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Sample records for interleukin-6 polymorphisms modify

  1. 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

  2. Interleukin-6 Receptor Polymorphisms Contribute to the Neurological Status of Korean Patients with Ischemic Stroke.

    PubMed

    Kim, Dong Hwan; Yoo, Seung Don; Chon, Jinmann; Yun, Dong Hwan; Kim, Hee-Sang; Park, Hae Jeong; Kim, Su Kang; Chung, Joo-Ho; Kang, Jin Kyu; Lee, Seung Ah

    2016-03-01

    To investigate the contribution of the interleukin-6 receptor (IL-6R) gene single nucleotide polymorphisms (SNPs) to the neurological status of Korean patients with ischemic stroke (IS), two SNPs of the IL-6R gene (rs4845617, 5 UTR; rs2228144, Ala31Ala) were selected. IS patients were classified into clinical phenotypes according to two well-defined scores: the National Institutes of Health Stroke Survey (NIHSS) and the Modified Barthel Index scores. There were 121 IS patients and 291 control subjects. The SNP rs4845617 significantly contributed to the neurological status of patients with IS (P = 0.011 in codominant model 2, P = 0.006 in recessive model, and P = 0.008 in log-additive model). Allele frequencies of rs4845617 and rs2228144 demonstrated no significant difference in IS patients and controls. The AG and GG haplotypes differed between the NIHSS 1 (NIHSS scores < 6) group and the NIHSS 2 (NIHSS scores ≥ 6) group in patients with IS (P = 0.014, P = 0.0024). These results suggest that rs4845617 of the IL-6R gene is associated with the neurologic status of Korean patients with IS. PMID:26955245

  3. Interleukin-6 Receptor Polymorphisms Contribute to the Neurological Status of Korean Patients with Ischemic Stroke

    PubMed Central

    Yoo, Seung Don; Chon, Jinmann; Yun, Dong Hwan; Kim, Hee-Sang; Park, Hae Jeong; Kim, Su Kang; Chung, Joo-Ho; Kang, Jin Kyu

    2016-01-01

    To investigate the contribution of the interleukin-6 receptor (IL-6R) gene single nucleotide polymorphisms (SNPs) to the neurological status of Korean patients with ischemic stroke (IS), two SNPs of the IL-6R gene (rs4845617, 5 UTR; rs2228144, Ala31Ala) were selected. IS patients were classified into clinical phenotypes according to two well-defined scores: the National Institutes of Health Stroke Survey (NIHSS) and the Modified Barthel Index scores. There were 121 IS patients and 291 control subjects. The SNP rs4845617 significantly contributed to the neurological status of patients with IS (P = 0.011 in codominant model 2, P = 0.006 in recessive model, and P = 0.008 in log-additive model). Allele frequencies of rs4845617 and rs2228144 demonstrated no significant difference in IS patients and controls. The AG and GG haplotypes differed between the NIHSS 1 (NIHSS scores < 6) group and the NIHSS 2 (NIHSS scores ≥ 6) group in patients with IS (P = 0.014, P = 0.0024). These results suggest that rs4845617 of the IL-6R gene is associated with the neurologic status of Korean patients with IS. PMID:26955245

  4. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults.

    PubMed

    Kilpinen, S; Hulkkonen, J; Wang, X Y; Hurme, M

    2001-03-01

    .02); respective median values were 6.3 pg/ml (2.2-12.9) and 2.7 pg/ml (1.7-4.1). These findings were also supported when in vitro IL-6 production by neonatal mononuclear cells was compared carriers of the G allele and non-carriers of the G allele. IL-6 levels were significantly lower in carriers of the G allele than in non-carriers (p < 0.04); respective median values were 6,980 pg/ml (4,175-16,800) and 17,425 pg/ml (11,400-33,900). In vivo or in vitro production of IL-6 of adult controls was not associated with the IL-6 -174 polymorphