Nguyen Ngoc; Van Thuc, Nguyen; Truman, Richard; Spencer, John S.; Adams, Linda; Thai, Vu Hong; Alcais, Alexandre; Schurr, Erwin

    2013-01-01

    Leprosy is a persistent infectious disease caused by Mycobacterium leprae that still affects over 200,000 new patients annually. The host genetic background is an important risk factor for leprosy susceptibility and the PARK2 gene is a replicated leprosy susceptibility candidate gene. The protein product of PARK2, Parkin, is an E3 ubiquitin ligase that is involved in the development of various forms of Parkinsonism. The human macrophage is both a natural host cell of M. leprae as well as a primary mediator of natural immune defenses, in part by secreting important pro-inflammatory cytokines and chemokines. Here, we report that down-regulation of Parkin in THP-1 macrophages, human monocyte-derived macrophages and human Schwann cells resulted in a consistent and specific decrease in interleukin-6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1/CCL2) production in response to mycobacteria or LPS. Interestingly, production of IL-6 at 6 hours by THP-1 cells stimulated with live M. leprae and M. bovis BCG was dependent on pretreatment with 1,25-dihydroxyvitamin D3 (VD). Parkin knockdown in VD-treated cells blocked IL-6 induction by mycobacteria. However, IκB-α phosphorylation and levels of IκB-ξ, a nuclear protein required for IL-6 expression, were not affected by Parkin silencing. Phosphorylation of MAPK ERK1/2 and p38 was unaffected by Parkin silencing while JNK activation was promoted but did not explain the altered cytokine production. In a final set of experiments we found that genetic risk factors of leprosy located in the PARK2 promoter region were significantly correlated with M. leprae sonicate triggered CCL2 and IL6 transcript levels in whole blood assays. These results associated genetically controlled changes in the production of MCP-1/CCL2 and IL-6 with known leprosy susceptibility factors. PMID:23350010

  17. The pro-inflammatory cytokine, interleukin-6, enhances the polarization of alternatively activated macrophages.

    PubMed

    Fernando, Maria Ruweka; Reyes, Jose Luis; Iannuzzi, Jordan; Leung, Gabriella; McKay, Derek Mark

    2014-01-01

    Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated) subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM)) subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells - immunoregulatory features not observed in the 'parent' IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT)-3, was partially dependent on up-regulation of the IL4Rα chain, and was independent of autocrine IL-10. In the presence of IFNγ, IL-6 promoted the production of IL-1β and TNFα suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its' anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6.

  18. Correlation between interleukin-6 and ammonia in patients with overt hepatic encephalopathy due to cirrhosis.

    PubMed

    Luo, Ming; Li, Lei; Yang, Er-Na; Dai, Chen-Yang; Liang, Shu-Ren; Cao, Wu-Kui

    2013-09-01

    Previous studies have shown that elevated serum levels of interleukin-6 (IL-6) correlate with the severity of overt hepatic encephalopathy (OHE) in cirrhotic patients. However, the correlation between serum IL-6 levels and plasma ammonia levels in these patients remains unclear. Therefore, the present study investigated this correlation between both variables in cirrhotic patients with OHE. Fifty-five cirrhotic patients with various grades of OHE, 29 cirrhotic patients without OHE, and 30 healthy controls were recruited. Concentrations of plasma ammonia and serum IL-6 were simultaneously measured. In cirrhotic patients with OHE, the severity of OHE, represented by the West Haven criteria, correlated with serum IL-6 levels (r=0.43, P<0.05) and plasma ammonia levels (r=0.59, P<0.05). IL-6 and ammonia were found to be significant independent predictors of OHE severity (P<0.05 for both variables). Furthermore, the severity of liver cirrhosis, determined by Child-Pugh scores, correlated with serum IL-6 levels (r=0.45, P<0.05) and plasma ammonia levels (r=0.68, P<0.05) in these patients. Moreover, there was a significant positive correlation between serum IL-6 levels and plasma ammonia levels (r=0.58, P<0.05) in cirrhotic patients with OHE, but not in patients without OHE (r=0.42, P>0.05) or healthy controls (r=0.27, P>0.05). The correlation between IL-6 and ammonia was independent of infectious precipitating factors. The results of the present study suggest that IL-6 might be involved in the mechanism by which ammonia contributes to the pathogenesis of OHE. There is also evidence of a potential synergistic interaction between proinflammatory cytokines and ammonia in the pathogenesis of OHE. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  19. Direct regulation of interleukin-6 expression by Notch signaling in macrophages

    PubMed Central

    Wongchana, Wipawee; Palaga, Tanapat

    2012-01-01

    Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine produced by various types of cells, including macrophages. Within the IL-6 gene promoter region, the signature binding motif of CBF1/Su(H)/Lag-1 (CSL), a key DNA-binding protein in the Notch signaling pathway, was identified and found to overlap with a consensus nuclear factor (NF)-κB-binding site. Notch signaling is highly conserved and is involved in the regulation of biological functions in immune cells. In this study, we investigated the role of Notch signaling in the regulation of the IL-6 transcript in murine macrophages. The upregulation of Notch1 protein levels and the appearance of cleaved Notch1 (Val1744) correlated well with the increased IL-6 mRNA expression levels in murine primary bone marrow-derived macrophages (BMMφ) after activation by lipopolysaccharide (LPS) together with interferon-gamma (IFN-γ). Treatment of BMMφ with the γ-secretase inhibitor IL-CHO to suppress the transduction of Notch signaling resulted in a partial decrease in the level of IL-6 mRNA and the amount of IL-6 protein produced. In contrast, the overexpression of a constitutively activated intracellular Notch1 protein (NIC) in the RAW264.7 macrophage-like cell line resulted in significantly higher IL-6 transcript expression levels than in cells transfected with the empty vector control. The NF-κB inhibitor completely abrogated IL-6 mRNA expression induced by the overexpression of NIC. Chromatin immunoprecipitation (ChIP) using an anti-Notch1 antibody demonstrated that Notch1 is associated with the IL-6 promoter in RAW264.7 cells activated by LPS/IFN-γ but not in unstimulated cells. Taken together, these results strongly suggest that Notch1 positively regulates IL-6 expression via NF-κB in activated macrophages. PMID:21983868

  20. Interleukin-6 receptor in spindle-shaped stromal cells, a prognostic determinant of early breast cancer.

    PubMed

    Labovsky, Vivian; Martinez, Leandro Marcelo; Calcagno, María de Luján; Davies, Kevin Mauro; García-Rivello, Hernán; Wernicke, Alejandra; Feldman, Leonardo; Giorello, María Belén; Matas, Ayelén; Borzone, Francisco Raúl; Howard, Scott C; Chasseing, Norma Alejandra

    2016-10-01

    Spindle-shaped stromal cells, like carcinoma-associated fibroblasts and mesenchymal stem cells, influence tumor behavior and can serve as parameters in the clinical diagnosis, therapy, and prognosis of early breast cancer. Therefore, the aim of this study is to explore the clinicopathological significance of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) receptors (Rs) 2 and 4 (TRAIL-R2 and R4), and interleukin-6 R (IL-6R) in spindle-shaped stromal cells, not associated with the vasculature, as prognostic determinants of early breast cancer patients. Receptors are able to trigger the migratory activity, among other functions, of these stromal cells. We conducted immunohistochemical analysis for the expression of these receptors in spindle-shaped stromal cells, not associated with the vasculature, of primary tumors from early invasive breast cancer patients, and analyzed their association with clinicopathological characteristics. Here, we demonstrate that the elevated levels of TRAIL-R2, TRAIL-R4, and IL-6R in these stromal cells were significantly associated with a higher risk of metastatic occurrence (p = 0.034, 0.026, and 0.006; respectively). Moreover, high expression of TRAIL-R4 was associated with shorter disease-free survival and metastasis-free survival (p = 0.013 and 0.019; respectively). Also, high expression of IL-6R was associated with shorter disease-free survival, metastasis-free survival, and overall survival (p = 0.003, 0.001, and 0.003; respectively). Multivariate analysis showed that IL-6R expression was an independent prognostic factor for disease-free survival and metastasis-free survival (p = 0.035). This study is the first to demonstrate that high levels of IL-6R expression in spindle-shaped stromal cells, not associated with the vasculature, could be used to identify early breast cancer patients with poor outcomes.

  1. Tumor necrosis factor and interleukin-6 in Candida albicans infection in normal and granulocytopenic mice.

    PubMed Central

    Steinshamn, S; Waage, A

    1992-01-01

    We administered a neutralizing monoclonal antibody to tumor necrosis factor (TNF) during infection with Candida albicans in normal and granulocytopenic mice. Mice were rendered granulocytopenic (less than 0.1 x 10(9) granulocytes per liter) with cyclophosphamide. Growth of C. albicans from the kidneys was significantly increased in normal mice treated with the antibody to TNF, compared with that in control mice, after 36 h (3.6 x 10(4) +/- 1.2 x 10(4) CFU per kidney versus 9.1 x 10(3) +/- 6.2 x 10(3) CFU per kidney; P less than 0.05) and after 72 h (3.7 x 10(6) +/- 2.7 x 10(6) CFU per kidney versus 2.3 x 10(4) +/- 1.3 x 10(4) CFU per kidney; P less than 0.01). In granulocytopenic mice, the antibody to TNF had no effect on the growth of C. albicans from the kidneys. Furthermore, our study showed that the cytokines TNF and interleukin-6 (IL-6) were produced in a dose-dependent manner during C. albicans infection. TNF was detectable between 6 and 60 h, with peak levels at 24 h. Both TNF and IL-6 levels were significantly higher in cyclophosphamide-treated mice than in normal mice. Heat-inactivated C. albicans induced a TNF response different from that induced by viable C. albicans, with an early peak occurring at 3 to 4 h and declining to non-detectable levels after 15 to 24 h. Peak levels of TNF obtained with heat-inactivated C. albicans were lower than those obtained with viable C. albicans. Our study demonstrates that TNF and IL-6 are produced systemically during C. albicans infection and suggests that TNF is essential for granulocyte antifungal activity in vivo. Images PMID:1398912

  2. Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo

    PubMed Central

    Ranganath, Sheila; Bhandari, Ashok; Avitahl-Curtis, Nicole; McMahon, Jaimee; Wachtel, Derek; Zhang, Jenny; Leitheiser, Christopher; Bernier, Sylvie G.; Liu, Guang; Tran, Tran T.; Celino, Herodion; Tobin, Jenny; Jung, Joon; Zhao, Hong; Glen, Katie E.; Graul, Chris; Griffin, Aliesha; Schairer, Wayne C.; Higgins, Carolyn; Reza, Tammi L.; Mowe, Eva; Rivers, Sam; Scott, Sonya; Monreal, Alex; Shea, Courtney; Bourne, Greg; Coons, Casey; Smith, Adaline; Tang, Kim; Mandyam, Ramya A.; Masferrer, Jaime; Liu, David; Patel, Dinesh V.; Fretzen, Angelika; Murphy, Craig A.; Milne, G. Todd; Smythe, Mark L.; Carlson, Kenneth E.

    2015-01-01

    Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman’s Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology. PMID:26555695

  3. Melphalan exposure induces an Interleukin-6 deficit in bone marrow stromal cells and osteoblasts

    PubMed Central

    Rellick, Stephanie L.; Piktel, Debbie; Walton, Cheryl; Hall, Brett; Petros, William; Fortney, James E.; Gencheva, Marieta; Denvir, Jim; Hobbs, Gerald; Craig, Michael; Gibson, Laura F.

    2012-01-01

    Bone marrow stromal cells (BMSC) and osteoblasts are critical components of the microenvironment that support hematopoietic recovery following bone marrow transplantation. Aggressive chemotherapy not only affects tumor cells, but also influences additional structural and functional components of the microenvironment. Successful reconstitution of hematopoiesis following stem cell or bone marrow transplantation after aggressive chemotherapy is dependent upon components of the microenvironment maintaining their supportive function. This includes secretion of soluble factors and expression of cellular adhesion molecules that impact on development of hematopoietic cells. In the current study, we investigated the effects of chemotherapy treatment on BMSC and human osteoblast (HOB) expression of Interleukin-6 (IL-6) as one regulatory factor. IL-6 is a pleiotrophic cytokine which has diverse effects on hematopoietic cell development. In the current study we demonstrate that exposure of BMSC or HOB to melphalan leads to decreases in IL-6 protein expression. Decreased IL-6 protein is the most pronounced following melphalan exposure compared to several other chemotherapeutic agents tested. We also observed that melphalan decreased IL-6 mRNA in both BMSC and HOB. Finally, using a model of BMSC or HOB co-cultured with myeloma cells exposed to melphalan, we observed that IL-6 protein was also decreased, consistent with treatment of adherent cells alone. Collectively, these observations are of dual significance. First, suggesting that chemotherapy induced IL-6 deficits in the bone marrow occur which may result in defective hematopoietic support of early progenitor cells. In contrast, the decrease in IL-6 protein may be a beneficial mechanism by which melphalan acts as a valuable therapeutic agent for treatment of multiple myeloma, where IL-6 present in the bone marrow acts as a proliferative factor and contributes to disease progression. Taken together, these data emphasize the

  4. Circulating interleukin-6 and cancer: A meta-analysis using Mendelian randomization

    PubMed Central

    Tian, Geng; Mi, Jia; Wei, Xiaodan; Zhao, Dongmei; Qiao, Lingyan; Yang, Chunhua; Li, Xianglin; Zhang, Shuping; Li, Xuri; Wang, Bin

    2015-01-01

    Interleukin-6 (IL-6) plays a contributory role in the progression and severity of many forms of cancer; it however remains unclear whether the relevance between circulating IL-6 and cancer is causal. We therefore meta-analyzed published articles in this regard using IL-6 gene -174G/C variant as an instrument. Seventy-eight and six articles were eligible for the association of -174G/C variant with cancer and circulating IL-6, respectively. Overall analyses failed to identify any significance between -174G/C and cancer risk. In Asians, carriers of the -174CC genotype had an 1.95-fold increased cancer risk compared with the -174GG genotype carriers (P = 0.009). By cancer type, significance was only attained for liver cancer with the -174C allele conferring a reduced risk under allelic (odds ratio or OR = 0.74; P = 0.001), homozygous genotypic (OR = 0.59; P = 0.029) and dominant (OR = 0.67; P = 0.004) models. Carriers of the -174CC genotype (weighted mean difference or WMD = −4.23 pg/mL; P < 0.001) and -174C allele (WMD = −3.43 pg/mL; P < 0.001) had circulating IL-6 reduced significantly compared with the non-carriers. In further Mendelian randomization analysis, a reduction of 1 pg/mL in circulating IL-6 was significantly associated with an 12% reduced risk of liver cancer. Long-term genetically-reduced circulating IL-6 might be causally associated with a lower risk of liver cancer. PMID:26096712

  5. Interleukin-6 Enhances Glucose-Stimulated Insulin Secretion From Pancreatic β-Cells

    PubMed Central

    Suzuki, Toshinobu; Imai, Junta; Yamada, Tetsuya; Ishigaki, Yasushi; Kaneko, Keizo; Uno, Kenji; Hasegawa, Yutaka; Ishihara, Hisamitsu; Oka, Yoshitomo; Katagiri, Hideki

    2011-01-01

    OBJECTIVE Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic β-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic β-cell functions both in vivo and in vitro. RESEARCH DESIGN AND METHODS First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine β-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells. RESULTS Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-β1, but not with a protein kinase A inhibitor, H-89, inhibited IL-6–induced enhancement of GSIS. An inositol triphosphate (IP3) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6. CONCLUSIONS The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic β-cells and enhances GSIS. The PLC-IP3–dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS. PMID:21270264

  6. Interleukin-6 enhances porcine parthenote development in vitro, through the IL-6/Stat3 signaling pathway.

    PubMed

    Shen, Xing-Hui; Cui, Xiang-Shun; Lee, Sung-Hyun; Kim, Nam-Hyung

    2012-01-01

    Signal transducer and activator of transcription-3 (Stat3) plays a central role in interleukin-6 (IL-6)-mediated cell proliferation by inhibiting apoptosis in a variety of cell types. The Stat3 pathway is essential for embryonic development. The aim of this study was to determine the effects of recombinant IL-6 on the viability and development of porcine diploid parthenotes cultured in vitro. Four-cell parthenotes, derived in vitro, were cultured to the blastocyst stage, with or without recombinant IL-6. The addition of 10 or 100 ng/ml of recombinant swine IL-6 into PZM3 medium increased the development rate of parthenotes to the blastocyst stage (P<0.05). When supplemented with 10 ng/ml of recombinant swine IL-6, the number of parthenotes at the blastocyst stage increased (P<0.05) and apoptosis decreased (P<0.05). Real-time RT-PCR experiments revealed that the addition of recombinant swine IL-6 decreased the mRNA expression of the pro-apoptotic gene Caspase3 (P<0.01) but increased the expression levels of the anti-apoptotic genes Bcl2l1 and Survivin. IL-6 receptors and Stat3 mRNA expression were upregulated after treatment with 10 ng/ml recombinant swine IL-6. Immunoblots and fluorescence labeling experiments showed that the levels of phosphorylated Stat3 were upregulated. These results suggest that recombinant swine IL-6 prevents apoptosis of porcine parthenotes and enhances porcine embryo viability through the IL-6/Stat3 signaling pathway in vitro.

  7. Kinetics of interleukin-6 production after experimental infection of mice with Schistosoma mansoni.

    PubMed Central

    Khalil, R M; Hültner, L; Mailhammer, R; Luz, A; Moeller, J; Mohamed, A A; Omran, S; Dörmer, P

    1996-01-01

    It has been reported that interleukin-6 (IL-6) is expressed in cells of acute inflammatory granulomas experimentally induced in mice by eggs of Schistosoma mansoni. Moreover, in vitro IL-6 was shown to enhance the cytotoxic activity of human platelets against larvae of S. mansoni. To elucidate further a proposed biological significance of this cytokine during the course of schistosomiasis, we studied the kinetics of IL-6 production and concomitantly performed a histopathological analysis of the livers in BALB/c mice subcutaneously infected with S. mansoni cercariae. Over a period of 24 weeks postinfection (p.i.) we monitored serum IL-6 levels, IL-6 production in vitro by pokeweed mitogen (PWM)-stimulated spleen cells as well as IL-6 mRNA expression in livers, spleens and kidneys. We found significantly elevated IL-6 levels in PWM-stimulated spleen cell-conditioned media (SCM) at weeks 6 to 20 p.i., peaking at week 10 p.i. In contrast, serum IL-6 concentrations started to rise not before week 8 but remained significantly elevated above normal control values until week 24 p.i. The time pattern of enhanced IL-6 mRNA expression detected in spleens and livers, but not in kidneys, as well as the rises of IL-6 in SCM and with a delay of 2 weeks in serum samples correlated with the onset of the egg-induced inflammatory reactions as well as the incidence and the number of the granulomas observed histopathologically in the livers of infected mice. Our data emphasize both a local and a systemic role of IL-6 in the host immune response following infection of mice with S. mansoni. Images Figure 3 PMID:8943723

  8. Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection

    PubMed Central

    Kurtz, Sherry L.; Foreman, Oded; Bosio, Catharine M.; Anver, Miriam R.

    2013-01-01

    We employed Francisella tularensis live vaccine strain (LVS) to study mechanisms of protective immunity against intracellular pathogens and, specifically, to understand protective correlates. One potential molecular correlate identified previously was interleukin-6 (IL-6), a cytokine with pleotropic roles in immunity, including influences on T and B cell functions. Given its role as an immune modulator and the correlation with successful anti-LVS vaccination, we examined the role IL-6 plays in the host response to LVS. IL-6-deficient (IL-6 knockout [KO]) mice infected with LVS intradermally or intranasally or anti-IL-6-treated mice, showed greatly reduced 50% lethal doses compared to wild-type (WT) mice. Increased susceptibility was not due to altered splenic immune cell populations during infection or decreased serum antibody production, as IL-6 KO mice had similar compositions of each compared to WT mice. Although LVS-infected IL-6 KO mice produced much less serum amyloid A and haptoglobin (two acute-phase proteins) than WT mice, there were no other obvious pathophysiological differences between LVS-infected WT and IL-6 KO mice. IL-6 KO or WT mice that survived primary LVS infection also survived a high-dose LVS secondary challenge. Using an in vitro overlay assay that measured T cell activation, cytokine production, and abilities of primed splenocytes to control intracellular LVS growth, we found that IL-6 KO total splenocytes or purified T cells were slightly defective in controlling intracellular LVS growth but were equivalent in cytokine production. Taken together, IL-6 is an integral part of a successful immune response to primary LVS infection, but its exact role in precipitating adaptive immunity remains elusive. PMID:23230288

  9. Serum interleukin-6 levels in murine models of Candida albicans infection.

    PubMed

    Kovács, Renátó; Czudar, Anita; Horváth, László; Szakács, Levente; Majoros, László; Kónya, József

    2014-03-01

    Two Balb/C mouse models of Candida infection were used to detect serum interleukin-6 (IL-6) responses. The first model used systemic infection by Candida albicans ATCC 10231 strain infected through the lateral tail vein of mice without any specific pretreatment. The median Candida burdens of the kidneys were 1.5 × 106 CFU/ml 24 h postinoculation (p.i.) and 1.2 × 107 CFU/ml 72 h p.i., while median serum IL-6 levels were 479.3 pg/ml and 934.5 pg/ml, respectively. The Candida burden showed significant correlation with serum IL-6 24 h p.i. (R2 = 0.6358; P = 0.0082) but not 72 h p.i.The second model was a mouse vaginitis model applying intravaginal inoculation of mice pretreated with subcutaneous estradiol-valerate (10 mg/ml) 3 days before infection. Candida cell count in vaginal lavage fluid was 2.8 × 106 CFU/ml 24 h p.i. and 1.4 × 108 CFU/ml 72 h p.i. Serum IL-6 response was detected in 4 of 15 mice 24 h p.i. and 9 of 15 mice 72 h p.i. Even the responders had low IL-6 serum levels (mean values 29.9 pg/ml and 60.1 pg/ml, respectively) not correlating with Candida cell count in vaginal lavage fluid.In conclusion, serum IL-6 had strong relationship with systemic C. albicans infection while the local C. albicans infection of the vagina led to partial, prolonged and limited serum IL-6 response.

  10. Modulation of Kaposi's sarcoma-associated herpesvirus interleukin-6 function by hypoxia-upregulated protein 1.

    PubMed

    Giffin, Louise; Yan, Feng; Ben Major, M; Damania, Blossom

    2014-08-01

    Kaposi's sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8) is linked to the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV expresses several proteins that modulate host cell signaling pathways. One of these proteins is viral interleukin-6 (vIL-6), which is a homolog of human IL-6 (hIL-6). vIL-6 is able to prevent apoptosis and promote proinflammatory signaling, angiogenesis, and cell proliferation. Although it can be secreted, vIL-6 is mainly an intracellular protein that is retained in the endoplasmic reticulum (ER). We performed affinity purification and mass spectrometry to identify novel vIL-6 binding partners and found that a cellular ER chaperone, hypoxia-upregulated protein 1 (HYOU1), interacts with vIL-6. Immunohistochemical staining reveals that both PEL and KS tumor tissues express significant amounts of HYOU1. We also show that HYOU1 increases endogenous vIL-6 protein levels and that HYOU1 facilitates vIL-6-induced JAK/STAT signaling, migration, and survival in endothelial cells. Furthermore, our data suggest that HYOU1 also modulates vIL-6's ability to induce CCL2, a chemokine involved in cell migration. Finally, we investigated the impact of HYOU1 on cellular hIL-6 signaling. Collectively, our data indicate that HYOU1 is important for vIL-6 function and may play a role in the pathogenesis of KSHV-associated cancers. KSHV vIL-6 is detectable in all KSHV-associated malignancies and promotes tumorigenesis and inflammation. We identified a cellular protein, called hypoxia-upregulated protein 1 (HYOU1), that interacts with KSHV vIL-6 and is present in KSHV-infected tumors. Our data suggest that HYOU1 facilitates the vIL-6-induced signaling, migration, and survival of endothelial cells. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  11. Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression

    SciTech Connect

    Patchen, M.L.; MacVittie, T.J.; Williams, J.L.; Schwartz, G.N.; Souza, L.M. )

    1991-02-01

    Hematopoietic depression and subsequent susceptibility to potentially lethal opportunistic infections are well-documented phenomena following radiotherapy. Methods to therapeutically mitigate radiation-induced myelosuppression could offer great clinical value. In vivo studies have demonstrated that interleukin-6 (IL-6) stimulates pluripotent hematopoietic stem cell (CFU-s), granulocyte-macrophage progenitor cell (GM-CFC), and erythroid progenitor cell (CFU-e) proliferation in normal mice. Based on these results, the ability of IL-6 to stimulate hematopoietic regeneration following radiation-induced hematopoietic injury was also evaluated. C3H/HeN female mice were exposed to 6.5 Gy 60Co radiation and subcutaneously administered either saline or IL-6 on days 1 through 3 or 1 through 6 postexposure. On days 7, 10, 14, 17, and 22, femoral and splenic CFU-s, GM-CFC, and CFU-e contents and peripheral blood white cell, red cell, and platelet counts were determined. Compared with saline treatment, both 3-day and 6-day IL-6 treatments accelerated hematopoietic recovery; 6-day treatment produced the greater effects. For example, compared with normal control values (N), femoral and splenic CFU-s numbers in IL-6-treated mice 17 days postirradiation were 27% N and 136% N versus 2% N and 10% N in saline-treated mice. At the same time, bone marrow and splenic GM-CFC values were 58% N and 473% N versus 6% N and 196% N in saline-treated mice; bone marrow and splenic CFU-e numbers were 91% N and 250% N versus 31% N and 130% N in saline-treated mice; and peripheral blood white cell, red cell, and platelet values were 210% N, 60% N, and 24% N versus 18% N, 39% N, and 7% N in saline-treated mice. These studies demonstrate that therapeutically administered IL-6 can effectively accelerate multilineage hematopoietic recovery following radiation-induced hematopoietic injury.

  12. Interleukin-6 Directly Impairs the Erythroid Development of Human TF-1 Erythroleukemic Cells

    PubMed Central

    McCranor, Bryan J.; Kim, Min Jung; Cruz, Nicole M.; Xue, Qian-Li; Berger, Alan E.; Walston, Jeremy D.; Civin, Curt I.; Roy, Cindy N.

    2013-01-01

    Anemia of inflammation or chronic disease is a highly prevalent form of anemia. The inflammatory cytokine interleukin-6 (IL-6) negatively correlates with hemoglobin concentration in many disease states. The IL-6-hepcidin antimicrobial peptide axis promotes iron-restricted anemia; however the full role of IL-6 in anemia of inflammation is not well-defined. We previously reported that chronic inflammation had a negative impact on maturation of erythroid progenitors in a mouse model. We hypothesized that IL-6 may be responsible for impaired erythropoiesis, independent of iron restriction. To test the hypothesis we utilized the human erythroleukemia TF-1 cell line to model erythroid maturation and exposed them to varying doses of IL-6 over six days. At 10 ng/ml, IL-6 significantly repressed erythropoietin-dependent TF-1 erythroid maturation. While IL-6 did not decrease the expression of genes associated with hemoglobin synthesis, we observed impaired hemoglobin synthesis as demonstrated by decreased benzidine staining. We also observed that IL-6 down regulated expression of the gene SLC4a1 which is expressed late in erythropoiesis. Those findings suggested that IL-6-dependent inhibition of hemoglobin synthesis might occur. We investigated the impact of IL-6 on mitochondria. IL-6 decreased the mitochondrial membrane potential at all treatment doses, and significantly decreased mitochondrial mass at the highest dose. Our studies indicate that IL-6 may impair mitochondrial function in maturing erythroid cells resulting in impaired hemoglobin production and erythroid maturation. Our findings may indicate a novel pathway of action for IL-6 in the anemia of inflammation, and draw attention to the potential for new therapeutic targets that affect late erythroid development. PMID:24119518

  13. [Effect of intraoperative intravenous lidocaine on pain and plasma interleukin-6 in patients undergoing hysterectomy].

    PubMed

    Oliveira, Caio Marcio Barros de; Sakata, Rioko Kimiko; Slullitel, Alexandre; Salomão, Reinaldo; Lanchote, Vera Lucia; Issy, Adriana Machado

    2015-01-01

    Interleukin-6 (IL-6) is a predictor of trauma severity. The purpose of this study was to evaluate the effect of intravenous lidocaine on pain severity and plasma IL-6 after hysterectomy. A prospective, randomized, comparative, double-blind study with 40 patients, aged 18-60 years. G1 received lidocaine (2mg.kg(-1).h(-1)) or G2 received 0.9% saline solution during the operation. Anesthesia was induced with O2/isoflurane. Pain severity (T0: awake and 6, 12, 18 and 24hours), first analgesic request, and dose of morphine in 24hours were evaluated. IL-6 was measured before starting surgery (T0), five hours after the start (T5), and 24hours after the end of surgery (T24). There was no difference in pain severity between groups. There was a decrease in pain severity between T0 and other measurement times in G1. Time to first supplementation was greater in G2 (76.0±104.4min) than in G1 (26.7±23.3min). There was no difference in supplemental dose of morphine between G1 (23.5±12.6mg) and G2 (18.7±11.3mg). There were increased concentrations of IL-6 in both groups from T0 to T5 and T24. There was no difference in IL-6 dosage between groups. Lidocaine concentration was 856.5±364.1 ng.mL(-1) in T5 and 30.1±14.2 ng.mL(-1) in T24. Intravenous lidocaine (2mg.kg(-1).h(-1)) did not reduce pain severity and plasma levels of IL-6 in patients undergoing abdominal hysterectomy. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  14. Expression of interleukin-6 by a recombinant rabies virus enhances its immunogenicity as a potential vaccine.

    PubMed

    Luo, Jun; Zhang, Boyue; Wu, Yuting; Tian, Qin; Zhao, Jing; Lyu, Ziyu; Zhang, Qiong; Mei, Mingzhu; Luo, Yongwen; Guo, Xiaofeng

    2017-02-07

    Several studies have confirmed that interleukin-6 (IL6) mediates multiple biological effects that enhance immune responses when used as an adjuvant. In the present study, recombinant rabies virus (RABV) expressing canine IL6 (rHEP-CaIL6) was rescued and its pathogenicity and immunogenicity were investigated in mice. We demonstrated that mice received a single intramuscular immunization with rHEP-CaIL6 showed an earlier increase and higher maximum titres of virus-neutralizing antibody (VNA) as well as anti-RABV antibodies compared with mice immunized with the parent strain. Moreover, survival rates of mice immunized with rHEP-CaIL6 were higher compared with mice immunized with parent HEP-Flury according to the challenge assay. Flow cytometry further confirmed that immunization with rHEP-CaIL6 induced the strong recruitment of mature B cells and CD8(+) T cells to lymph nodes, which may partially explain the high levels of VNA and enhanced cellular immunity. Quantitative real-time PCR indicated that rHEP-CaIL6 induced stronger inflammatory and immune responses in the central nervous system, which might have allowed virus clearance in the early infection phase. Furthermore, mice infected intranasally with rHEP-CaIL6 developed no clinical symptoms while mice infected with HEP-Flury showed piloerection. In summary, these data indicate that rHEP-CaIL6 induces a strong, protective immune response with a good safety profile. Therefore, a recombinant RABV strain expressing canine IL6 may aid the development of an effective, safe attenuated rabies vaccine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Inhibition of Interleukin-6 Receptor in a Murine Model of Myocardial Ischemia-Reperfusion

    PubMed Central

    Vreeswijk-Baudoin, Inge; Groot, Hilde E.; van de Kolk, Kees W. A.; de Boer, Rudolf A.; Mateo Leach, Irene; Vliegenthart, Rozemarijn; Sillje, Herman H. W.; van der Harst, Pim

    2016-01-01

    Background Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). Methods CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. Results I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28±4% vs. 35±6%, p = 0.02; sham 45±6% vs. 43±4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. Conclusion Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling. PMID:27936014

  16. [Serum/tissue interleukin-6 concentrations and constitutional abnormalities in 4 patients with cardiac myxoma].

    PubMed

    Saji, T; Matsuo, N; Shiono, N; Yokomuro, H; Watanabe, Y; Takanashi, Y; Komatsu, H

    1993-09-01

    Immunological features and the production of interleukin-6 (IL-6) in 4 patients with cardiac myxoma were studied. The patients' age ranged from 11 years old to 57 years old; all 4 patients were female. Case 1, an 11-year-old female patient with myxoma located in the right ventricle, was considered to be a familial case. Her mother had myxomas in the right and left atrium, and had undergone removal of both tumors 3 years before. Peripheral blood examination revealed various inflammatory parameters in all of these patients. White blood cell (WBC) count was over 8,000/cmm in 3 of the 4 patients, positive CRP was found in 2 patients, IgG was higher than 1,500 mg/dl in 3 patients, positive anti-nuclear antibody was seen in 1 patient, and positive rheumatoid factor was identified in 1 patient. The OKT 4/8 ratio of lymphocyte subpopulation was 4.65 in one patient. The lymphocyte mitogenic response to PHA was increased in 2 patients. Serum IL-6 increased in 3 of 4 patients, and returned to normal within 3 to 4 weeks after operation. The IL-6 concentration in the homogenized sample remarkably increased in all 4 patients. Tumors larger than 4 cm contained higher tissue IL-6 concentrations than those smaller than 2 cm. The cultured myxoma cells produced abundant IL-6 in the culture medium supernatant. We conclude that inflammatory signs and immunological abnormalities are common in patients with large cardiac myxoma, and, in addition, serum IL-6 levels may increase in such patients.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Interleukin-6 and IL-6 receptor cell expression in testis of rats with autoimmune orchitis.

    PubMed

    Rival, Claudia; Theas, María S; Guazzone, Vanesa A; Lustig, Livia

    2006-06-01

    Experimental autoimmune orchitis (EAO) is an organ-specific model of autoimmunity characterized by an interstitial lymphomononuclear cell infiltrate as well as sloughing and apoptosis of germ cells. EAO was induced in adult male Sprague-Dawley rats by active immunization with testicular homogenate and adjuvants. Rats injected with saline solution and adjuvants were used as control group. The aim of this work was to study the expression of interleukin-6 (IL-6) and its receptor (IL-6R) in the testis of rats with EAO and analyze whether IL-6 could be involved in germ cell apoptosis. By immunohistochemistry, we detected IL-6 expression in testicular macrophages and Leydig cells of control and EAO rats. Sertoli cells showed IL-6 immunoreactivity in most of the seminiferous tubules of control rats, while a few IL-6+ Sertoli cells were found in the testis of rats with EAO. IL-6R immunoreactivity was observed in macrophages, Leydig and germ cells. A significant increase was noted in the number of IL-6R+ germ cells in rats with EAO compared to control rats. The content of IL-6 (ELISA) in the conditioned media obtained from testicular macrophages of rats with orchitis was significantly higher than in the control group. By immunofluorescence performed on isolated testicular macrophages, IL-6 was shown to be expressed by monocytes recently arrived from circulation (ED1+ cells), while resident macrophages (ED2+ cells) were negative. In vitro experiments (trypan blue and MTS assays) showed that IL-6 (50 ng/ml) reduced germ cell viability. We demonstrated also using the TUNEL technique that IL-6 added to cultures of seminiferous tubule segments induced apoptosis of germ cells. Our results suggest that IL-6 and IL-6R may be involved in the pathogenesis of autoimmune orchitis by promoting testicular inflammation and germ cell apoptosis.

  18. Temporomandibular disorder and optimism: relationships to ischemic pain sensitivity and interleukin-6.

    PubMed

    Costello, Nancy L; Bragdon, Edith E; Light, Kathleen C; Sigurdsson, Asgeir; Bunting, Shelley; Grewen, Karen; Maixner, William

    2002-11-01

    The current study examined patients with temporomandibular disorders (TMD) (n=20) and pain-free controls (n=28) under stress and relaxation conditions. Interleukin-6 (IL-6), norepinephrine and epinephrine (NE and E) were measured both before and during each of two conditions: a non-stressful relaxation period and a speech stressor. Ischemic pain sensitivity was also assessed after each of these conditions. Optimism (Life Orientation Test (LOT)), which has been associated with better outcomes in relationship to health and disease, was also evaluated in relationship to ischemic pain tolerance and unpleasantness ratings as well as to IL-6 levels under the two conditions. Regression analysis determined the unique contribution of each predictor and the interaction between Optimism and Group (TMD versus controls) after controlling for gender and blood pressure. During stress, IL-6 levels appeared to parallel NE with only controls displaying significant increases. After controlling for depressed mood, TMD patients as a whole showed a significantly blunted response in IL-6 levels produced during stress as compared to controls (beta=0.31*). Although TMD subjects as a whole did not show the expected greater pain sensitivity to the ischemic task, those displaying a less optimistic style did exhibit lower pain tolerance times (beta=-0.61*) and higher pain unpleasantness ratings (beta=0.48*), compared with low optimism controls and high optimism TMD patients. Less optimistic TMD patients also had higher NE and IL-6 levels during stress than other TMD patients, while optimism was unrelated to responses in controls (*P<0.05).

  19. Interleukin-6 modulates oxidative stress produced during the development of cisplatin nephrotoxicity.

    PubMed

    Mitazaki, Satoru; Hashimoto, Midori; Matsuhashi, Yui; Honma, Shigeyoshi; Suto, Miwako; Kato, Naho; Nakagawasai, Osamu; Tan-No, Koichi; Hiraiwa, Kouichi; Yoshida, Makoto; Abe, Sumiko

    2013-04-09

    We reported that interleukin-6 (IL-6) plays a protective role in the development of cisplatin-induced acute renal failure (ARF) through upregulation of anti-oxidative stress factors. In this study, we examined the effects of dimethylthiourea (DMTU), a hydroxyl radical scavenger, on the development of cisplatin-induced ARF in wild-type (WT) and IL-6(-/-) mice to determine how IL-6 contributes to modulation of oxidative stress caused by cisplatin. WT and IL-6(-/-) male mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. DMTU (100mg/kg) or saline was given 30 min before cisplatin or saline administration. Blood and kidney samples were collected on days 1 and 3 after cisplatin administration. In WT mice, DMTU markedly improved cisplatin-induced renal dysfunction and survival rate. DMTU reduced the expression levels of TNF-α, Bax and c-fos and increased the expression levels of IL-6, Bcl-xL and Nrf2 in WT mice. Reduced reactive oxygen species (ROS) by DMTU resulted in increases of IL-6, anti-apoptosis and anti-oxidant gene expression levels. In IL-6(-/-) mice, DMTU also improved cisplatin-induced renal dysfunction and reduced expression levels of TNF-α, Bax and c-fos, but not Bcl-xL and Nrf2. Since Nrf2 induces IL-6 expression, IL-6 and Nrf2 may influence each other during anti-oxidant responses. The basal level of HO-1 in IL-6(-/-) mice was higher than that in WT mice. In IL-6(-/-) mice, overproduction of ROS by cisplatin results in upregulation of HO-1 expression in order to eliminate oxidative stress. IL-6 mediates the generation and elimination of ROS during cisplatin-induced ARF. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. The effect of sunlight exposure on interleukin-6 levels in depressive and non-depressive subjects

    PubMed Central

    2013-01-01

    Background The objective of this epidemiological study was to evaluate the effect of length of sunlight exposure on interleukin 6 (IL-6) levels in depressive and non-depressive subjects. Methods This was a cross-sectional study with 154 subjects (54 males, mean age: 43.5 ± 12.8 years) who were living in a rural area in south Brazil. Chronobiological and light parameters were assessed using the Munich Chronotype Questionnaire. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index. Depressive symptoms were assessed with the Beck Depression Inventory. Plasma levels of inflammatory cytokines (IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, and interferon) were collected during the daytime and measured. Results IL-6 levels showed a positive correlation with light exposure (r = 0.257; p < 0.001) and a negative correlation with the mid-sleep phase on work-free days (r = -0.177; p = 0.028). Multiple linear regression analysis showed that only the length of light exposure was an independent factor for predicting IL-6 levels (ß = 0.26; p = 0.002). In non-depressed subjects, exposure to a different intensity of light did not affect IL-6 levels (t = -1.6; p = 0.1). However, when the two depressive groups with low and high light exposure were compared, the low light exposure group had lower levels of IL-6 compared with the high light exposure group (t = -2.19 and p = 0.0037). Conclusions The amount of time that participants are exposed to sunlight is directly related to their IL-6 levels. Additionally, depressed subjects differ in their IL-6 levels if they are exposed to light for differing amounts of time. PMID:23497121

  1. Serum interleukin-6 in the diagnosis of bacterial infection in cirrhotic patients

    PubMed Central

    Wu, Yinlian; Wang, Mingfang; Zhu, Yueyong; Lin, Su

    2016-01-01

    Abstract Background: The diagnostic accuracy of interleukin-6 (IL-6) in predicting bacterial infection in cirrhotic patients remains unclear. The aim of this meta-analysis is to explore the potential diagnostic value of IL-6 in cirrhotic patients. Methods: We systematically searched PubMed, Embase (via OvidSP), Web of Science, the Cochrane Library, and Scopus for studies published from inception to October 2015. Studies were enrolled if they included assessment of the accuracy of IL-6 in the diagnosis of bacterial infection in cirrhotic patients and provided sufficient data to construct a 2 × 2 contingency table. Results: Totally, 535 studies were searched in the initial database and finally 6 studies involving 741 patients were included for the final analysis. The pooled sensitivity, specificity and diagnostic odds ratio were 0.85 (95% confidence interval [CI], 0.64–0.94), 0.91 (95% CI, 0.80–0.96) and 52.89 (95% CI, 15.21–183.86), respectively. The pooled positive likelihood ratio was 8.99 (95% CI, 4.13–19.55) and the pooled negative likelihood ratio was 0.17 (95% CI, 0.07–0.43). The area under the receiver operating characteristic curve was 0.94 (95% CI, 0.92–0.96). Conclusion: This meta-analysis suggests IL-6 has a high diagnostic value for the differentiation of bacterial infection in patients with cirrhosis. PMID:27741137

  2. Blockade of interleukin-6 receptor suppresses the proliferation of H460 lung cancer stem cells.

    PubMed

    Yi, Hee; Cho, Hee-Jung; Cho, Soo-Min; Jo, Kyul; Park, Jin-A; Kim, Na-Hyun; Amidon, Gordon L; Kim, Jin-Suk; Shin, Ho-Chul

    2012-07-01

    IL-6/6R signaling is closely associated with tumor growth and poor prognosis. Although there is evidence that interleukin-6 receptor (IL-6R)-mediated signaling promotes the growth and malignancy of cancer, the role of IL-6R in cancer stem cells (CSCs) is poorly defined. This study investigated the role of IL-6R in the proliferation of CSCs. Sphere-forming cells were isolated from the H460 non-small cell lung cancer (NSCLC) cell line and identified as CSCs using confocal microscopy, RT-PCR and WST-1 assay. The H460 spheres demonstrated the typical characteristics of CSCs, including CD133 expression, upregulation of Nanog, self-renewal, and drug resistance to methotrexate (MTX) and fluorouracil (5-FU). The release of IL-6R and its ligand, IL-6, were quantitatively determined and compared between CSCs and non-CSCs. The concentration of soluble IL-6R (sIL-6R) was remarkably high in CSCs compared to that in non-CSCs. Furthermore, significant upregulation of the IL-6R gene was also observed in the CSCs. The growth of CSCs was significantly inhibited by transfection with IL-6R small-interfering RNA (siRNA), as well as with the IL-6R monoclonal antibody (mAb). In addition, blocking both IL-6R and IL-6 using siRNA or mAbs intensified the inhibition of CSC proliferation. These findings indicate that IL-6R is present in CSCs and has an important role in the proliferation of CSCs in the H460 lung cancer cell line. Therefore, we suggest that IL-6R is both a viable target for the development of CSC-directed lung cancer therapeutics and a potential CSC marker in NSCLC.

  3. p38α Stabilizes Interleukin-6 mRNA via Multiple AU-rich Elements*

    PubMed Central

    Zhao, Wenpu; Liu, Min; Kirkwood, Keith L.

    2009-01-01

    AU-rich elements (AREs) in the 3′-untranslated region (UTR) of unstable mRNA dictate their degradation or mediate translational repression. Cell signaling through p38α MAPK is necessary for post-transcriptional regulation of many pro-inflammatory cytokines. Here, the cis-acting elements of interleukin-6 (IL-6) 3′-UTR mRNA that required p38α signaling for mRNA stability and translation were identified. Using mouse embryonic fibroblasts (MEFs) derived from p38α+/+ and p38α−/− mice, we observed that p38α is obligatory for the IL-1-induced IL-6 biosynthesis. IL-6 mRNA stability is promoted by p38α via 3′-UTR. To understand the mechanism of cis-elements regulated by p38α at post-transcriptional level, truncation of 3′-UTR and the full-length 3′-UTR with individual AUUUA motif mutation placed in gene reporter system was employed. Mutation-based screen performed in p38α+/+ and p38α−/− mouse embryonic fibroblast cells revealed that ARE1, ARE2, and ARE5 in IL-6 3′-UTR were targeted by p38α, and truncation-based screen showed that IL-6 3′-UTR-(56–173) was targeted by p38α to stable mRNA. RNA secondary structure analysis indicated that modulated reporter gene expression was consistent with predicted secondary structure changes. PMID:18042545

  4. Increased methylation of interleukin 6 gene is associated with obesity in Korean women.

    PubMed

    Na, Yeon Kyung; Hong, Hae Sook; Lee, Won Kee; Kim, Young Hun; Kim, Dong Sun

    2015-05-01

    Obesity is the fifth leading risk for death globally, and a significant challenge to global health. It is a common, complex, non-malignant disease and develops due to interactions between the genes and the environment. DNA methylation can act as a downstream effector of environmental signals; analysis of this process therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. To assess the effects of excessive weight and obesity on gene-specific methylation levels of promoter regions, we determined the methylation status of four genes involved in inflammation and oxidative stress [interleukin 6 (IL6), tumor necrosis factor α (TNFα), mitochondrial transcription factor A (TFAM), and glucose transport 4 (GLUT4)] in blood cell-derived DNA from healthy women volunteers with a range of body mass indices (BMIs) by methylation-specific PCR. Interestingly, the samples from obese individuals (BMI ≥ 30 kg/m(2)) showed significantly increased hypermethylation for IL6 gene compared to normal weight (BMI < 23 kg/m(2)) and overweight samples (23 kg/m(2) ≤ BMI < 30 kg/m(2)) (P = 0.034 and P = 0.026). However, there was no statistically significant difference in promoter methylation of the other 3 genes between each group. These findings suggest that aberrant DNA methylation of IL6 gene promoter may play an important role in the etiology and pathogenesis of obesity and IL6 methylation could be used as molecular biomarker for obesity risk assessment. Further studies are required to elucidate the potential mechanisms underlying this relationship.

  5. Salivary estradiol, interleukin-6 production, and the relationship to substrate metabolism during exercise in females.

    PubMed

    Ives, Stephen J; Blegen, Mark; Coughlin, Mary A; Redmond, Jan; Matthews, Tracey; Paolone, Vincent

    2011-08-01

    Estradiol (E(2)) has been documented to have anti-inflammatory effects on the immune system. Interleukin-6 (IL-6), is classified as a "myokine", and has known metabolic consequences. Thus, the purpose of this study was to determine the effects of menstrual phase and exercise on the interaction of E(2) and IL-6, and the role of IL-6 in substrate metabolism. Ten female subjects completed three separate testing sessions: baseline evaluation, and 1 h of treadmill exercise at 65% of peak [Formula: see text] during both the midfollicular (MF) and midluteal (ML) menstrual phases. Saliva was collected prior to, during, and post-exercise for determination of E(2) and IL-6. Expired gases and an additional saliva sample were collected 30 min post-exercise. No significant differences were observed in any of the measured variables across menstrual phase. Exercise resulted in an acute rise in estradiol and IL-6; however, E(2) was not related to IL-6 at baseline or in response to exercise. IL-6 remained elevated at the end of exercise and was found to be related to energy expenditure from fat, and to total energy expenditure at 60 min, and 30 min post-exercise. No relationships were found between the anti-inflammatory estrogen E(2) and the cytokine IL-6. However, relationships were found between IL-6 and indices of substrate metabolism. Based on the data from the current research, IL-6 likely plays a metabolic role in healthy individuals during exercise when released from the muscle as a result of reduced energy availability, acting as a "myokine", in comparison to inflammation-induced IL-6 release.

  6. Identification of high responders for interleukin-6 and creatine kinase following acute eccentric resistance exercise in elderly obese women.

    PubMed

    Tajra, Vitor; Tibana, Ramires Alsamir; Vieira, Denis Cesar Leite; de Farias, Darlan Lopes; Teixeira, Tatiane Gomes; Funghetto, Silvana Schwerz; Silva, Alessandro Oliveira; de Sousa, Nuno Manuel Frade; Willardson, Jeffrey; Karnikowski, Margô Gomes Oliveira; Prestes, Jonato

    2014-11-01

    Resistance exercise is used as a non-pharmacological tool to elicit both gains in and maintenance of physical function in the elderly. Thus, the present study examined the acute response of creatine kinase and interleukin-6 following an eccentric resistance exercise session in elderly obese women classified as high responders or normal responders. Cross-sectional field study. Ninety elderly obese women (69.4 ± 6.01 years) were tested for a 10 repetition maximum on the leg extension exercise and then completed an acute eccentric resistance exercise session consisting of seven sets of 10 repetitions at 110% of 10 repetition maximum with a rest of 3 min between sets. Subjects were divided into normal response or high response on the basis of the peak serum interleukin-6 (NR = 59 and HR = 7) and creatine kinase (NR = 81 and HR = 9) concentration being greater than (HR) or less than (NR) the 90th percentile. Creatine kinase was higher at 0 h, 3h, 24h and 48 h following the ERE for the HR group. The peak creatine kinase was significantly higher in HR group versus the normal response group. The average increase in the serum interleukin-6 Δ for the HR group (∼ 850%) was significantly higher versus the normal response group (∼ 55%). Serum interleukin-6 was significantly higher at 0 h and 24h following eccentric resistance exercise only for the high response group, while peak levels were significantly higher in high response group versus the normal response group (p ≤ 0.005). Only one subject met the criteria to be classified as high response for both creatine kinase and interleukin-6 responsiveness. Elderly individuals classified as high response experienced greater creatine kinase and interleukin-6 responses to ERE. Thus, a prudent approach for eccentric resistance exercise prescription might be programming additional recovery days and/or lower intensity training, especially in the beginning stages of a program. Copyright © 2013 Sports Medicine Australia

  7. Tocilizumab: A Novel Humanized Anti-Interleukin 6 Receptor Antibody for the Treatment of Patients with Rheumatoid Arthritis

    PubMed Central

    Alten, Rieke

    2011-01-01

    Tocilizumab (TCZ; RoActemra® or Actemra®) is a recombinant humanized monoclonal antibody that acts as an interleukin 6 (IL-6) receptor antagonist. For rheumatoid arthritis (RA), intravenous (IV) TCZ 8 mg/kg every 4 weeks has been approved since 2008 in Japan (where it is also approved for polyarticular juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman's disease), and since 2009 in Europe in combination with methotrexate (MTX) for the treatment of moderate to severe active RA in adult patients with inadequate response to, or intolerance of, disease-modifying antirheumatic drug (DMARD) or tumor necrosis factor (TNF) antagonist therapy. It may also be administered as monotherapy in the same dose regimen in patients with methotrexate intolerance or with inadequate response to MTX. Since January 2011 in the United States, the indication for treatment with TCZ for RA patients with an inadequate response to one or more TNF antagonists was extended to patients with moderately to severely active RA, and the recommended starting dose is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response. All of these approvals are based on the effectiveness and safety of the 8 mg/kg dose regimen when administered either as monotherapy or in combination with conventional DMARDs in well-designed clinical studies in adult patients with moderate to severe RA. TCZ at this dose is more effective than placebo, MTX or other DMARDs in reducing disease activity and improving health-related quality of life (HR-QoL). Although there were fewer responses with the 4 mg/kg dose, this dose every 4 weeks was not statistically different to 8 mg/kg when administered in combination with MTX, and this dose is the recommended starting dose in the US. Both doses have also been shown to inhibit structural joint damage in patients with an inadequate response to MTX. Thus, TCZ is an important new treatment option in patients with moderate to severe

  8. The relationship between asthma and bronchiolitis is modified by TLR4, CD14, and IL-13 polymorphisms.

    PubMed

    Jung, Young-Ho; Seo, Ju-Hee; Kim, Hyung Young; Kwon, Ji-Won; Kim, Byoung-Ju; Kim, Hyo-Bin; Lee, So-Yeon; Jang, Gwang Cheon; Song, Dae Jin; Kim, Woo Kyung; Shim, Jung Yeon; Hong, Soo-Jong

    2015-01-01

    Asthma is a complex genetic disorder that is associated with both genetic and environmental factors. The aim of study was to investigate the combined effect of toll-like receptor 4 (TLR4), cluster of differentiation 14 (CD14), and interleukin-13 (IL-13) polymorphisms and bronchiolitis in the development of childhood asthma. A modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was used to survey 1,341 elementary school children and 919 nursery children in Seoul, Korea. TLR4 (rs1927911), CD14 (rs2569190), and IL-13 (rs20541) polymorphisms were genotyped by the TaqMan assay. In elementary school and nursery children, parental history of asthma (adjusted odds ratio [aOR] 2.56 [95% CI 1.16-5.63], aOR 3.60 [95% CI 1.66-7.76], respectively), and past history of bronchiolitis (aOR 3.11 [95% CI 1.84-5.24], aOR 3.94 [95% CI 2.27-6.84], respectively) were independent risk factors for asthma diagnosis. When compared to children with each CC of TLR4 polymorphism or TT of CD14 polymorphism or GG of IL13 polymorphism and no past history of bronchiolitis, children with CT or TT of TLR4 polymorphism and past history of bronchiolitis had 4.23 and 5.34 times higher risk to develop asthma, respectively; children with TT of CD14 polymorphism and past history of bronchiolitis had 3.57 and 7.22 times higher risk for asthma, respectively; children with GA or AA of IL-13 polymorphism and past history of bronchiolitis had 3.21 and 4.13 times higher risk for asthma, respectively. Family history of asthma or allergic rhinitis and past history of bronchiolitis could be independent risk factors for the development of childhood asthma. The relationship between asthma and bronchiolitis is modified by the TLR4, CD14, and IL-13 polymorphisms in Korean children. © 2013 Wiley Periodicals, Inc.

  9. Interleukin-6 responses to water immersion therapy after acute exercise heat stress: a pilot investigation.

    PubMed

    Lee, Elaine C; Watson, Greig; Casa, Douglas; Armstrong, Lawrence E; Kraemer, William; Vingren, Jakob L; Spiering, Barry A; Maresh, Carl M

    2012-01-01

    Cold-water immersion is the criterion standard for treatment of exertional heat illness. Cryotherapy and water immersion also have been explored as ergogenic or recovery aids. The kinetics of inflammatory markers, such as interleukin-6 (IL-6), during cold-water immersion have not been characterized. To characterize serum IL-6 responses to water immersion at 2 temperatures and, therefore, to initiate further research into the multidimensional benefits of immersion and the evidence-based selection of specific, optimal immersion conditions by athletic trainers. Controlled laboratory study. Human performance laboratory Patients or Other Participants: Eight college-aged men (age = 22 ± 3 years, height = 1.76 ± 0.08 m, mass = 77.14 ± 9.77 kg, body fat = 10% ± 3%, and maximal oxygen consumption = 50.48 ± 4.75 mL·kg(-1) min(-1)). Participants were assigned randomly to receive either cold (11.70°C ± 2.02°C, n = 4) or warm (23.50°C ± 1.00°C, n = 4) water-bath conditions after exercise in the heat (temperature = 37°C, relative humidity = 52%) for 90 minutes or until volitional cessation. Whole-body cooling rates were greater in the cold water-bath condition for the first 6 minutes of water immersion, but during the 90-minute, postexercise recovery, participants in the warm and cold water-bath conditions experienced similar overall whole-body cooling. Heart rate responses were similar for both groups. Participants in the cold water-bath condition experienced an overall slight increase (30.54% ± 77.37%) in IL-6 concentration, and participants in the warm water-bath condition experienced an overall decrease (-69.76% ± 15.23%). We have provided seed evidence that cold-water immersion is related to subtle IL-6 increases from postexercise values and that warmer water-bath temperatures might dampen this increase. Further research will elucidate any anti-inflammatory benefit associated with water-immersion treatment and possible multidimensional uses of cooling

  10. Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice.

    PubMed Central

    Ryffel, B.; Car, B. D.; Gunn, H.; Roman, D.; Hiestand, P.; Mihatsch, M. J.

    1994-01-01

    The ability of interleukin-6 (IL-6) to modulate immune parameters and mesangial cell function suggests a role for this cytokine in the development of autoimmune glomerulonephritis. This hypothesis was tested in 6-month-old female (NZB x NZW)F1 mice that were administered recombinant human IL-6 (rhIL-6) (50 and 250 micrograms/kg s.c.) for 12 weeks, resulting in an accelerated and severe form of membranoproliferative glomerulonephritis associated with marked upregulation of mesangial major histocompatibility complex class II antigen and glomerular ICAM-1 expression. To distinguish direct effects of rhIL-6 on the renal mesangium from those mediated through the immune system, (NZB x NZW)F1 mice were immunosuppressed with cyclosporin. Immunosuppression by cyclosporin inhibited the development of glomerulonephritis, decreased class II antigen expression, and abrogated IL-6-mediated effects. Administration of neutralizing anti-IL-6 antibody had no effect on the spontaneous development of glomerulonephritis in (NZB x NZW)F1 mice. This finding, together with undetectable IL-6 serum levels, makes a pathogenetic role of endogenously produced IL-6 in this disease model unlikely. In contrast to (NZB x NZW)F1 mice, parental NZW or BALB/c mice given high doses of rhIL-6 (500 micrograms/kg) or recombinant murine IL-6 (100 micrograms/kg) daily for 4 weeks failed to develop morphological or biochemical evidence of glomerulonephritis. Induction of acute phase proteins, anemia, thrombocytosis, and induction of renal class II antigen confirmed the biological activity of IL-6 in these mice. In conclusion, while non-nephritogenic in normal mice, IL-6 accelerates the development of the genetically determined glomerulonephritis of (NZB x NZW)F1 mice through effects mediated by a modulated immune system. Since neutralizing IL-6 antibody treatment did not prevent the development of glomerulonephritis, it is unlikely that increased IL-6 production plays a role in the pathogenesis of lupus

  11. Endogenous gamma interferon, tumor necrosis factor, and interleukin-6 in Staphylococcus aureus infection in mice.

    PubMed Central

    Nakane, A; Okamoto, M; Asano, M; Kohanawa, M; Minagawa, T

    1995-01-01

    The production and roles of endogenous gamma interferon (IFN-gamma), tumor necrosis factor (TNF), and interleukin-6 (IL-6) in both lethal and nonlethal infections of Staphylococcus aureus were investigated in mice. In the case of nonlethal infection, although no bacteria were detected in the bloodstreams, bacteria that colonized and proliferated persistently for 3 weeks were found in the kidneys. All mice given lethal injections died within 7 days, and large numbers of bacteria were detected in the bloodstreams, spleens, and kidneys. The first peaks of IFN-gamma, TNF, and IL-6 were observed in the bloodstreams and spleens of the mice with nonlethal and lethal infections within 24 h. Thereafter, in the nonlethal cases, IFN-gamma, TNF, and IL-6 peaked again in the spleens and kidneys during the period of maximum growth of bacteria in the kidneys, although only IL-6 was detected in the sera. In contrast, in the case of lethal infection, the titers of IFN-gamma and IL-6 in the sera and TNF in the kidneys peaked before death. Effects of in vivo administration of monoclonal antibodies (MAbs) against IFN-gamma and TNF on the fates of S. aureus-infected mice were studied. In the nonlethal infections, anti-TNF alpha (anti-TNF-alpha) MAb-treated mice, but not anti-IFN-gamma MAb-treated mice, died as a result of worsening infection, suggesting that endogenous TNF plays a protective role in host resistance to S. aureus infection. In the mice that received lethal doses, injection of anti-TNF-alpha MAb accelerated death. However, although injection of anti-IFN-gamma MAb inhibited host resistance of the infected mice early in infection, most of the animals survived the lethal infection by injection of anti-IFN-gamma MAb, suggesting that endogenous IFN-gamma plays a detrimental role in S. aureus infection. Thus, this study demonstrated that IFN-gamma and TNF play different roles in S. aureus infection. PMID:7890367

  12. The role of interleukin-6 (IL-6) in human sulfur mustard (HD) toxicology.

    PubMed

    Arroyo, C M; Broomfield, C A; Hackley, B E

    2001-01-01

    The authors applied in vitro models of controlled damage to human epidermal keratinocytes (HEKs), human skin fibroblasts (HSFs), and human breast skin tissue (HBST) to examine the mechanism responsible for sulfur mustard (HD)-induced interleukin-6 (IL-6) alterations. Treatment with 100 microM HD for 24 hours resulted in a significant increased amount of IL-6 being secreted by HEKs (HD-exposed to control ratio [E/C] = 4.15 +/- 0.07) and by HSFs (E/C = 7.66 +/- 0.04). Furthermore, the HD-induced secretion of IL-6 in HEKs was neutralized with monoclonal human IL-6 antibodies. The secretion of IL-6 in HBST supernatant exposed to HD produced conflicting results. Although an increase of IL-6 was observed in control superfusion media from HBST, IL-6 levels were observed to decrease as the concentration of HD increased. Time course of IL-6 mRNA levels were performed using a competitive polymerase chain reaction (PCR) and human IL-6 mRNA assay detection kit in control and HD (100 microM)-treated HEKs cells. IL-6 mRNA transcripts in HD-exposed HEKs were first observed within 2 hours, dropped at 5 to 6 hours, and increased by approximately 2.2-fold and 8.5-fold at 24 to 48 hours after HD exposure, respectively, as detected by the Xplore mRNA Quantification System. Surface-enhanced laser desorption ionization (SELDI) mass spectrometry was also applied to study the secretion pattern of IL-6 on lysate preparations of HBST. A peak in the area of 23,194 to 23,226 Da was detected using antibody coupled to the chip. This peak was assigned to correspond to the mass of the IL-6 glycoprotein. Recombinant human IL-6 (rhIL-6) exposed to HD lacked the second disulfide bridge and was partially unfolded, as determined by nuclear magnetic resonance-nuclear Overhauser enhancement and exchange spectroscopy (NMR-NOESY). The disappearance of the resonance peak at 3.54 ppm and the appearance of a new chemical shift at 1.85 ppm suggested that a change in structure had occurred in the presence of

  13. Systematic Review of Tocilizumab for Rheumatoid Arthritis: A New Biologic targeting the Interleukin-6 Receptor

    PubMed Central

    Navarro-Millán, Iris; Singh, Jasvinder A; Curtis, Jeffrey R

    2013-01-01

    Objective To summarize the efficacy and safety profile of Tocilizumab (TCZ), a humanized monoclonal antibody against interleukin-6 (IL-6), approved for the treatment of rheumatoid arthritis (RA). Methods A systematic literature review was conducted to identify English language articles within Pubmed and the Cochrane Library from January 1989 to August 2011 reporting results from phase III TCZ double-blinded randomized controlled trials (RCT), non-controlled clinical trials and open-label extensions with duration ≥ 6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, 70; tender/swollen joint count, HAQ disability, radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in phase III RCTs. To review TCZ pharmacology, relevant studies were selected to evaluate pharmacokinetics and pharmacodynamics. Results Ten published clinical trials (7 phase 3, 3 phase 2) for TCZ were retrieved (7,833 articles initially identified) and 31 from Cochrane library. Compared to MTX monotherapy, TCZ 8 mg/Kg monotherapy had higher rates of ACR20 (p<0.001), ACR50 (p=0.002) and ACR70 (p<0.001) scores at week 24. TCZ 8mg/Kg IV + oral MTX had a higher ACR20 response rate than placebo + oral MTX in patients with RA that failed to respond to MTX or anti-TNF therapy (p<0.001). Patients on TCZ 8mg/Kg had less radiographic progression on Sharp-Genant Score, (85% had no progression) than the control group (67% had no progression, p<0.001). The rate of serious infections was 4.7 events /100 patient years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytropenia, hyperlipidemia, and transaminitis was observed with TCZ compared to placebo. Conclusion The short term efficacy and safety profile of TCZ is promising. Additional long term safety data are needed to better characterize the risk-benefit profile of this agent. PMID:22444783

  14. Clinical validity of urinary interleukin 18 and interleukin 6 determinations in preterm newborns.

    PubMed

    Miklaszewska, Monika; Korohodai, Przemysław; Kwinta, Przemko; Tomasik, Tomasz; Zachwieja, Katarzyna; Klich, Barbara; Tkaczyk, Marcin; Droźdź, Dorota; Pietrzyk, Jacek A

    2015-01-01

    Preterm newborns are at a particular risk of acute kidney injury (AKI) and sepsis. Assessment of urinary interleukin 18 (ulL-18) and urinary interleukin 6 (ulL-6) concentrations in association with AKI and sepsis respectively in newborns hospitalized in Neonatal Intensive Care Unit (NICU). An evaluation was carried out of the dependence of ulL-18 on neonatal birth weight (BW) and AKI as well as ulL6 on sepsis. In prospective study, the evaluation included 58 children with BW up to 2000 g. Clinical observations spanned the period between the 1st and 28th day of life. The mean gestational age was 30.3 Hbd, mean BW was 1361.9 g. AKI was diagnosed in 35 (60.3%), sepsis in 22 (39.7%) neonates. For median values of uIL-18 and ulL-18/mgCr, as well as for mean logarithmically transformed values of ulL-18 and ulL-18/mgCr, negative, statistically significant linear correlations were demonstrated for BW. In population, median value of ulL-18 and ulL-18/mgCr decreased respectively by 8.21 pg/ml and 84.8 pg/mgCr per each 100 g increment of BW. A negative, statistically significant linear correlation with an average strength was noted for the dependency of the duration of AKI and BW. No significant differences were observed in uIL-18 and ulL-181 mgCr values between the investigated days of AKI and reference group. There was noted a significant increase of the values of uIL-6 and uIL-6/ mgCr on day 0 of sepsis confirmed by the ROC analysis with AUROC 78% and 74%, respectively. ulL-18 and ulL-18/mgCr values might be a reliable marker of renal tubules maturation in newborns; ulL-18 is not a reliable marker in diagnosing AKI in neonatal population; ulL-6 and uIL-6/ mgCr concentration values measured on actual days may be regarded an early marker of sepsis; AKI duration in preterm neonates is negatively correlated with BW.

  15. Interleukin-6 stimulates cell migration, invasion and integrin expression in HTR-8/SVneo cell line.

    PubMed

    Jovanović, M; Vićovac, L

    2009-04-01

    Interleukin-6 (IL-6) is present in human endometrium throughout menstrual cycle and in pregnancy. Trophoblast also expresses IL-6. IL-6R and its associated signal transducer gp130 were found in trophoblast as well. IL-6 is generally assumed to be relevant for trophoblast invasion. This study was undertaken to determine influence of endogenous and externally added IL-6 on invasion and migration of first trimester of pregnancy trophoblast in vitro. Integrins alpha(5)beta(1) and alpha(1)beta(1) have been shown to play an important role in trophoblast invasion and the effect of IL-6 on the expression of these integrin subunits was studied. We are showing that in both isolated first trimester of pregnancy cytotrophoblast (CTB) and HTR-8/SVneo cell line IL-6 and IL-6R are present. The effect on migration was studied using cell wounding and migration test on HTR-8/SVneo cells. Effect of IL-6 and function blocking anti-IL-6 antibody in Matrigel invasion tests was studied on both cell types. The effect of IL-6 on integrin subunit expression was determined by cell-based ELISA and Western blot on HTR-8/SVneo cells. The results obtained show that exogenous IL-6 has stimulatory effect on cell migration in HTR-8/SVneo and invasion by both cell types. Function blocking anti-IL-6 inhibited unstimulated invasion by isolated first trimester cytotrophoblast and both cell migration and invasion in unstimulated HTR-8/SVneo. Integrin alpha(5) expression was stimulated by IL-6 to 134% (p<0.05), alpha(1) to 135% (p<0.005), and beta(1) to 134% (p<0.001) of control in cell-based ELISA, but also in Western blot. The data obtained show for the first time sensitivity of extravillous trophoblast cell line HTR-8/SVneo to IL-6, in addition to isolated first trimester cytotrophoblast. We conclude that both exogenous and endogenous IL-6 stimulate trophoblast cell migration and invasion, which may be partly attributable to stimulation of expression of the studied integrin subunits.

  16. Effect of interleukin-6 inhibition on coronary microvascular and endothelial function in myocardial infarction.

    PubMed

    Holte, Espen; Kleveland, Ola; Ueland, Thor; Kunszt, Gabor; Bratlie, Marte; Broch, Kaspar; Michelsen, Annika E; Bendz, Bjørn; Amundsen, Brage H; Aakhus, Svend; Damås, Jan Kristian; Gullestad, Lars; Aukrust, Pål; Wiseth, Rune

    2017-04-21

    Interleukin-6 (IL-6) is a driver of inflammation and associated endothelial cell activation in acute coronary syndromes. We evaluated the effect of the IL-6 receptor antagonist tocilizumab on coronary microvascular function and endothelial dysfunction measured by coronary flow reserve (CFR) and markers of endothelial cell activation in patients with non-ST-elevation myocardial infarction (NSTEMI). This substudy was part of a two-centre, double-blind, randomised, placebo-controlled trial evaluating the effect of a single dose of tocilizumab in NSTEMI. Markers of endothelial cell activation (vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1 and von Willebrand factor) were assessed in 117 patients. In 42 of these patients, 20 assigned to placebo and 22 to tocilizumab, we measured CFR. Blood samples were obtained at seven consecutive time points between day 1 and 3. CFR was measured by transthoracic echocardiography during hospitalisation and after 6 months. Tocilizumab did not affect CFR during hospitalisation (tocilizumab: 3.4±0.8 vs placebo: 3.3±1.2, p=0.80). CFR improved significantly in both groups at 6 months. Patients in the tocilizumab group had significantly higher area under the curve for VCAM-1 (median 622 vs 609 ng/mL/hour, tocilizumab and placebo respectively, p=0.003). There were inverse correlations between VCAM-1 and CFR in the placebo (hospitalisation: r=-0.74, p<0.01, 6 months: r=-0.59, p<0.01), but not in the tocilizumab group (hospitalisation: r=0.20, p=0.37, 6 months r=-0.28, p=0.20). Tocilizumab did not affect CFR during hospitalisation or after 6 months. Tocilizumab increased VCAM-1 levels during hospitalisation, but this was not associated with reduced CFR in these patients. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  17. Cardiovascular Response and Serum Interleukin-6 Level in Concentric Vs. Eccentric Exercise.

    PubMed

    Agarwal, Mayank; Singh, Shraddha; Narayan, Jagdish; Pandey, Shivani; Tiwari, Sunita; Sharma, Priyanka

    2017-04-01

    Cardiovascular Disease (CVD) is a leading cause of morbidity and mortality in India. Resistance exercise is strongly recommended for implementation in CVD prevention programs. Dynamic resistance exercise comprises of concentric (muscle shortening) and eccentric (muscle lengthening) phase. The contraction of skeletal muscle promotes the synthesis and secretion of cytokines and peptides from myocytes, known as 'myokines'. Interleukin-6 (IL-6) is the first myokine to be released in the blood in response to exercise. To compare the cardiovascular response and serum IL-6 level in concentric and eccentric exercise done at same absolute workload. In this non-randomised crossover study 24, apparently healthy and young male adults performed an acute bout of concentric and eccentric exercise. Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR), Mean Arterial Pressure (MAP), Pulse Pressure (PP) and serum IL-6 were measured just before and immediately after exercise. Paired t-test or Wilcoxon signed-rank test were applied to compare the data within-group and in-between group. SBP, HR, MAP, PP, DBP and IL-6 level increased significantly after both, concentric and eccentric exercise. The mean change in SBP, HR, MAP, PP, and IL-6 after concentric exercise (18.54±3.06, 57.21±10.73, 8.35±1.40, 15.25±5.29, 5.40±3.13 respectively) was significantly higher than after eccentric exercise (13.38±1.72, 43.25±8.34, 6.50±1.0, 10.21±3.16, 4.36±2.54 respectively). A non-significant rise in DBP was obtained after concentric exercise (3.25±2.79) as compared to eccentric exercise (3.08±1.89). Eccentric exercise not only caused a lesser cardiovascular demand as compared to concentric exercise but also a significant increment in IL-6 level. Exercise-induced IL-6 may prevent the initiation and development of CVD. Hence, eccentric exercise training might be recommended for reducing morbidity and mortality in individuals with- or at a risk of developing CVD.

  18. Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease.

    PubMed Central

    Mancuso, G; Tomasello, F; Migliardo, M; Delfino, D; Cochran, J; Cook, J A; Teti, G

    1994-01-01

    Previous studies have shown that tumor necrosis factor alpha (TNF-alpha) plays a pathophysiologic role in sepsis induced in rat pups by group B streptococci (GBS). In this model, TNF-alpha is also partially responsible for the induction of interleukin-6 (IL-6). The present study was undertaken to investigate the role of IL-6 in neonatal BALB/c mice infected with type III GBS. The effect of anti-IL-6 monoclonal antibodies and recombinant IL-6 on lethality and TNF-alpha production was investigated. In mouse pups infected with GBS strain COH1, plasma IL-6 reached levels of 3,067 +/- 955 and 1,923 +/- 891 U/ml when measured at 22 and 48 h, respectively (P < 0.05 compared with uninfected controls). Pretreatment with 25 micrograms of anti-IL-6 antibodies totally prevented the increase in circulating IL-6 bioactivity at both 22 and 48 h after infection (P < 0.05). Treatment with anti-IL-6 also induced a moderate decrease in survival time of mice infected with lethal doses of strains COH1 and COH31, as evidenced by increased lethality (P < 0.05) at 24 to 48 h but not at 96 h. Mouse recombinant IL-6 (12,500 U) given 6 h before challenge with strains COH1 and COH31 consistently increased survival time, as evidenced by decreased (P < 0.05) lethality at 48 to 72 h but not at 96 h. The effects of IL-6 pretreatment were dose dependent, since no protection was observed with doses lower than 12,500 U. In addition, no effects on lethality were noted when IL-6 was given at the time of challenge or at later times. TNF-alpha elevations (P < 0.05 compared with uninfected controls) were measured at 12, 22, and 48 h after challenge with strain COH1 (68 +/- 28, 233 +/- 98, and 98 +/- 34 U, respectively). Pretreatment with IL-6 significantly (P < 0.05) decreased plasma TNF-alpha levels at 12 and 22 h, with 55 and 69% inhibitions, respectively. Anti-IL-6 had an opposite effect, as evidenced by a 145% increase (P < 0.05) in TNF-alpha levels at 48 h after challenge. Collectively, our data are

  19. Evaluation of systemic inflammatory response in cardiovascular surgery via interleukin-6, interleukin-8, and neopterin.

    PubMed

    Uyar, Ihsan Sami; Onal, Suleyman; Uysal, Ayhan; Ozdemir, Ugur; Burma, Oktay; Bulut, Vedat

    2014-02-01

    The aim of this study was to evaluate the serum levels of interleukin-6 (IL-6), IL-8, and neopterin as a sign of systemic inflammatory response syndrome after open-heart surgery. In this study, we evaluated the influences on the levels of IL-6, IL-8, and neopterin of coronary artery bypass grafting (CABG) and valve replacement surgeries with and without the use of extracorporeal circulation (ECC). This prospective study was performed in 30 patients. In this study, we evaluated patients who underwent valve replacement surgery (group 1, n = 10), CABG with ECC (group 2, n = 10), or CABG using the beating-heart technique (group 3, n = 10). With the Human Investigation Ethics Committee consent, blood samples were obtained from the patients before the surgery (T0) and after 1 hour (T1), 4 hours (T2), 24 hours (T3), and 48 hours (T4) of protamine injection. IL-6, IL-8, and neopterin levels were measured using commercial enzyme-linked immunosorbent assay kits. The demographic data and preoperative and operative characteristics of the patients were similar. Neopterin IL-6 and IL-8 levels significantly increased first at the fourth hour after the surgery. When compared to the levels before the surgery, this increase was statistically significant. Unlike the other 2 groups of patients, those who experienced CABG with the beating-heart technique (group 3) had decreased neopterin levels at the first hour after the surgery, but this decrease was not statistically significant. Neopterin levels increased later in the OPCAB group, but these increased levels were not as high as the neopterin levels of groups 1 and 2. Neopterin reached maximum levels at the 24th hour and, unlike groups 1 and 2, in group started to decrease at the 48th. Complement activation, cytokine production, and related cellular responses are important factors during open-heart surgery. It is certain that ECC activates the complement systems, and activated complement proteins cause the production of several

  20. Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.

    PubMed

    Kumar, R G; Diamond, M L; Boles, J A; Berger, R P; Tisherman, S A; Kochanek, P M; Wagner, A K

    2015-03-01

    Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n=114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2weeks-3months) serum inflammatory marker load and long-term global outcome 6-12months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6months (adjusted OR=3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p⩽0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1β and IL-6 levels compared with the low TRAJ group (p⩽0.05). Lastly, injury type (isolated TBI vs. TBI+polytrauma) was associated with IL-6 TRAJ group (χ(2)=5.31, p=0.02). Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated

  1. Interleukin-6 and pro inflammatory status in the breast tumor microenvironment.

    PubMed

    Sanguinetti, Alessandro; Santini, Donatella; Bonafè, Massimiliano; Taffurelli, Mario; Avenia, Nicola

    2015-03-28

    Greater than 50,000 new cases of breast cancer cases were diagnosed in Italy during 2013, with nearly 15,000 women succumbing to the disease. These epidemiological statistics highlight the overwhelming clinical dilemma of breast cancer and emphasize the need for novel therapeutic targets and prevention strategies. Countless studies in the fields of mammary gland development and breast cancer have led to an appreciation of a breast tumor microenvironment that actively contributes to the heterogeneous nature of breast cancer. The current review will focus on the impact of IL-6 and in the breast tumor microenvironment. Excessive IL-6 has been demonstrated in primary breast tumors and breast cancer patient sera and is associated with poor clinical outcomes in breast cancer. These clinical associations are corroborated by emerging preclinical data revealing that IL-6 is a potent growth factor and promotes an epithelial-mesenchyme (EMT) phenotype in breast cancer cells to indicate that IL-6 in the breast tumor microenvironment is clinically relevant. High serum levels of interleukin-6 correlate with poor outcome in breast cancer patients. However, few data are yet available on the relationship between IL-6 and stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Mammospheres (MS) from node invasive breast carcinoma tissues express IL-6 mRNA at higher levels than MS from matched non-neoplastic mammary glands. IL-6 mRNA is detectable only in basal-like breast carcinoma tissues; our results reveal that IL-6 triggers a Notch-3-dependent upregulation of the Notch ligand Jagged-1, whose interaction with Notch-3 promotes the growth of MS and Michigan Cancer Foundation-7 (MCF-7)-derived spheroids. IL-6 induces a Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promotes a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. In conclusion, our data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing

  2. The Impact of Hyperthermia on Receptor-Mediated Interleukin-6 Regulation in Mouse Skeletal Muscle

    PubMed Central

    Welc, Steven S.; Morse, Deborah A.; Mattingly, Alex J.; Laitano, Orlando; King, Michelle A.; Clanton, Thomas L.

    2016-01-01

    In inflammatory cells, hyperthermia inhibits lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) gene expression and protein secretion. Since hyperthermia alone stimulates IL-6 in skeletal muscle, we hypothesized that it would amplify responses to other receptor-mediated stimuli. IL-6 regulation was tested in C2C12 myotubes and in soleus during treatment with epinephrine (EPI) or LPS. In EPI-treated myotubes (100 ng/ml), 1 h exposure at 40.5°C-42°C transiently increased IL-6 mRNA compared to EPI treatment alone at 37°C. In LPS-treated myotubes (1 μg/ml), exposure to 41°C-42°C also increased IL-6 mRNA. In isolated mouse soleus, similar amplifications of IL-6 gene expression were observed in 41°C, during both low (1 ng/ml) and high dose (100 ng/ml) EPI, but only in high dose LPS (1 μg/ml). In myotubes, heat increased IL-6 secretion during EPI exposure but had no effect or inhibited secretion with LPS. In soleus there were no effects of heat on IL-6 secretion during either EPI or LPS treatment. Mechanisms for the effects of heat on IL-6 mRNA were explored using a luciferase-reporter in C2C12 myotubes. Overexpression of heat shock factor-1 (HSF-1) had no impact on IL-6 promoter activity during EPI stimulation, but elevated IL-6 promoter activity during LPS stimulation. In contrast, when the activator protein-1 (AP-1) element was mutated, responses to both LPS and EPI were suppressed in heat. Using siRNA against activating transcription factor-3 (ATF-3), a heat-stress-induced inhibitor of IL-6, no ATF-3-dependent effects were observed. The results demonstrate that, unlike inflammatory cells, hyperthermia in muscle fibers amplifies IL-6 gene expression to EPI and LPS. The effect appears to reflect differential engagement of HSF-1 and AP-1 sensitive elements on the IL-6 gene, with no evidence for involvement of ATF-3. The functional significance of increased IL-6 mRNA expression during heat may serve to overcome the well-known suppression of protein synthetic

  3. Interleukin 6 deficiency modulates the hypothalamic expression of energy balance regulating peptides during pregnancy in mice.

    PubMed

    Pazos, Patricia; Lima, Luis; Casanueva, Felipe F; Diéguez, Carlos; García, María C

    2013-01-01

    Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations. Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. To explore the role of IL6 in the central mechanisms governing dam's energy homeostasis, early, mid and late pregnant (gestational days 7, 13 and 18) wild-type (WT) and Il6 knockout mice (Il6-KO) were compared with virgin controls at diestrus. Food intake, body weight and composition as well as indirect calorimetry measurements were performed in vivo. Anabolic and orexigenic peptides: neuropeptide Y (Npy) and agouti-related peptide (Agrp); and catabolic and anorectic neuropeptides: proopiomelanocortin (Pomc), corticotrophin and thyrotropin-releasing hormone (Crh and Trh) mRNA levels were determined by in situ hybridization. Real time-PCR and western-blot were used for additional tissue gene expression and protein studies. Non-pregnant Il6-KO mice were leaner than WT mice due to a decrease in fat but not in lean body mass. Pregnant Il6-KO mice had higher fat accretion despite similar body weight gain than WT controls. A decreased fat utilization in absence of Il6 might explain this effect, as shown by increased respiratory exchange ratio (RER) in virgin Il6-KO mice. Il6 mRNA levels were markedly enhanced in adipose tissue but reduced in hypothalamus of mid and late pregnant WT mice. Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect. Conversely, in late pregnant mice lessened hypothalamic Il6 receptor alpha (Il6ra), Pomc and Crh mRNA were observed. Il6 deficiency during this stage up-regulated Npy and Agrp expression, while restoring Pomc mRNA levels to virgin values. Together these results demonstrate that IL6/IL6Ra system modulates Npy/Agrp, Pomc and Trh expression during mouse pregnancy, supporting a role of IL6 in the central

  4. Interleukin 6 Deficiency Modulates the Hypothalamic Expression of Energy Balance Regulating Peptides during Pregnancy in Mice

    PubMed Central

    Pazos, Patricia; Lima, Luis; Casanueva, Felipe F.; Diéguez, Carlos; García, María C.

    2013-01-01

    Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations. Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. To explore the role of IL6 in the central mechanisms governing dam's energy homeostasis, early, mid and late pregnant (gestational days 7, 13 and 18) wild-type (WT) and Il6 knockout mice (Il6-KO) were compared with virgin controls at diestrus. Food intake, body weight and composition as well as indirect calorimetry measurements were performed in vivo. Anabolic and orexigenic peptides: neuropeptide Y (Npy) and agouti-related peptide (Agrp); and catabolic and anorectic neuropeptides: proopiomelanocortin (Pomc), corticotrophin and thyrotropin-releasing hormone (Crh and Trh) mRNA levels were determined by in situ hybridization. Real time-PCR and western-blot were used for additional tissue gene expression and protein studies. Non-pregnant Il6-KO mice were leaner than WT mice due to a decrease in fat but not in lean body mass. Pregnant Il6-KO mice had higher fat accretion despite similar body weight gain than WT controls. A decreased fat utilization in absence of Il6 might explain this effect, as shown by increased respiratory exchange ratio (RER) in virgin Il6-KO mice. Il6 mRNA levels were markedly enhanced in adipose tissue but reduced in hypothalamus of mid and late pregnant WT mice. Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect. Conversely, in late pregnant mice lessened hypothalamic Il6 receptor alpha (Il6ra), Pomc and Crh mRNA were observed. Il6 deficiency during this stage up-regulated Npy and Agrp expression, while restoring Pomc mRNA levels to virgin values. Together these results demonstrate that IL6/IL6Ra system modulates Npy/Agrp, Pomc and Trh expression during mouse pregnancy, supporting a role of IL6 in the central

  5. Exhaled Interleukine-6 and 8-isoprostane in chronic obstructive pulmonary disease: effect of carbocysteine lysine salt monohydrate (SCMC-Lys).

    PubMed

    Carpagnano, Giovanna E; Resta, O; Foschino-Barbaro, Maria P; Spanevello, Antonio; Stefano, Antonio; Di Gioia, Giuseppe; Serviddio, Gaetano; Gramiccioni, Enzo

    2004-11-28

    Chronic obstructive pulmonary disease (COPD) is characterized by an airways inflammation and by an enhanced generation of reactive oxygen species. The aim of our study was to assess the inflammation and the oxidative stress in airways of COPD patients with acute exacerbation of disease and in stability. Furthermore, we investigated the anti-inflammatory and antioxidant effects of 6 months treatment with carbocysteine lysine salt monohydrate (SCMC-Lys) in COPD. We studied 30 mild acute COPD, 10 mild stable COPD and 15 healthy subjects. 8-isoprostane and Interleukine-6 were measured in their breath condensate through immunoassay. Significantly higher concentrations of exhaled 8-isoprostane and Interleukine-6 were found in acute COPD patients compared to stable COPD and healthy controls (21.8+/-5.1 vs. 13.2+/-2.0 vs. 4.7+/-1.8 pg/ml and 7.4+/-0.9 vs. 5.8+/-0.2 vs. 2.7+/-0.6 pg/ml, p<0.0001). COPD patients treated with SCMC-Lys showed a marked reduction of exhaled 8-isoprostane and Interleukine-6 (8.9+/-1.5 and 4.6+/-0.8 pg/ml, p<0.0001). These findings suggest that there is an increase of 8-isoprostane and Interleukine-6 concentrations in the breath condensate of COPD patients compared to healthy controls especially during acute exacerbations of the disease. Moreover, we showed an anti-inflammatory and antioxidant effect of short-term administration of SCMC-Lys in COPD, suggesting the importance of a further placebo-controlled study that should evaluate the effects of this drug.

  6. The Role of Interleukin-6/GP130 Signaling in Prostate Cancer Progression and Its Contribution to Bone Metastasis Morbidity

    DTIC Science & Technology

    2007-03-01

    interleukin-6 (IL-6) is strongly implicated in primary prostate cancer ( PrCa ) growth and the progression to bone metastasis. While expression and...localization of IL-6 and its receptors gp130 and IL-6R have been studied in organ-confined PrCa , these key mediators of the IL-6/gp130 signaling pathway...have not been previously assessed in prostatic bone metastases. Thus far, our investigations with archival patient biopsies revealed that all PrCa

  7. Role of interleukin 6 and transforming growth factor-beta in the induction of depressed splenocyte responses following sepsis.

    PubMed

    Ayala, A; Knotts, J B; Ertèl, W; Perrin, M M; Morrison, M H; Chaudry, I H

    1993-01-01

    We examined whether (1) there is an association between elevated circulating levels of transforming growth factor-beta (TGF-beta) and splenocyte dysfunction during sepsis, and (2) administration of monoclonal antibodies to interleukin 6 (an inducer of TGF-beta release) or TGF-beta could ablate these changes. Blood and splenocytes were obtained from C3H/HeN mice at 1, 4, or 24 hours following cecal ligation and puncture or sham operation. Only at 24 hours after cecal ligation and puncture was there an association between elevated blood TGF-beta value and depressed splenocyte interleukin 2 release. Administration of monoclonal antibodies against interleukin 6, but not against TGF-beta (intraperitoneally immediately following cecal ligation and puncture), significantly decreased the blood levels of TGF-beta at 24 hours following cecal ligation and puncture and improved splenocyte interleukin 2 release. Thus, the judicious use of monoclonal antibodies against interleukin 6 may block the subsequent elevation of TGF-beta, thereby attenuating host immunosuppression during sepsis.

  8. Nicotine suppresses interleukin-6 production from vascular endothelial cells: a possible therapeutic role of nicotine for preeclampsia.

    PubMed

    Sharentuya, Namuxila; Tomimatsu, Takuji; Mimura, Kazuya; Tskitishvili, Ekaterine; Kinugasa-Taniguchi, Yukiko; Kanagawa, Takeshi; Kimura, Tadashi

    2010-06-01

    Normal pregnancy is the controlled state of inflammation and this systemic inflammatory response is reported to be more intense in preeclampsia. The current study tested the hypothesis that maternal serum stimulates interleukin 6 (IL-6) production from endothelial cells and that nicotine inhibits these effects. Human umbilical vein endothelial cells (HUVECs) were incubated with or without 0.5% serum from healthy pregnant women at term (n = 5) and treated with or without nicotine (10(-9) to 10(-6) mol/L) in the presence of 0.5% serum. Cell survival was determined by colorimetric assay. Interleukin 6 concentration and nuclear transcription factor kappa B (NF-kB) activities were determined by enzyme-linked immunosorbent assay (ELISA)-based method. Interleukin 6 production by endothelial cells was significantly stimulated in the presence of maternal serum. Nicotine significantly preserved cell survival and suppressed IL-6 production from endothelial cells. Nicotine also significantly inhibited NF-kB activation in endothelial cells. Nicotine inhibited inflammatory reaction through NF-kB suppression in vitro model of maternal vascular endothelium, and this effect may be one of the explanations for the reduced risk of preeclampsia in smokers.

  9. Human cancer xenografts in outbred nude mice can be confounded by polymorphisms in a modifier of tumorigenesis.

    PubMed

    Zeineldin, Maged; Jensen, Derek; Paranjape, Smita R; Parelkar, Nikhil K; Jokar, Iman; Vielhauer, George A; Neufeld, Kristi L

    2014-08-01

    Tumorigenicity studies often employ outbred nude mice, in the absence of direct evidence that this mixed genetic background will negatively affect experimental outcome. Here we show that outbred nude mice carry two different alleles of Pla2g2a, a genetic modifier of intestinal tumorigenesis in mice. Here, we identify previous unreported linked polymorphisms in the promoter, noncoding and coding sequences of Pla2g2a and show that outbred nude mice from different commercial providers are heterogeneous for this polymorphic Pla2g2a allele. This heterogeneity even extends to mice obtained from a single commercial provider, which display mixed Pla2g2a genotypes. Notably, we demonstrated that the polymorphic Pla2g2a allele affects orthotopic xenograft establishment of human colon cancer cells in outbred nude mice. This finding establishes a non-cell-autonomous role for Pla2g2a in suppressing intestinal tumorigenesis. Using in vitro reporter assays and pharmacological inhibitors, we show promoter polymorphisms and nonsense-mediated RNA decay (NMD) as underlying mechanisms that lead to low Pla2g2a mRNA levels in tumor-sensitive mice. Together, this study provides mechanistic insight regarding Pla2g2a polymorphisms and demonstrates a non-cell-autonomous role for Pla2g2a in suppressing tumors. Moreover, our direct demonstration that mixed genetic backgrounds of outbred nude mice can significantly affect baseline tumorigenicity cautions against future use of outbred mice for tumor xenograft studies.

  10. Human Cancer Xenografts in Outbred Nude Mice Can Be Confounded by Polymorphisms in a Modifier of Tumorigenesis

    PubMed Central

    Zeineldin, Maged; Jensen, Derek; Paranjape, Smita R.; Parelkar, Nikhil K.; Jokar, Iman; Vielhauer, George A.; Neufeld, Kristi L.

    2014-01-01

    Tumorigenicity studies often employ outbred nude mice, in the absence of direct evidence that this mixed genetic background will negatively affect experimental outcome. Here we show that outbred nude mice carry two different alleles of Pla2g2a, a genetic modifier of intestinal tumorigenesis in mice. Here, we identify previous unreported linked polymorphisms in the promoter, noncoding and coding sequences of Pla2g2a and show that outbred nude mice from different commercial providers are heterogeneous for this polymorphic Pla2g2a allele. This heterogeneity even extends to mice obtained from a single commercial provider, which display mixed Pla2g2a genotypes. Notably, we demonstrated that the polymorphic Pla2g2a allele affects orthotopic xenograft establishment of human colon cancer cells in outbred nude mice. This finding establishes a non-cell-autonomous role for Pla2g2a in suppressing intestinal tumorigenesis. Using in vitro reporter assays and pharmacological inhibitors, we show promoter polymorphisms and nonsense-mediated RNA decay (NMD) as underlying mechanisms that lead to low Pla2g2a mRNA levels in tumor-sensitive mice. Together, this study provides mechanistic insight regarding Pla2g2a polymorphisms and demonstrates a non-cell-autonomous role for Pla2g2a in suppressing tumors. Moreover, our direct demonstration that mixed genetic backgrounds of outbred nude mice can significantly affect baseline tumorigenicity cautions against future use of outbred mice for tumor xenograft studies. PMID:24913681

  11. Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation.

    PubMed

    Frydecka, Dorota; Misiak, Błażej; Pawlak-Adamska, Edyta; Karabon, Lidia; Tomkiewicz, Anna; Sedlaczek, Paweł; Kiejna, Andrzej; Beszłej, Jan Aleksander

    2015-09-01

    The influence of the immune system deregulation on the risk of schizophrenia is increasingly recognized. The aim of this study was to assess the influence of serum interleukin-6 (IL-6) level together with the polymorphism in its gene (IL6 -174G/C) and high sensitivity C-reactive protein (hsCRP) levels on clinical manifestation and cognition in schizophrenia patients. We recruited 151 patients with schizophrenia and 194 healthy control subjects. Psychopathology was evaluated using Operational Criteria for Psychotic Illness checklist, Positive and Negative Syndrome Scale (PANSS) and Scales for Assessment of Positive and Negative Symptoms. Cognitive performance in schizophrenia patients was assessed using following tests: Rey Auditory Verbal Learning Test, Trail Making Test, Verbal Fluency Tests, Stroop and subscales from Wechsler Adults Intelligence Scale-R-Pl (Similarities, Digit Symbol Coding, Digit Span Forward and Backward). Serum IL-6 and hsCRP levels were significantly higher in schizophrenia patients in comparison with healthy controls. Both hsCRP and IL-6 levels were associated with insidious psychosis onset, duration of illness and chronic schizophrenia course with deterioration. After adjustment for age, education level, number of years of completed education, illness duration, total PANSS score, depression severity and chlorpromazine equivalent, there was still a positive association between IL-6 and hsCRP levels and worse cognitive performance. The IL6 -174G/C polymorphism did not influence IL-6 level, but it was associated with the severity of positive symptoms. Our results suggest that elevated IL-6 levels may play the role in cognitive impairment and serve as potential inflammatory biomarker of deterioration in schizophrenia.

  12. Levels of interleukin-6 in tears before and after excimer laser treatment.

    PubMed

    Resan, Mirko; Stanojević, Ivan; Petković, Aleksandra; Pajić, Bojan; Vojvodić, Danilo

    2015-04-01

    Immune response and consequent inflammatory process which originate on ocular surface after a trauma are mediated by cytokines. Photoablation of corneal stroma performed by excimer laser causes surgically induced trauma. Interleukin-6 (IL-6) is mostly known as a proinflammatory cytokine. However, it also has regenerative and anti-inflammatory effects. It is supposed that this cytokine is likely to play a significant role in the process of corneal wound healing response after photoablation of stroma carried out by laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) methods. The aim of this study was to determine and compare the levels of IL-6 in tears before and after treatment with LASIK and PRK methods. The study included 68 shortsighted eyes up to -3.0 diopter sphere, i.e. 198 samples of tears (per three samples taken from each of the eyes), divided into two groups according to the kind of excimer laser intervention performed: the group 1--eyes treated by LASIK method (n=31), and the group 2--eyes treated by the PRK method (n=37). The samples of tears were taken from each eye at the following time points: before excimer laser treatment (0 h, the control group), 1 h after the treatment (1 h) and 24 h after the treatment (24 h). The patients did not use anti-inflammatory therapy 24 h after the intervention. Tear samples were collected using microsurgical sponge. Level of IL-6 in tear fluid was determined by the flow cytometry method, applying a commercial test kit which allowed cytokine detection from a small sample volume. Results. The values of IL-6 were detectable in 16% of samples before LASIK treatment and in 30% of samples before PRK treatment. One h after the treatment IL-6 was detectable in 29% of samples for the LASIK group and 43% of samples for the PRK group, and 24 h after the treatment it was detectable in 19% of samples for the LASIK group and in 57% of samples for the PRK group. When we analyzed the dynamics of IL76 production

  13. An interleukin-6-neutralizing antibody prevents cyclosporine-induced nephrotoxicity in mice.

    PubMed

    LaSpina, Mark; Tripathi, Sudipta; Gatto, Louis A; Bruch, David; Maier, Kristopher G; Kittur, Dilip S

    2008-08-01

    Chronic use of cyclosporine A (CyA) induces nephrotoxicity primarily due to endothelial dysfunction. In our previous studies, potential mechanisms were identified in vitro and implicated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and interleukin-6 (IL-6) as key components in causing endothelial dysfunction. In this study, we tested the hypothesis that NADPH oxidase activity and IL-6 are key components in renal damage in an in vivo model. Male mice C57B/6 mice from Jackson Laboratory (Bar Harbor, ME) at 6-8 wks were subjected to a low-salt diet throughout the trial. After 1 week on a low-salt diet, the mice were injected daily with treatments in 50 muL vehicle composed of 75% cremaphor (Sigma, St. Louis, MO) and ethanol for 5 wks. A vehicle-alone group was also set aside. Mice were weighed and 25 mg/kg/day cyclosporine (Novartis Pharma, St. Louis, MO) was injected daily. Apocynin (Calbiochem, Gibbstown, NJ) 20 mg/kg were injected either alone or concomitantly with CyA. Another group of mice were administered IL-6 antibody (Cat no. MAB406; R&D Systems, Minneapolis, MN) at 2 mug/day along with CyA. The kidneys were removed en bloc immediately and submitted in formalin for paraffin sections. Trichrome stains were performed. Slides were blinded and 10 photographs of cortical areas per treatment group were taken, which covered an estimate of 10% surface area in random fashion. Areas of renal damage, which were determined by tubular necrosis, were identified and quantified by amount of necrosis per photograph. Each photograph was divided into 10 blocks, and the number of blocks that contained necrotic tubules per photo was recorded. The two control mice (low salt only) had no damage. The four vehicle mice had trace amounts of tubular necrosis. CyA treatment group demonstrated the highest amount of damage (29/70; 41%). CyA with apocynin, a specific NADPH oxidase inhibitor, was found to have 36% (22/60) damage, whereas the CyA with IL-6 antibody only was

  14. Human Herpesvirus 8 Interleukin-6 Interacts with Calnexin Cycle Components and Promotes Protein Folding.

    PubMed

    Chen, Daming; Xiang, Qiwang; Nicholas, John

    2017-09-06

    Viral interleukin-6 (vIL-6) encoded by human herpesvirus 8 (HHV-8) is believed to contribute via mitogenic, survival, and angiogenic activities to HHV-8-associated Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease through autocrine or paracrine mechanisms during latency or productive replication. There is direct evidence that vIL-6 promotes latently infected PEL cell viability and proliferation and also viral productive replication in PEL and endothelial cells. These activities are mediated largely through endoplasmic reticulum (ER)-localized vIL-6, which can induce signal transduction via the gp130 signaling receptor, activating mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) signaling, and interactions of vIL-6 with the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). The latter functional axis involves suppression of pro-apoptotic lysosomal protein cathepsin D by promotion of the ER-associated degradation of ER-transiting, pre-proteolytically processed pro-cathepsin D. Other interactions of VKORC1v2 and activities of vIL-6 via the receptor have not been reported. Here, we show that both vIL-6 and VKORC1v2 interact with calnexin cycle proteins UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), catalyzing monoglucosylation of N-glycans, and oppositely-acting glucosidase II (GlucII) and that vIL-6 can promote protein folding. This activity was found to require VKORC1v2 and UGGT1, to involve vIL-6 associations with VKORC1v2, UGGT1 and GlucII, and to operate in the context of productively infected cells. These findings document new VKORC1v2-associated interactions and activities of vIL-6, revealing novel mechanisms of vIL-6 function within the ER compartment.IMPORTANCE HHV-8 vIL-6 pro-survival (latent) and pro-replication functions are mediated from the ER compartment through both gp130 receptor-mediated signal transduction and

  15. Genetic Polymorphisms of Catechol-O-Methyltransferase Modify the Neurobehavioral Effects of Mercury in Children

    PubMed Central

    Woods, James S.; Heyer, Nicholas J.; Russo, Joan E.; Martin, Michael D.; Pillai, Pradeep B.; Bammler, Theodor K.; Farin, Federico M.

    2014-01-01

    Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8–12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene–Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure. PMID:24593143

  16. eNOS gene polymorphisms modify the association of PM(10) with oxidative stress.

    PubMed

    Kim, Jin Hee; Choi, Yoon-Hyeong; Bae, Sanghyuk; Park, Hye-Yin; Hong, Yun-Chul

    2012-11-15

    Previous studies have suggested that air pollution increases various health outcomes through oxidative stress and oxidative stress-related genes modify the relationship between air pollution and health outcomes. Therefore, we evaluated the effect of PM(10) on the levels of malondialdehyde (MDA), oxidative stress biomarker, and the effect modification by genetic polymorphisms of eNOS, oxidative stress-related gene, in the 560 Korean elderly. We obtained urine samples repeatedly from participants during five medical examinations between 2008 and 2010 and all ambient air pollutant concentration data from the Korea National Institute of Environmental Research air quality monitoring system. We measured urinary levels of MDA to assess oxidative stress and genotyped eNOS (rs1799983, rs2853796, and rs7830). Mixed-effect model was used to estimate the effect of PM(10) on the level of oxidative stress biomarker and their modification by genotypes. PM(10) showed apparent positive effect on MDA level after adjusting for age, sex, BMI, cotinine level, temperature, dew point, levels of SO(2), O(3), NO(2), and CO, and season (p=0.0133). Moreover, the association of PM(10) with MDA was found only in participants with eNOS GG genotype for rs1799983 (p=0.0107), TT genotype for rs2853796 (p=0.0289), or GT genotype for rs7830 (p=0.0158) and in participants with a set of risky haplotypes (GTT, GTG, GGT, and TGT) (p=0.0093). Our results suggest that PM(10) affect oxidative stress in the elderly and eNOS genotype affect the oxidative stress level in regard of exposure to PM(10).

  17. Neuroprotective effect of interleukin-6 regulation of voltage-gated Na(+) channels of cortical neurons is time- and dose-dependent.

    PubMed

    Xia, Wei; Peng, Guo-Yi; Sheng, Jiang-Tao; Zhu, Fang-Fang; Guo, Jing-Fang; Chen, Wei-Qiang

    2015-04-01

    Interleukin-6 has been shown to be involved in nerve injury and nerve regeneration, but the effects of long-term administration of high concentrations of interleukin-6 on neurons in the central nervous system is poorly understood. This study investigated the effects of 24 hour exposure of interleukin-6 on cortical neurons at various concentrations (0.1, 1, 5 and 10 ng/mL) and the effects of 10 ng/mL interleukin-6 exposure to cortical neurons for various durations (2, 4, 8, 24 and 48 hours) by studying voltage-gated Na(+) channels using a patch-clamp technique. Voltage-clamp recording results demonstrated that interleukin-6 suppressed Na(+) currents through its receptor in a time- and dose-dependent manner, but did not alter voltage-dependent activation and inactivation. Current-clamp recording results were consistent with voltage-clamp recording results. Interleukin-6 reduced the action potential amplitude of cortical neurons, but did not change the action potential threshold. The regulation of voltage-gated Na(+) channels in rat cortical neurons by interleukin-6 is time- and dose-dependent.

  18. The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate.

    PubMed

    Broberg, Karin E; Warholm, Margareta; Tinnerberg, Håkan; Axmon, Anna; Jönsson, Bo A; Sennbro, Carl Johan; Littorin, Margareta; Rannug, Agneta

    2010-02-01

    Toluene di-isocyanate (TDI) is widely used in the production of polyurethane foams and paints. As TDI causes respiratory disease in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Polymorphisms in TDI metabolising genes may affect elimination kinetics, resulting in differences in body retention, and in its turn differences in adverse effects. To analyze how genotype modifies the associations between (i) TDI in air (2,4-TDI and 2,6-TDI) and its metabolites toluene diamine (TDA; 2,4-TDA and 2,6-TDA) in hydrolyzed urine; and (ii) 2,4-TDA and 2,6-TDA in hydrolyzed plasma and 2,4-TDA and 2,6-TDA in urine. Workers exposed to TDI were analyzed for 2,4-TDI and 2,6-TDI in air (N=70), 2,4-TDA and 2,6-TDA in hydrolyzed urine (N=124) and in plasma (N=128), and genotype: CYP1A1*2A, CYP1A1*2B, GSTA1-52, GSTM1O, GSTM3B, GSTP1 I105V, GSTP1 A114V, GSTT1O, MPO-463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, and SULT1A1 R213H. GSTP1 105 strongly modified the relationship between 2,4-TDA in plasma and in urine: ValVal carriers had about twice as steep regression slope than IleIle carriers. A similar pattern was found for 2,6-TDA. CYP1A1*2A, GSTM1, GSTP1, GSTT1, and MPO possibly influenced the relationship between TDA in plasma and urine. Our results show, for the first time, genetic modification on the human TDI metabolism. The findings suggest that GSTP1 genotype should be considered when evaluating biomarkers of TDI exposure in urine and plasma. Moreover, the results support earlier findings of GSTP1 105 Val as protective against TDI-related asthma.

  19. Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy.

    PubMed

    2010-06-15

    Menopausal hormone therapy (HT) is associated with increased breast cancer risk among postmenopausal women. Nuclear receptors are involved in steroid hormone- and xenobiotic-mediated signal transduction playing a crucial role in regulating gene expression. Therefore, variations within these genes may influence HT-associated breast cancer risk. We investigated 3,149 postmenopausal breast cancer patients and 5,489 controls from 2 German population-based case-control studies. Thirty-three polymorphisms selected on the basis of known or putative functional relevance located in ESR1, ESR2, PGR, PXR and AR were genotyped. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen-progestagen therapy and of estrogen monotherapy with regard to breast cancer risk assuming log-additive and codominant modes of inheritance. We observed an increased risk for women carrying short AR_(CAG) alleles of <22 repeats associated with combined estrogen-progestagen therapy compared with those with long alleles (> or =22 repeats) (p(interaction) = 0.03). Additionally, risk associated with combination therapy use was significantly modified by 2 PXR polymorphisms with reduction of risk effects in carriers of the minor PXR_rs6785049_G and PXR_rs1054191_A alleles (p(interaction) = 0.04 and 0.05, respectively). Variants in both ESR1 and ESR2 modified risk associated with estrogen monotherapy use. Higher risk were observed in homozygotes for the major ESR1_rs910416_T allele (p(interaction) < 0.01) and in homozygotes for the minor ESR2_rs1271572_T, major ESR2_rs4986938_G and minor ESR2_rs928554_G alleles (p(interaction) = 0.02, 0.05, 0.02, respectively). Risk effect modification by ESR1_rs910416 and AR_(CAG)n polymorphisms remained significant after correction for multiple testing. We conclude that genetic variants in nuclear receptor genes may modify HT-associated postmenopausal breast cancer risk.

  20. CYP7A1 Gene Polymorphism Located in the 5′ Upstream Region Modifies the Risk of Coronary Artery Disease

    PubMed Central

    Iwanicki, Tomasz; Balcerzyk, Anna; Niemiec, Pawel; Nowak, Tomasz; Ochalska-Tyka, Anna; Krauze, Jolanta; Kosiorz-Gorczynska, Sylwia; Grzeszczak, Wladyslaw; Zak, Iwona

    2015-01-01

    Background. 7-Alpha cholesterol hydroxylase (CYP7A1), the first enzyme of classic conversion pathway leading from cholesterol to bile acids synthesis, is encoded by CYP7A1 gene. Its single nucleotide polymorphisms (SNPs) influence serum lipid levels and may be related to impaired lipid profile leading to coronary artery disease (CAD). The aim of the present study was to analyze the possible association between the rs7833904 CYP7A1 polymorphism and premature CAD. Material and Methods. Serum lipid levels and rs7833904 SNP were determined in 419 subjects: 200 patients with premature CAD and 219 age and sex matched controls. Results. The A allele carrier state was associated with CAD (OR = 1.76, 95% CI; 1.14–2.71, P = 0.014). The effect was even stronger in the male subgroups (OR = 2.16, 95% CI; 1.28–3.65, P = 0.003). There was no effect in the females. Risk factors of CAD and clinical phenotype of atherosclerosis were not associated with genotype variants of the rs7833904 SNP. Lipid profiles also did not differ significantly between individual genotypes. Conclusion. The CYP7A1 rs7833904 polymorphism may modify the risk of CAD. This effect is especially strong in male subjects. The studied polymorphism does not significantly influence serum lipid levels, in the present study. PMID:25944972

  1. CYP7A1 gene polymorphism located in the 5' upstream region modifies the risk of coronary artery disease.

    PubMed

    Iwanicki, Tomasz; Balcerzyk, Anna; Niemiec, Pawel; Nowak, Tomasz; Ochalska-Tyka, Anna; Krauze, Jolanta; Kosiorz-Gorczynska, Sylwia; Grzeszczak, Wladyslaw; Zak, Iwona

    2015-01-01

    7-Alpha cholesterol hydroxylase (CYP7A1), the first enzyme of classic conversion pathway leading from cholesterol to bile acids synthesis, is encoded by CYP7A1 gene. Its single nucleotide polymorphisms (SNPs) influence serum lipid levels and may be related to impaired lipid profile leading to coronary artery disease (CAD). The aim of the present study was to analyze the possible association between the rs7833904 CYP7A1 polymorphism and premature CAD. Serum lipid levels and rs7833904 SNP were determined in 419 subjects: 200 patients with premature CAD and 219 age and sex matched controls. The A allele carrier state was associated with CAD (OR = 1.76, 95% CI; 1.14-2.71, P = 0.014). The effect was even stronger in the male subgroups (OR = 2.16, 95% CI; 1.28-3.65, P = 0.003). There was no effect in the females. Risk factors of CAD and clinical phenotype of atherosclerosis were not associated with genotype variants of the rs7833904 SNP. Lipid profiles also did not differ significantly between individual genotypes. The CYP7A1 rs7833904 polymorphism may modify the risk of CAD. This effect is especially strong in male subjects. The studied polymorphism does not significantly influence serum lipid levels, in the present study.

  2. The role of interleukin-6 in vitamin A deficiency during Plasmodium falciparum malaria and possible consequences for vitamin A supplementation.

    PubMed Central

    Tabone, M D; Muanza, K; Lyagoubi, M; Jardel, C; Pied, S; Amedee-Manesme, O; Grau, G E; Mazier, D

    1992-01-01

    Kinetics of serum levels of interleukin-6 (IL-6) were studied in patients with acute Plasmodium falciparum malaria in relation to vitamin A and its binding proteins, retinol binding protein (RBP) and pre-albumin. It was found that IL-6 levels followed the rise and decrease of parasitaemia by 12 hr and correlated inversely with levels of vitamin A and its binding proteins. These data suggest that vitamin A supplementation alone might still be insufficient to restore a malaria-induced vitamin A deficiency. PMID:1572702

  3. Increased cerebrospinal fluid progranulin correlates with interleukin-6 in the acute phase of neuromyelitis optica spectrum disorder.

    PubMed

    Kimura, Akio; Takemura, Masao; Saito, Kuniaki; Serrero, Ginette; Yoshikura, Nobuaki; Hayashi, Yuichi; Inuzuka, Takashi

    2017-04-15

    We examined progranulin (PGRN) levels in cerebrospinal fluid (CSF) samples during the acute phase in 15 patients with neuromyelitis optica spectrum disorders (NMOSD) and compared the results with those from 17 patients with multiple sclerosis (MS), 30 patients with other inflammatory neurological diseases (OIND), and 20 non-inflammatory controls (NIC). CSF PGRN levels of NMOSD patients were significantly higher than those of MS patients and NICs. These levels correlated with CSF interleukin-6 levels, CSF cell counts, CSF protein levels, improvements in the Expanded Disability Status Scale score, and affected total spinal cord lesion length in the NMOSD patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Genetic polymorphisms of the Pmo1 and Pmo2 salivary proteins detected by the modified protein staining method.

    PubMed

    Minaguchi, K; Suzuki, K

    1988-07-01

    Two polymorphic proteins, Pmo1 and Pmo2, were found in human parotid saliva by modifying the protein staining method of Sung & Smithies (1969). The inheritance of each polymorphism was controlled by a dominant allele at an autosomal locus. This hypothesis was supported by studies in 50 families including 103 children. The gene frequencies were Pmo1+ = 0.308, Pmo1- = 0.692, Pmo2+ = 0.026, Pmo2- = 0.974. The Pmo1 and Pmo2 proteins reacted immunologically with antisera prepared to salivary proline-rich proteins (Pr and Gl). The isoelectric point was in excess of 8.58. These results showed that the Pmo1 and Pmo2 proteins belong to the basic proline-rich proteins in human parotid saliva.

  5. Interleukin-6 (IL-6) rs1800796 and cyclin dependent kinase inhibitor (CDKN2A/CDKN2B) rs2383207 are associated with ischemic stroke in indigenous West African Men.

    PubMed

    Akinyemi, Rufus; Arnett, Donna K; Tiwari, Hemant K; Ovbiagele, Bruce; Sarfo, Fred; Srinivasasainagendra, Vinodh; Irvin, Marguerite Ryan; Adeoye, Abiodun; Perry, Rodney T; Akpalu, Albert; Jenkins, Carolyn; Owolabi, Lukman; Obiako, Reginald; Wahab, Kolawole; Sanya, Emmanuel; Komolafe, Morenikeji; Fawale, Michael; Adebayo, Philip; Osaigbovo, Godwin; Sunmonu, Taofiki; Olowoyo, Paul; Chukwuonye, Innocent; Obiabo, Yahaya; Akpa, Onoja; Melikam, Sylvia; Saulson, Raelle; Kalaria, Raj; Ogunniyi, Adesola; Owolabi, Mayowa

    2017-08-15

    Inherited genetic variations offer a possible explanation for the observed peculiarities of stroke in sub - Saharan African populations. Interleukin-6 polymorphisms have been previously associated with ischemic stroke in some non-African populations. Herein we investigated, for the first time, the association of genetic polymorphisms of IL-6, CDKN2A- CDKN2B and other genes with ischemic stroke among indigenous West African participants in the Stroke Investigative Research and Education Network (SIREN) Study. Twenty-three previously identified single nucleotide polymorphisms (SNPs) in 14 genes of relevance to the neurobiology of ischemic stroke were investigated. Logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of the 23 SNPs in rigorously phenotyped cases (N=429) of ischemic stroke (Men=198; Women=231) and stroke- free (N=483) controls (Men=236; Women=247). Interleukin-6 (IL6) rs1800796 (C minor allele; frequency: West Africans=8.6%) was significantly associated with ischemic stroke in men (OR=2.006, 95% CI=[1.065, 3.777], p=0.031) with hypertension in the model but not in women. In addition, rs2383207 in CDKN2A/CDKN2B (minor allele A with frequency: West Africans=1.7%) was also associated with ischemic stroke in men (OR=2.550, 95% CI=[1.027, 6.331], p=0.044) with primary covariates in the model, but not in women. Polymorphisms in other genes did not show significant association with ischemic stroke. Polymorphisms rs1800796 in IL6 gene and rs2383207 in CDKN2A/CDKN2B gene have significant associations with ischemic stroke in indigenous West African men. CDKN2A/CDKN2B SNP rs2383207 is independently associated with ischemic stroke in indigenous West African men. Further research should focus on the contributions of inflammatory genes and other genetic polymorphisms, as well as the influence of sex on the neurobiology of stroke in people of African ancestry. Copyright © 2017 Elsevier B

  6. Riboflavin status modifies the effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms on homocysteine.

    PubMed

    García-Minguillán, Carlos J; Fernandez-Ballart, Joan D; Ceruelo, Santiago; Ríos, Lídia; Bueno, Olalla; Berrocal-Zaragoza, Maria Isabel; Molloy, Anne M; Ueland, Per M; Meyer, Klaus; Murphy, Michelle M

    2014-11-01

    Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), riboflavin-dependent enzymes, participate in homocysteine metabolism. Reported effects of riboflavin status on the association between the MTHFR 677C>T polymorphism and homocysteine vary, and the effects of the MTRR 66A>G or MTRR 524C>T polymorphisms on homocysteine are unclear. We tested the hypothesis that the effects of the MTHFR 677C>T, MTRR 66A>G and MTRR 524C>T polymorphisms on fasting plasma total homocysteine (tHcy) depend on riboflavin status (erythrocyte glutathionine reductase activation coefficient, optimum: <1.2; marginally deficient: 1.2-1.4; deficient: ≥1.4) in 771 adults aged 18-75 years. MTHFR 677T allele carriers with middle or low tertile plasma folate (<14.7 nmol/L) had 8.2 % higher tHcy compared to the 677CC genotype (p < 0.01). This effect was eliminated when riboflavin status was optimal (p for interaction: 0.048). In the lowest cobalamin quartile (≤273 pmol/L), riboflavin status modifies the relationship between the MTRR 66 A>G polymorphism and tHcy (p for interaction: 0.034). tHcy was 6.6 % higher in MTRR 66G allele carriers compared to the 66AA genotype with marginally deficient or optimal riboflavin status, but there was no difference when riboflavin status was deficient (p for interaction: 0.059). tHcy was 13.7 % higher in MTRR 524T allele carriers compared to the 524CC genotype when cobalamin status was low (p < 0.01), but no difference was observed when we stratified by riboflavin status. The effect of the MTHFR 677C>T polymorphism on tHcy depends on riboflavin status, that of the MTRR 66A>G polymorphism on cobalamin and riboflavin status and that of the MTRR 524C>T polymorphism on cobalamin status.

  7. Interleukin-6 -174 genotype, periodontal disease and adverse pregnancy outcomes: a pilot study.

    PubMed

    Dashash, M; Nugent, J; Baker, P; Tansinda, D; Blinkhorn, F

    2008-05-01

    This study was undertaken to investigate whether maternal periodontal disease and variant genotypes of IL-6 gene are associated with adverse pregnancy outcomes. A total of 145 pregnant women were recruited from St Mary's Hospital, Manchester, UK. Bleeding on probing (BOP) and pocket depth indices were recorded on all teeth. Amplification refractory mutation system-polymerase chain reaction was used for -174 IL-6 genotyping. Birth weight was assessed using the individualized birth ratio (IBR) with intrauterine growth restriction (IUGR) defined as an IBR below the fifth percentile. The G/G genotype results in more BOP % sites in Caucasian (P < 0.001) and Afro-Caribbean pregnant women (P = 0.035). In addition, a marginal significant association between the -174 C/C genotype and IUGR was observed (P = 0.06). The -174* C allele was more frequent in women with IUGR than in normal women (63 vs 37%, P = 0.05). Moreover, the combination between the carriage of -174C allele and increased bleeding sites have increased the risk of IUGR (P = 0.006). Future studies, with a larger sample size, are required to better clarify the relationship between the IL-6 gene polymorphism, periodontal disease, and IUGR.

  8. Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease.

    PubMed

    Moreau, Caroline; Meguig, Sayah; Corvol, Jean-Christophe; Labreuche, Julien; Vasseur, Francis; Duhamel, Alain; Delval, Arnaud; Bardyn, Thomas; Devedjian, Jean-Christophe; Rouaix, Nathalie; Petyt, Gregory; Brefel-Courbon, Christine; Ory-Magne, Fabienne; Guehl, Dominique; Eusebio, Alexandre; Fraix, Valérie; Saulnier, Pierre-Jean; Lagha-Boukbiza, Ouhaid; Durif, Frank; Faighel, Mirela; Giordana, Caroline; Drapier, Sophie; Maltête, David; Tranchant, Christine; Houeto, Jean-Luc; Debû, Bettina; Azulay, Jean-Philippe; Tison, François; Destée, Alain; Vidailhet, Marie; Rascol, Olivier; Dujardin, Kathy; Defebvre, Luc; Bordet, Régis; Sablonnière, Bernard; Devos, David

    2015-05-01

    After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3

  9. Allelic polymorphism of GSTM1 and NAT2 genes modifies dietary-induced DNA damage in colorectal mucosa.

    PubMed

    Kiss, I; Sándor, J; Ember, I

    2000-12-01

    Typically, cancer is caused by the interaction of genetic and environmental factors. In colorectal carcinogenesis, diet and nutritional habits are the most important external risk determinants. Allelic polymorphisms of certain metabolizing enzymes may have an influence on cancer risk by modifying the concentration of active carcinogenic compounds in the body. In the present study we investigated the interaction between nutritional and genetic susceptibility factors in human colon carcinogenesis. Healthy volunteers were divided into four groups, based on allelic polymorphisms of N-acetyltransferase 2 and glutathione-S-transferase M1 enzymes. Comet assay was used to determine the level of DNA strand breaks in exfoliated colorectal mucosal cells, following a 2-day vegetarian diet, and after switching to a 2-day 'high-meat' diet. The 'high-meat' diet statistically significantly increased the amount of single-strand breaks in rapid acetylators and among individuals with a GSMT1 + genotype, while it caused only a slight and not significant increase in the other groups. Our study emphasizes the importance of using susceptibility markers in cancer epidemiology, since environmental effects are strongly modified by these genetic factors.

  10. Interleukin-6 enhances whereas tumor necrosis factor alpha and interferons inhibit integrin expression and adhesion of human mast cells to extracellular matrix proteins.

    PubMed

    Schoeler, Dagmar; Grützkau, Andreas; Henz, Beate M; Küchler, Jens; Krüger-Krasagakis, Sabine

    2003-05-01

    Integrins are expressed on mast cells and constitute an essential prerequisite for the accumulation of the cells at sites of inflammation. In order to clarify a potential contribution of inflammatory cytokines to this process, we have studied the modulation of integrin expression and adhesion of immature human mast cells (HMC-1) to extracellular matrix proteins by interleukin-6, tumor necrosis factor alpha, interferon-alpha and interferon-gamma. Corticosteroids were used for comparison. On fluorescence-activated cell sorter analysis, preincubation of cells for 48 h with different concentrations of interleukin-6 induced a significant, up to 40%, increase of alpha v alpha 5, CD49b (alpha 2), CD49e (alpha 5), CD49f (alpha 6), and CD51 (alpha v). In contrast, different concentrations of tumor necrosis factor alpha, interferon-alpha, interferon-gamma, and dexamethasone (10-8-10-10 M) inhibited expression of adhesion receptors by up to 60%, reaching significance for some but not all integrins. On semiquantitative polymerase chain reaction analysis, interleukin-6, the other cytokines, and corticosteroids significantly modulated expression of alpha1, alpha v and alpha 5 integrin chains at mRNA level. Functional significance of these findings was proven in adhesion assays using fibronectin, laminin, and vitronectin, with interleukin-6 causing significant enhancement of adhesion in all cases, tumor necrosis factor alpha and dexamethasone inducing significant reduction of adhesion to fibronectin and laminin, and interferon-gamma significantly inhibiting adhesion to fibronectin only. Specificity of interleukin-6-induced changes was demonstrated using antibodies against alpha1 and alpha 5 integrins in unstimulated and interleukin-6-prestimulated cells. These data show that interleukin-6 stimulates mast cell adhesion to extracellular matrix and thus allows for the accumulation of the cells at tissue sites by enhancing integrin expression, whereas tumor necrosis factor alpha

  11. Differential modulation of cytokine production by macrolides: interleukin-6 production is increased by spiramycin and erythromycin.

    PubMed Central

    Bailly, S; Pocidalo, J J; Fay, M; Gougerot-Pocidalo, M A

    1991-01-01

    Antibiotics do not act alone but act in conjunction with the host defense system. In particular, it has been shown that some antibiotics can modify cytokine production. We compared the in vitro effects of three macrolides (roxithromycin, spiramycin, and erythromycin) actively concentrated by leukocytes on interleukin-1 alpha, (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha production by human monocytes stimulated with lipopolysaccharide. Our results show that the three macrolides tested have different effects on production of these cytokines. Spiramycin and, to a lesser extent, erythromycin increased total IL-6 production without affecting IL-1 alpha, IL-1 beta, or tumor necrosis factor alpha production, whereas roxithromycin had no effect. To our knowledge, this is the first time that an antibiotic has been shown to increase IL-6 production. PMID:1759822

  12. MiRNAs and miRNA Polymorphisms Modify Drug Response

    PubMed Central

    Li, Mu-Peng; Hu, Yao-Dong; Hu, Xiao-Lei; Zhang, Yan-Jiao; Yang, Yong-Long; Jiang, Chun; Tang, Jie; Chen, Xiao-Ping

    2016-01-01

    Differences in expression of drug response-related genes contribute to inter-individual variation in drugs’ biological effects. MicroRNAs (miRNAs) are small noncoding RNAs emerging as new players in epigenetic regulation of gene expression at post-transcriptional level. MiRNAs regulate the expression of genes involved in drug metabolism, drug transportation, drug targets and downstream signal molecules directly or indirectly. MiRNA polymorphisms, the genetic variations affecting miRNA expression and/or miRNA-mRNA interaction, provide a new insight into the understanding of inter-individual difference in drug response. Here, we provide an overview of the recent progress in miRNAs mediated regulation of biotransformation enzymes, drug transporters, and nuclear receptors. We also describe the implications of miRNA polymorphisms in cancer chemotherapy response. PMID:27834829

  13. [Changes in the interleukin-6 and interleukin-10 concentrations in the blood plasma of miners working in deep coal mines].

    PubMed

    Plotkin, V Ia; Rebrov, B A; Belkina, E B

    2000-03-01

    Blood plasma levels of interleukin-6 (IL-6) and interleukin-10 (IL-10) were measured in 45 miners working in a deep coal mine immediately after work shift using an immunoenzyme technique. The highest IL-6 level was recorded in those miners engaged in hard work under most adverse conditions of underground workings--it was found to exceed the control values. The same group of workers demonstrated the lowest level of IL-10 that differed from the control value. Miners aged between 41 to 50 years working in a coal mine, their underground service duration 16 to 20 years, displayed a decline in the level of IL-6. The coal mine miners with the 11- to 15-year service duration revealed an increase in the level of IL-10.

  14. Autocrine interleukin-6 drives skin-derived mesenchymal stem cell trafficking via regulating voltage-gated Ca(2+) channels.

    PubMed

    Ke, Fang; Zhang, Lingyun; Liu, Zhaoyuan; Liu, Jinlin; Yan, Sha; Xu, Zhenyao; Bai, Jing; Zhu, Huiyuan; Lou, Fangzhou; Wang, Hong; Shi, Yufang; Jiang, Yong; Su, Bing; Wang, Honglin

    2014-10-01

    Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential for a variety of diseases including autoimmune disorders. A fundamental requirement for MSC-mediated in vivo immunosuppression is their effective trafficking. However the mechanism underlying MSC trafficking remains elusive. Here we report that skin-derived MSCs (S-MSCs) secrete high levels of interleukin-6 (IL-6) in inflammatory conditions. Disruption of the il6 or its signaling transducer gp130 blocks voltage-gated calcium (Ca(2+) ) channels (VGCC) critically required for cell contraction involved in the sequential adhesion and de-adhesion events during S-MSC migration. Deletion of il6 gene leads to a severe defect in S-MSC's trafficking and immunosuppressive function in vivo. Thus, this unexpected requirement of autocrine IL-6 for activating Ca(2+) channels uncovers a previously unrecognized link between the IL-6 signaling and the VGCC and provides novel mechanistic insights for the trafficking and immunomodulatory activities of S-MSCs.

  15. d(GGGT)4 and r(GGGU)4 are both HIV-1 inhibitors and interleukin-6 receptor aptamers

    PubMed Central

    Magbanua, Eileen; Zivkovic, Tijana; Hansen, Björn; Beschorner, Niklas; Meyer, Cindy; Lorenzen, Inken; Grötzinger, Joachim; Hauber, Joachim; Torda, Andrew E.; Mayer, Günter; Rose-John, Stefan; Hahn, Ulrich

    2013-01-01

    Aptamers are oligonucleotides that bind targets with high specificity and affinity. They have become important tools for biosensing, target detection, drug delivery and therapy. We selected the quadruplex-forming 16-mer DNA aptamer AID-1 [d(GGGT)4] with affinity for the interleukin-6 receptor (IL-6R) and identified single nucleotide variants that showed no significant loss of binding ability. The RNA counterpart of AID-1 [r(GGGU)4] also bound IL-6R as quadruplex structure. AID-1 is identical to the well-known HIV inhibitor T30923, which inhibits both HIV infection and HIV-1 integrase. We also demonstrated that IL-6R specific RNA aptamers not only bind HIV-1 integrase and inhibit its 3′ processing activity in vitro, but also are capable of preventing HIV de novo infection with the same efficacy as the established inhibitor T30175. All these aptamer target interactions are highly dependent on formation of quadruplex structure. PMID:23235494

  16. Human Herpesvirus 8 Viral Interleukin-6 Signaling through gp130 Promotes Virus Replication in Primary Effusion Lymphoma and Endothelial Cells

    PubMed Central

    Cousins, Emily; Gao, Yang; Sandford, Gordon

    2014-01-01

    The contributions of human herpesvirus 8 (HHV-8) viral interleukin-6 (vIL-6) to virus biology remain unclear. Here we examined the role of vIL-6/gp130 signaling in HHV-8 productive replication in primary effusion lymphoma and endothelial cells. Depletion and depletion-complementation experiments revealed that endoplasmic reticulum-localized vIL-6 activity via gp130 and gp130-activated signal transducer and activator of transcription (STAT) signaling, but not extracellular signal-regulated kinase (ERK) activation, was critical for vIL-6 proreplication activity. Our data significantly extend current understanding of vIL-6 function and associated mechanisms in HHV-8 biology. PMID:25078695

  17. Trans-presentation of interleukin-6 by dendritic cells is required for priming pathogenic TH17 cells

    PubMed Central

    Heink, Sylvia; Yogev, Nir; Garbers, Christoph; Herwerth, Marina; Aly, Lilian; Gasperi, Christiane; Husterer, Veronika; Croxford, Andrew L.; Möller-Hackbarth, Katja; Bartsch, Harald S.; Sotlar, Karl; Krebs, Stefan; Regen, Tommy; Blum, Helmut; Hemmer, Bernhard; Misgeld, Thomas; Wunderlich, Thomas F.; Hidalgo, Juan; Oukka, Mohamed; Rose-John, Stefan; Schmidt-Supprian, Marc; Waisman, Ari; Korn, Thomas

    2016-01-01

    The cellular sources of interleukin-6 (IL-6) that are relevant for the differentiation of TH17 cells remain unclear. Here, we used a novel strategy of IL-6 conditional deletion of distinct IL-6-producing cell types to show that Sirpα+ dendritic cells (DC) were essential for the generation of pathogenic TH17 cells. During the process of cognate interaction, Sirpα+ DCs trans-presented IL-6 to T cells using their own IL-6Rα. While ambient IL-6 was sufficient to suppress the induction of the transcription factor Foxp3 in T cells, IL-6 trans-presentation by DC-bound IL-6Rα (here defined as IL-6 cluster signaling) was required to prevent premature induction of IFN-γ in T cells and to generate pathogenic TH17 cells in vivo. These findings will guide therapeutic approaches for TH17-mediated autoimmune diseases. PMID:27893700

  18. Interleukin 6 Is Required for Pancreatic Cancer Progression by Promoting MAPK Signaling Activation and Oxidative Stress Resistance

    PubMed Central

    Zhang, Yaqing; Yan, Wei; Collins, Meredith A.; Bednar, Filip; Rakshit, Sabita; Zetter, Bruce R.; Stanger, Ben Z.; Chung, Ivy; Rhim, Andrew D.; di Magliano, Marina Pasca

    2013-01-01

    Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the step-wise progression of the human disease. The inflammatory cytokine interleukin 6 (IL6) is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL6 synergizes with oncogenic Kras to activate the reactive oxygen species (ROS) detoxification program downstream of the MAPK/ERK signaling cascade. In addition, IL6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL6 emerges as a key player at all stages of pancreatic carcinogenesis, and a potential therapeutic target. PMID:24097820

  19. Interleukin-6 and tumor necrosis factor in the pathogenesis of adverse reactions after treatment of lymphatic filariasis and onchocerciasis.

    PubMed

    Turner, P F; Rockett, K A; Ottesen, E A; Francis, H; Awadzi, K; Clark, I A

    1994-05-01

    Adverse reactions following treatment of onchocerciasis and bancroftian filariasis are common and frequently severe. They are generally caused not by direct drug toxicity but by host inflammatory responses to dying microfilariae. To define the responsible mechanism, serial blood levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were studied in 15 microfilaria-positive patients (10 with bancroftian filariasis, 5 with onchocerciasis) and 4 microfilaria-negative persons after diethylcarbamazine treatment. Elevations in IL-6 correlated with the occurrence and severity of clinical symptoms after treatment; for the onchocerciasis patients IL-6 levels directly reflected pretreatment intensity of infection. Serum TNF levels also rose but did not correlate directly with infection intensity or reaction severity. Microfilaria-negative controls remained asymptomatic with no significant rise in either cytokine. These findings suggest an etiologic role for systemically elevated cytokines in the inflammatory reactions developing after treatment of filarial infections in humans.

  20. Modeling and simulation with Hybrid Functional Petri Nets of the role of interleukin-6 in human early haematopoiesis.

    PubMed

    Troncale, Sylvie; Tahi, Fariza; Campard, David; Vannier, Jean-Pierre; Guespin, Janine

    2006-01-01

    The regulation of human haematopoiesis is a complex biological system with numerous interdependent processes. In vivo Haematopoietic Stem Cells (HSCs) self-renew so as to maintain a constant pool of these cells. It would be very interesting to maintain these cells in vitro, in view of their therapeutical importance. Unfortunately, there is currently no known process to activate HSCs self-renewal in vitro. Since the difficulties related to in vitro experiments, modeling and simulating this process is indispensable. Moreover, the complexity of haematopoiesis makes it necessary to integrate various functionalities: both discrete and continuous models as well as consumption and production of resources. We thus focus on the use of Hybrid Functional Petri Nets, which offer a number of features and flexibility. We begin by modeling and simulating the role of a specific cytokine, interleukin-6, in the regulation of early haematopoiesis. Results obtained in silico lead to the disappearence of HSCs, which is in agreement with in vitro results.

  1. Genetic polymorphisms in metabolizing enzymes modify the association between Smoking and Inflammatory Bowel Diseases

    PubMed Central

    Ananthakrishnan, Ashwin N; Nguyen, Deanna D; Sauk, Jenny; Yajnik, Vijay; Xavier, Ramnik J

    2014-01-01

    Introduction Cigarette smoking is a well established environmental risk factor for Crohn's disease (CD) and ulcerative colitis (UC). The exact mechanism of its effect remains unexplained. Genetic polymorphisms in metabolizing enzymes may influence susceptibility to the effect of smoking and shed light on its mechanism of action. Methods We utilized a prospective cohort of patients with CD, UC, and healthy controls. Smoking status was defined as current, former, or never smoking. Patients were genotyped for polymorphisms in CYP2A6, glutathione transferase enzymes (GSTP1 and GSTM1), NAD(P)H quinone oxidoreductase (NQO), and Heme Oxygenase 1 using a Sequenom platform. Multivariate logistic regression models with CD or UC as the outcome, stratified by genotype were developed and interaction p-values calculated. Results Our study included 634 patients with CD, 401 with UC, and 337 healthy controls. Ever smokers had an increased risk of CD (OR 3.88, 95% CI 2.35 – 6.39) compared to non-smokers among patients with AG/AA genotypes at CYP2A6. However, ever smoking was not associated with CD among patients with the AA genotype (pinteraction 0.001). Former smoking was associated with an increased risk for UC only in the presence of GG/AG genotypes for GSTP1, but not in those with the AA genotype (Pinteraction 0.012). Polymorphisms at the NQO and HMOX loci did not demonstrate a statistically significant interaction with smoking and risk of CD or UC. Conclusion Genetic polymorphisms in metabolizing enzymes may influence the association between smoking and CD and UC. Further studies of gene-environment interaction in IBD are warranted. PMID:24651583

  2. Genetic polymorphisms in metabolizing enzymes modifying the association between smoking and inflammatory bowel diseases.

    PubMed

    Ananthakrishnan, Ashwin N; Nguyen, Deanna D; Sauk, Jenny; Yajnik, Vijay; Xavier, Ramnik J

    2014-05-01

    Cigarette smoking is a well-established environmental risk factor for Crohn's disease (CD) and ulcerative colitis (UC). The exact mechanism of its effect remains unexplained. Genetic polymorphisms in metabolizing enzymes may influence susceptibility to the effect of smoking and shed light on its mechanism of action. We used a prospective cohort of patients with CD, UC, and healthy controls. Smoking status was defined as current, former, or never smoking. Patients were genotyped for polymorphisms in CYP2A6, glutathione transferase enzymes (GSTP1 and GSTM1), NAD(P)H quinone oxidoreductase (NQO), and heme oxygenase 1 using a Sequenom platform. Multivariate logistic regression models with CD or UC as the outcome, stratified by genotype, were developed and interaction P-values calculated. Our study included 634 patients with CD, 401 with UC, and 337 healthy controls. Ever smokers had an increased risk of CD (odds ratio = 3.88, 95% confidence interval = 2.35-6.39) compared with nonsmokers among patients with AG/AA genotypes at CYP2A6. However, ever smoking was not associated with CD among patients with the AA genotype (Pinteraction = 0.001). Former smoking was associated with an increased risk for UC only in the presence of GG/AG genotypes for GSTP1 but not in those with the AA genotype (Pinteraction = 0.012). Polymorphisms at the NQO and HMOX loci did not demonstrate a statistically significant interaction with smoking and risk of CD or UC. Genetic polymorphisms in metabolizing enzymes may influence the association between smoking and CD and UC. Further studies of gene-environment interaction in inflammatory bowel disease are warranted.

  3. HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions

    PubMed Central

    Villaronga, MA; Lavery, DN; Bevan, CL; Llanos, S; Belandia, B

    2012-01-01

    The hairy/enhancer-of-split related with YRPW motif 1 (HEY1) is a member of the basic-helix-loop-helix-Orange (bHLH-O) family of transcriptional repressors that mediate Notch signaling. Several cancer-related pathways also regulate HEY1 expression, and HEY1 itself acts as an indirect positive regulator of the p53 tumor suppressor protein and a negative regulator of androgen receptor activity. In this study we show how a naturally occurring non-synonymous polymorphism at codon 94 of HEY1, which results in a substitution of leucine by methionine (Leu94Met), converts HEY1 from an androgen receptor corepressor to an androgen receptor co-activator without affecting its intrinsic transcriptional repressive domains. The polymorphism Leu94Met also abolishes HEY1-mediated activation of p53 and suppresses the ability of HEY1 to induce p53-dependent cell-cycle arrest and aberrant cell differentiation in human osteosarcoma U2OS cells. Moreover, expression of HEY1, but not of the variant Leu94Met, confers sensitivity to p53-activating chemotherapeutic drugs on U2OS cells. In addition, we have identified motifs in HEY1 that are critical for the regulation of its subcellular localization and analysed how mutations in those motifs affect both HEY1 and HEY1-Leu94Met functions. These findings suggest that the polymorphism Leu94Met in HEY1 radically alters its biological activities and may affect oncogenic processes. PMID:19802006

  4. Polymorphism of Metallothionein 2A Modifies Lead Body Burden in Workers Chronically Exposed to the Metal.

    PubMed

    Fernandes, Kelly Christine Marques; Martins, Airton Cunha; Oliveira, Andréia Ávila Soares de; Antunes, Lusânia Maria Greggi; Cólus, Ilce Mara de Syllos; Barbosa, Fernando; Barcelos, Gustavo Rafael Mazzaron

    2016-01-01

    Lead (Pb) is a metal that accumulates in the human body, inducing several adverse health effects. One of the proteins responsible for the distribution of metal in the body is metallothionein (MT), which is expressed by different genes, and it is supposed that genetic variation in the genes that encode MTs may affect the Pb body burden. The present study aimed to evaluate the genetic effects of the polymorphism of MT2A (single nucleotide polymorphism rs10636; Cx2192;G) on blood Pb levels (BLL) of workers from car battery factories who are chronically exposed to the metal. In total, 221 men participated in the study; genomic DNA from whole blood was extracted, and genotyping of MT2A was performed by TaqMan assays; BLL were quantified by inductively coupled plasma mass spectrometry (ICP-MS). BLL were 25 ± 14 µg/dl (range 1.9-68); BLL were positively correlated with duration of work and smoking status. Individuals who carried at least one C allele had higher BLL than those with the GG genotype (β = -0.45; p = 0.025, multivariable linear regression analyses). Taken together, our data support the hypothesis that polymorphisms in genes related to the transport of Pb, such as MTs, may modulate the concentrations of the metal in the body and, consequently, adverse health effects induced by Pb exposure.

  5. Phenylketonuria is not a risk factor for changes of inflammation status as assessed by interleukin 6 and interleukin 8 concentrations.

    PubMed

    Mozrzymas, Renata; Duś-Żuchowska, Monika; Kałużny, Łukasz; Wenska-Chyży, Ewa; Walkowiak, Jarosław

    2016-01-01

    High oxidative stress and a reduced potential for free radical scavenging in phenylketonuria (PKU) patients, a phenomenon confirmed in a few studies, may lead to systemic chronic inflammation. The aim of this study was to compare the inflammation status, as assessed by interleukin 6 and interleukin 8 concentrations, in patients with PKU and in healthy controls. Twenty patients with classical PKU, aged 18-34 years and under dietary control, were enrolled in the study. The control group comprised of 20 healthy subjects matched for age and sex. Interleukin 6 and 8 levels were measured by enzyme-linked immunosorbent assay (ELISA) kits in all study participants. IL-6 concentrations in the study group ranged from 0.74 pg/ml to 1.34 pg/ml. No significant differences were found between IL-6 concentration between the study group and the control group (p = 0.989). IL-8 concentrations ranged from 17.56 pg/ml to 20.87 pg/ml. The obtained results of IL-8 levels did not differ significantly between the study group and control group (p = 0.192). No significant correlation was observed between Phe blood levels and IL-6 or IL-8 concentrations in the study group (ρ respectively: -0.225, 0.177). In a multivariate analysis, neither IL-6 nor IL-8 concentrations were correlated with sex, age, BMI and Phe levels. Phenylketonuria is not a risk factor for changes of inflammation status as assessed by IL-6 and IL-8 concentrations.

  6. Rare alleles of the HRAS polymorphism do not modify the risk of breast or ovarian cancer in BRCA1 carriers

    SciTech Connect

    Phelan, C.; Tonin, P.; Lynch, H.T.

    1994-09-01

    The presence of one of the rare alleles of a minisatellite polymorphism at the HRAS locus on chromosome 11p15 has been associated with a roughly two-fold increase in the risk of breast cancer. The BRCA1 gene on chromosome 17q12-21 is responsible for the majority of the families with the breast-ovarian cancer syndrome. It is estimated that 87% of BRCA1 carriers will be affected with breast cancer by age 70. The relative risk for premenopausal breast cancer in carriers, compared to non-carriers, is roughly 100. Because of the wide range in ages of onset of cancer among BRCA1 carriers, it is likely that additional factors modify the risk of cancer. The role of other modifying genetic loci has not been studied. Through haplotype analysis we have identified 199 female BRCA1 carriers above the age of 20 years in 25 linked families. 127 of these women have been diagnosed with cancer and 72 are currently healthy. DNA was available on 59 carriers. Each sample was typed for the HRAS polymorphism by PCR, using primers flanking the minisatellite. Rare alleles were identified in 18 carriers. The penetrance of the BRCA1 gene was not higher among those women who carried a rare HRAS allele (mean age of onset 49 years) than among those who carried two common alleles (mean age of onset 43 years) (p= 0.59; log rank test). Similar results were obtained for ovarian cancer. These data do not support the hypothesis that the HRAS locus modified the risk of cancer among carriers of mutations in BRCA1.

  7. Tocilizumab improved clinical symptoms of a patient with systemic tophaceous gout who had symmetric polyarthritis and fever: An alternative treatment by blockade of interleukin-6 signaling

    PubMed Central

    Mokuda, Sho; Kanno, Masamoto; Takasugi, Kiyoshi; Okumura, Chikara; Ito, Yuki

    2014-01-01

    Chronic tophaceous gout is the end stage of gout. We employed a blockade of interleukin-6 signaling therapy by tocilizumab instead of anakinra, an interleukin-1 receptor antagonist, for a 61-year-old Japanese woman diagnosed with tophaceous gout. Laboratory data showed that serum interleukin-6 concentration was elevated. Serum interleukin-1β concentration was under the detectable level, although serum uric acid was elevated due to renal dysfunction. The secretion patterns of interleukin-1β, tumor-necrosis factor-α, interleukin-6, and interleukin-8 from peripheral mononuclear cells isolated from the patient exhibited no remarkable differences compared with those of healthy volunteers. After treatment with the interleukin-6 receptor antagonist tocilizumab, serum interleukin-6 concentration decreased followed by improved clinical symptoms, such as reduced size of the subcutaneous nodules, no fever, and no acute gouty attacks during the treatment. Our case suggests that tocilizumab markedly improves clinical and laboratory manifestations in tophaceous gout with arthritis and fever as well as interleukin-1 blockade therapy. PMID:27489636

  8. The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter

    PubMed Central

    Ma, Yiyi; Smith, Caren E.; Lai, Chao-Qiang; Irvin, Marguerite R.; Parnell, Laurence D.; Lee, Yu-Chi; Pham, Lucia D.; Aslibekyan, Stella; Claas, Steven A.; Tsai, Michael Y.; Borecki, Ingrid B.; Kabagambe, Edmond K.; Ordovás, José M.; Absher, Devin M.; Arnett, Donna K.

    2016-01-01

    Scope Omega-3 PUFAs (n-3 PUFAs) reduce IL-6 gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6. Methods and results Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL-6 plasma concentration (p = 0.03) and greater IL6 gene expression (p = 0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (p = 0.007) and lower IL-6 concentration (p = 0.02). Moreover, an allele of IL6 rs2961298 was associated with higher cg01770232 methylation (p = 2.55 × 10−7). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (p = 0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (p = 0.04) not in the homozygotes. Conclusion Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs. PMID:26518637

  9. [Influence of zinc administered by total parenteral nutrition on plasmatic zinc levels, on reactive C protein, on serum interleukin-6 and on serum interleukin-6 soluble receptor, in critical patients].

    PubMed

    Menéndez, A M; De Portela, M L; Weisstaub, A; Montemerlo, H; Guidoni, M E; Rusí, F; Zeni, S

    2009-01-01

    To study the interrelationship between serum Interleukin-6 (IL-6), serum Interleukin-6 soluble Receptor (IL-6 sR), C-Reactive Protein (C-RP), plasmatic Zinc levels (PlZn) and their response in relation to Zn administered by TPN, in critical patients. 17 patients, receiving TPN as a consequence of acute pancreatitis (n = 4) or after a major abdominal surgery due to intestinal cancer (n = 7), intestinal fístula (n = 3), intestinal obstruction (n = 2) or intestinal íleus (n = 1) were studied. At the beginning (To) and at the end of the TPN administration (6-21 days) serum IL-6 and IL-6 sR were determined by ELISA; C-RP ultrasensitive (C-RP us) by inmunoturbidimetric method; Zn was determined in TPN and in plasma by Atomic Absorption Spectrometry. Characteristics of the patients were (mean +/- SD and ranges): age: 60.6 +/- 11.7 (37-77) years; BMI (kg/m(2)): 26.0 +/- 3.4 (19.9-34.0). The results (mean +/- standard deviation and ranges) were: Zn provided by TPN (mg/d): 6.1 +/- 2.0 (range 2.8 to 10.8). Biochemical levels were, at To and Tf, respectively: (mean+/-SD and ranges) were at To y Tf, respectively: Zn Pl (microg/dl): 104 +/- 46 (35-177); 120 +/- 55 (52-229); IL-6 (pg/mL) 93 +/- 74 (10-262); 117 +/- 180 (7-761); IL6sR (pg/mL): 1,012 +/- 322 (589-1855); 1,269 +/- 451 (631-2195); C-RP us (mg/L): 71 +/- 63 (2-196); 65 +/- 43 (0-137). There was no correlation between variations of IL6, IL6sR, C-RP, PlZn levels and the daily amount of Zn administered in the TPN mixtures. Two patients presented a bad evolution; they received 4.2 and 5.2 md/d of Zn and showed an increase of IL6 levels, maintained high levels of IL6sR but C-RP levels decreased. the range of 2.8 to 10.8 mg/d of Zn administered in TPN mixtures did not exacerbate the inflammatory response.

  10. Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension

    PubMed Central

    González, Germán E.; Rhaleb, Nour-Eddine; D’ambrosio, Martin A.; Nakagawa, Pablo; Liu, Yunhe; Leung, Pablo; Dai, Xiangguo; Yang, Xiao-Ping; Peterson, Edward L.; Carretero, Oscar A.

    2014-01-01

    Objective Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II). Methods Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks. Results Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio. Conclusion In conclusion, absence of interleukin -6 did not alter the development of Ang II-high salt-induced hypertension and cardiac hypertrophy, but it prevented the development of cardiac dysfunction, myocardial inflammation, and fibrosis. This indicates that interleukin-6 plays an important role in hypertensive heart damage but not in the development of hypertension. PMID:25304471

  11. Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension.

    PubMed

    González, Germán E; Rhaleb, Nour-Eddine; D'Ambrosio, Martin A; Nakagawa, Pablo; Liu, Yunhe; Leung, Pablo; Dai, Xiangguo; Yang, Xiao-Ping; Peterson, Edward L; Carretero, Oscar A

    2015-01-01

    Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II). Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks. Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio. In conclusion, absence of interleukin -6 did not alter the development of Ang II-high salt-induced hypertension and cardiac hypertrophy, but it prevented the development of cardiac dysfunction, myocardial inflammation, and fibrosis. This indicates that interleukin-6 plays an important role in hypertensive heart damage but not in the development of hypertension.

  12. Correlates of elevated interleukin-6 and C-reactive protein in persons with or at high-risk for HCV and HIV infections

    PubMed Central

    Salter, Megan L.; Lau, Bryan; Mehta, Shruti H.; Go, Vivian F.; Leng, Sean; Kirk, Gregory D.

    2013-01-01

    Background HIV and HCV infections may increase interleukin-6 (IL-6) and C-reactive protein (CRP). However, relationships between inflammatory biomarkers, chronic viral infections, clinical factors, and behavioral factors remain poorly understood. Methods Using linear regression, we modeled cross-sectional associations between loge IL-6 or loge CRP levels and HCV, HIV, injection drug use, and comorbidity among 1191 injection drug users. Results Mean age was 47 years, 46.0% reported currently injecting drugs, 59.0% were HCV-monoinfected, and 27% were HCV/HIV-coinfected. In multivariable models, higher loge IL-6 was associated with HCV monoinfection (β=0.191, 95%CI: 0.043 to 0.339) and HCV/HIV coinfection (β=0.394, 95% CI: 0.214 to 0.574). In contrast, HCV monoinfection (β=−0.523, 95%CI: −0.275 to −0.789) and HCV/HIV coinfection (β=−0.554 95%CI: −0.260 to −0.847) were associated with lower CRP. Lower CRP with HCV infection was independent of liver fibrosis severity, synthetic function, or liver injury markers; CRP decreased with higher HCV RNA. Increased injection intensity was associated with higher IL-6 (p=0.003) and CRP (p<0.001); increasing comorbidity (p<0.001) and older age (p=0.028) were associated with higher IL-6; older age was associated with higher CRP among HCV-uninfected participants (p=0.021). Conclusion HIV and HCV infections contribute to chronic inflammation; however, reduced CRP possibly occurs through HCV-virally-mediated mechanisms. Findings highlight potentially modifiable contributors to inflammation. PMID:23978997

  13. Glutamine effects on heat shock protein 70 and interleukines 6 and 10: Randomized trial of glutamine supplementation versus standard parenteral nutrition in critically ill children.

    PubMed

    Jordan, Iolanda; Balaguer, Mònica; Esteban, M Esther; Cambra, Francisco José; Felipe, Aida; Hernández, Lluïsa; Alsina, Laia; Molero, Marta; Villaronga, Miquel; Esteban, Elisabeth

    2016-02-01

    To determine whether glutamine (Gln) supplementation would have a role modifying both the oxidative stress and the inflammatory response of critically ill children. Prospective, randomized, double-blind, interventional clinical trial. Selection criteria were children requiring parenteral nutrition for at least 5 days diagnosed with severe sepsis or post major surgery. Patients were randomly assigned to standard parenteral nutrition (SPN, 49 subjects) or standard parenteral nutrition with glutamine supplementation (SPN + Gln, 49 subjects). Glutamine levels failed to show statistical differences between groups. At day 5, patients in the SPN + Gln group had significantly higher levels of HSP-70 (heat shock protein 70) as compared with the SPN group (68.6 vs 5.4, p = 0.014). In both groups, IL-6 (interleukine 6) levels showed a remarkable descent from baseline and day 2 (SPN: 42.24 vs 9.39, p < 0.001; SPN + Gln: 35.20 vs 13.80, p < 0.001) but only the treatment group showed a statistically significant decrease between day 2 and day 5 (13.80 vs 10.55, p = 0.013). Levels of IL-10 (interleukine 10) did not vary among visits except in the SPN between baseline and day 2 (9.55 vs 5.356, p < 0.001). At the end of the study, no significant differences between groups for PICU and hospital stay were observed. No adverse events were detected in any group. Glutamine supplementation in critically-ill children contributed to maintain high HSP-70 levels for longer. Glutamine supplementation had no influence on IL-10 and failed to show a significant reduction of IL-6 levels. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  14. Interleukin-6 and risk of colorectal cancer: results from the CLUE II cohort and a meta-analysis of prospective studies.

    PubMed

    Kakourou, Artemisia; Koutsioumpa, Charalampia; Lopez, David S; Hoffman-Bolton, Judith; Bradwin, Gary; Rifai, Nader; Helzlsouer, Kathy J; Platz, Elizabeth A; Tsilidis, Konstantinos K

    2015-10-01

    The association between prediagnostic interleukin-6 (IL-6) concentrations and risk of colorectal cancer was evaluated in a nested case-control study and a meta-analysis of prospective studies. Colorectal cancer cases (n = 173) and matched controls (n = 345) were identified between 1989 and 2000 among participants in the CLUE II cohort of Washington Country, Maryland. Matched odds ratios and the corresponding 95 % confidence intervals (CIs) were estimated using conditional logistic regression models. Participants in the highest third of plasma IL-6 concentration had a 2.48 times higher risk of colon cancer compared to participants in the bottom third (95 % CI 1.26-4.87; p-trend 0.02) after multivariate adjustment. This association did not differ according to the stage of disease, age, sex, or other potential modifying variables and remained statistically significant after adjustment for C-reactive protein concentrations. No statistically significant association was observed for rectal cancer risk. The meta-analysis of six prospective studies yielded an increased but borderline statistically significant risk of colon cancer per 1 U increase in naturally logarithm-transformed IL-6 (summary RR 1.22; 95 % CI 1.00-1.49; I (2) 46 %). An inverse association was noted for rectal cancer (RR 0.69; 95 % CI 0.54-0.88; I (2) 0 %), but there was evidence for small-study effects (p 0.02). Our findings provide support for a modest positive association between IL-6 concentrations and colon cancer risk. More work is needed to determine whether IL-6 is a valid marker of colorectal inflammation and whether such inflammation contributes to colon and rectal cancer risk.

  15. Renin-angiotensin system gene polymorphisms as potential modifiers of hypertrophic and dilated cardiomyopathy phenotypes.

    PubMed

    Rani, Bindu; Kumar, Amit; Bahl, Ajay; Sharma, Rajni; Prasad, Rishikesh; Khullar, Madhu

    2017-03-01

    The renin-angiotensin (RAS) pathway has an important role in the etiology of heart failure and given the importance of RAS as a therapeutic target in various cardiomyopathies, genetic polymorphisms in the RAS genes may modulate the risk and severity of disease in cardiomyopathy patients. In the present study, we examined the association of RAS pathway gene polymorphisms, angiotensin converting enzyme (ACE), angiotensinogen (AGT), and angiotensin receptor type 1 (AGTR1) with risk and disease severity in Asian Indian idiopathic cardiomyopathy patients. The case-control study was conducted in 400 cardiomyopathy patients diagnosed with HCM, DCM, or restrictive cardiomyopathy (RCM) and 235 healthy controls. Genotyping of patients and controls was done by PCR-RFLP assays. Left ventricular wall thickness and left ventricular ejection fraction were measured by means of M-mode echocardiography. We observed significantly higher prevalence of ACE DD and AGTR1 1166CC genotypes in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) patients. Also, 235TT genotype of AGT (M235T) was significantly associated with enhanced risk of the disease phenotype in HCM, DCM, and RCM.

  16. The longitudinal relationship between circulating concentrations of C-reactive protein, interleukin-6 and interleukin-10 in patients undergoing resection for renal cancer.

    PubMed

    Ramsey, S; Lamb, G W A; Aitchison, M; McMillan, D C

    2006-10-23

    The systemic inflammatory response, as evidenced by elevated circulating concentrations of C-reactive protein, is a stage-independent prognostic factor in patients undergoing curative nephrectomy for localised renal cancer. However, it is not clear whether the systemic inflammatory response arises from the tumour per se or as a result of an impaired immune cytokine response. The aim of the present study was to examine C-reactive protein, interleukin-6 and interleukin-10 concentrations before and following curative resection of renal cancer. Sixty-four patients with malignant renal disease and 12 with benign disease, undergoing resection were studied. Preoperatively, a blood sample was collected for routine laboratory analysis with a further sample stored before analysis of interleukin-6 and interleukin-10 using an enzyme-linked immunosorbent assay (ELISA) technique. The blood sampling procedure and analyses were repeated at approximately 3 months following resection. Circulating concentrations of both interleukin-6 and interleukin (P< or =0.01) were higher and a greater proportion were elevated (P<0.05) in malignant compared with benign disease. The renal cancer patients were grouped according to whether they had evidence of a systemic inflammatory response. In the inflammatory group T stage was higher (P<0.01), both interleukin-6 and interleukin-10 concentrations were higher (P<0.001) and elevated (P<0.10) compared with the non-inflammatory group. Tumour volume was weakly correlated with C-reactive protein (r(2)=0.20, P=0.002), interleukin-6 (r(2)=0.20, P=0.002) and interleukin-10 (r(2)=0.24, P=0.001). Following nephrectomy the proportion of patients with elevated C-reactive protein, interleukin-6 and interleukin-10 concentrations did not alter significantly. An elevated preoperative C-reactive protein was associated with increased tumour stage, interleukin-6 and interleukin-10 concentrations. However, resection of the primary tumour did not appear to be

  17. The longitudinal relationship between circulating concentrations of C-reactive protein, interleukin-6 and interleukin-10 in patients undergoing resection for renal cancer

    PubMed Central

    Ramsey, S; Lamb, G W A; Aitchison, M; McMillan, D C

    2006-01-01

    The systemic inflammatory response, as evidenced by elevated circulating concentrations of C-reactive protein, is a stage-independent prognostic factor in patients undergoing curative nephrectomy for localised renal cancer. However, it is not clear whether the systemic inflammatory response arises from the tumour per se or as a result of an impaired immune cytokine response. The aim of the present study was to examine C-reactive protein, interleukin-6 and interleukin-10 concentrations before and following curative resection of renal cancer. Sixty-four patients with malignant renal disease and 12 with benign disease, undergoing resection were studied. Preoperatively, a blood sample was collected for routine laboratory analysis with a further sample stored before analysis of interleukin-6 and interleukin-10 using an enzyme-linked immunosorbent assay (ELISA) technique. The blood sampling procedure and analyses were repeated at approximately 3 months following resection. Circulating concentrations of both interleukin-6 and interleukin (P⩽0.01) were higher and a greater proportion were elevated (P<0.05) in malignant compared with benign disease. The renal cancer patients were grouped according to whether they had evidence of a systemic inflammatory response. In the inflammatory group T stage was higher (P<0.01), both interleukin-6 and interleukin-10 concentrations were higher (P<0.001) and elevated (P<0.10) compared with the non-inflammatory group. Tumour volume was weakly correlated with C-reactive protein (r2=0.20, P=0.002), interleukin-6 (r2=0.20, P=0.002) and interleukin-10 (r2=0.24, P=0.001). Following nephrectomy the proportion of patients with elevated C-reactive protein, interleukin-6 and interleukin-10 concentrations did not alter significantly. An elevated preoperative C-reactive protein was associated with increased tumour stage, interleukin-6 and interleukin-10 concentrations. However, resection of the primary tumour did not appear to be associated with

  18. Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention.

    PubMed

    Zhao, Min; Wang, Xiaobin; He, Mingli; Qin, Xianhui; Tang, Genfu; Huo, Yong; Li, Jianping; Fu, Jia; Huang, Xiao; Cheng, Xiaoshu; Wang, Binyan; Hou, Fan Fan; Sun, Ningling; Cai, Yefeng

    2017-05-01

    Elevated blood homocysteine concentration increases the risk of stroke, especially among hypertensive individuals. Homocysteine is largely affected by the methylenetetrahydrofolate reductase C677T polymorphism and folate status. Among hypertensive patients, we aimed to test the hypothesis that the association between homocysteine and stroke can be modified by the methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention. We analyzed the data of 20 424 hypertensive adults enrolled in the China Stroke Primary Prevention Trial. The participants, first stratified by methylenetetrahydrofolate reductase genotype, were randomly assigned to receive double-blind treatments of 10-mg enalapril and 0.8-mg folic acid or 10-mg enalapril only. The participants were followed up for a median of 4.5 years. In the control group, baseline log-transformed homocysteine was associated with an increased risk of first stroke among participants with the CC/CT genotype (hazard ratio, 3.1; 1.1-9.2), but not among participants with the TT genotype (hazard ratio, 0.7; 0.2-2.1), indicating a significant gene-homocysteine interaction (P=0.008). In the folic acid intervention group, homocysteine showed no significant effect on stroke regardless of genotype. Consistently, folic acid intervention significantly reduced stroke risk in participants with CC/CT genotypes and high homocysteine levels (tertile 3; hazard ratio, 0.73; 0.55-0.97). In Chinese hypertensive patients, the effect of homocysteine on the first stroke was significantly modified by the methylenetetrahydrofolate reductase C677T genotype and folic acid supplementation. Such information may help to more precisely predict stroke risk and develop folic acid interventions tailored to individual genetic background and nutritional status. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885. © 2017 American Heart Association, Inc.

  19. Interleukins 6 and 8 and abdominal fat depots are distinct correlates of lipid moieties in healthy pre- and postmenopausal women.

    PubMed

    Veldhuis, Johannes D; Dyer, Roy B; Trushin, Sergey A; Bondar, Olga P; Singh, Ravinder J; Klee, George G

    2016-12-01

    Available data associate lipids concentrations in men with body mass index, anabolic steroids, age, and certain cytokines. Data were less clear in women, especially across the full adult lifespan, and when segmented by premenopausal and postmenopausal status. 120 healthy women (60 premenopausal and 60 postmenopausal) in Olmsted County, MN, USA, a stable well studied clinical population. Dependent variables: measurements of 10 h fasting high-density lipoprotein cholesterol, total cholesterol, low-density lipoprotein cholesterol, and triglycerides. testosterone, estrone, estradiol, 5-alpha-dihydrotestosterone, and sex-hormone binding globulin (by mass spectrometry); insulin, glucose, and albumin; abdominal visceral, subcutaneous, and total abdominal fat [abdominal visceral fat, subcutaneous fat, total abdominal fat by computerized tomography scan]; and a panel of cytokines (by enzyme-linked immunosorbent assay). Multivariate forward-selection linear-regression analysis was applied constrained to P < 0.01. Lifetime data: High-density lipoprotein cholesterol was correlated jointly with age (P < 0.0001, positively), abdominal visceral fat (P < 0.0001, negatively), and interleukin-6 (0.0063, negatively), together explaining 28.1 % of its variance (P = 2.3 × 10(-8)). Total cholesterol was associated positively with multivariate age only (P = 6.9 × 10(-4), 9.3 % of variance). Triglycerides correlated weakly with sex-hormone binding globulin (P = 0.0115), and strongly with abdominal visceral fat (P < 0.0001), and interleukin-6 (P = 0.0016) all positively (P = 1.6 × 10(-12), 38.9 % of variance). Non high-density lipoprotein cholesterol and low-density lipoprotein cholesterol correlated positively with both total abdominal fat and interleukin-8 (P = 2.0 × 10(-5), 16.9 % of variance; and P = 0.0031, 9.4 % of variance, respectively). Premenopausal vs. postmenopausal comparisons identified specific

  20. The V471A Polymorphism in Autophagy-Related Gene ATG7 Modifies Age at Onset Specifically in Italian Huntington Disease Patients

    PubMed Central

    Metzger, Silke; Walter, Carolin; Riess, Olaf; Roos, Raymund A. C.; Nielsen, Jørgen E.; Craufurd, David; Nguyen, Huu Phuc

    2013-01-01

    The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis. PMID:23894380

  1. The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients.

    PubMed

    Metzger, Silke; Walter, Carolin; Riess, Olaf; Roos, Raymund A C; Nielsen, Jørgen E; Craufurd, David; Nguyen, Huu Phuc

    2013-01-01

    The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

  2. Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder.

    PubMed

    Ruhé, Henricus G; Ooteman, Wendy; Booij, Jan; Michel, Martin C; Moeton, Martina; Baas, Frank; Schene, Aart H

    2009-01-01

    In major depressive disorder, selective serotonin reuptake inhibitors target the serotonin transporter (SERT). Their response rates (30-50%) are modified by SERT promotor polymorphisms (5-HTTLPR). To quantify the relationship between SERT occupancy and response, and whether 5-HTTLPR is a modifier. Drug-free depressed outpatients (n=49; both sexes; aged 25-55 years), received paroxetine (20 mg/day). We quantified SERT occupancy with iodine-123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single-photon emission computed tomography imaging at baseline and after 6 weeks; we genotyped 5-HTTLPR (S, L(G), L(A)). percentage decrease in 17-item Hamilton Depression Rating Scale and response (> or =50% decrease of 17-item Hamilton Depression Rating Scale). A significant positive relationship between SERT occupancy and clinical response existed only in the L(A)/L(A) genotype (P<0.002). Relative to paroxetine serum concentrations maximal midbrain SERT occupancy was numerically higher for L(A)/L(A) compared with other genotypes, but this difference was nonsignificant (P=0.188). Higher SERT occupancy is only associated with more clinical improvement in the L(A)/L(A) genotype. We hypothesize that the L(A)/L(A) carriers have a more dynamic serotonergic system, which seems more responsive to selective serotonin reuptake inhibitors. (ISRCTN Trial Register ISRCTN44111488; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=193).

  3. Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease.

    PubMed

    Côté, Nancy; Mahmut, Ablajan; Fournier, Dominique; Boulanger, Marie-Chloé; Couture, Christian; Després, Jean-Pierre; Trahan, Sylvain; Bossé, Yohan; Pagé, Sylvain; Pibarot, Philippe; Mathieu, Patrick

    2014-01-01

    Calcific aortic valve disease (CAVD) is a chronic disorder characterized by the mineralization of the aortic valve and involving fibrosis. In this work we sought to determine if the fibrotic component of the remodeling process of CAVD was related to the use of angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). In 477 patients with CAVD, the aortic valve was examined by histology. A semiquantitative score of fibrosis was generated and associations with clinical/cardiometabolic variables examined. In a subset of 103 patients the aortic valve was available to study the infiltration by inflammatory cells and expression of interleukin-6 (IL-6) by quantitative real-time PCR. The fibrosis score of the aortic valve was independently related to the hemodynamic severity of CAVD measured by echocardiography. The fibrotic score of the aortic valve was also related to the expression of IL-6. The use of ARBs but not of ACEi was associated with a lower fibrosis score of the aortic valve even after correction for covariates. In addition, patients under ARBs had lower aortic valve inflammation and expression of IL-6. These findings suggest that ARBs may alter the fibrotic process of the aortic valve in CAVD, possibly by lowering tissue inflammation. Copyright © 2013 S. Karger AG, Basel.

  4. LLL12 inhibits endogenous and exogenous interleukin-6-induced STAT3 phosphorylation in human pancreatic cancer cells.

    PubMed

    Liu, Aiguo; Liu, Yan; Li, Pui-Kai; Li, Chenglong; Lin, Jiayuh

    2011-06-01

    Pancreatic cancer is one of the most serious types of cancer, with a five-year survival rate at only 6%. There is a critical need to develop more effective treatments for pancreatic cancer. Growing evidence shows that chronic inflammation plays a crucial role in tumor initiation and progression. Here we demonstrated that the endogenous expression of the inflammatory cytokine interleukin-6 (IL-6) correlates with signal transducer and activator of transcription 3 (STAT3) phosphorylation in human pancreatic cancer cells. Inhibition of the endogenous IL-6/STAT3 pathway reduces cell viability. Exogenous IL-6 induces STAT3 phosphorylation, but differently induces phosphorylation of STAT3 upstream kinases, Janus kinase 1(JAK1), JAK2, and tyrosine kinase 2 (TYK2). Interestingly, LLL12, a nonpeptide, cell-permeable small molecule, selectively blocked exogenous IL-6-induced STAT3 phosphorylation and nuclear translocation in both PANC-1 and ASPC-1 pancreatic cancer cell lines independently of the phosphorylation of JAK1, JAK2, and TYK2. These results suggest that the inhibition of endogenous and exogenous IL-6-mediated STAT3 signaling may be a potential therapeutic approach for pancreatic cancer.

  5. Muscle-specific interleukin-6 deletion influences body weight and body fat in a sex-dependent manner.

    PubMed

    Ferrer, Beatriz; Navia, Belén; Giralt, Mercedes; Comes, Gemma; Carrasco, Javier; Molinero, Amalia; Quintana, Albert; Señarís, Rosa M; Hidalgo, Juan

    2014-08-01

    Interleukin-6 (IL-6) is a major cytokine controlling not only the immune system but also basic physiological variables such as body weight and metabolism. While central IL-6 is clearly implicated in the latter, the putative role of peripheral IL-6 controlling body weight remains unclear. We herewith report results obtained in muscle-specific IL-6 KO (mIL-6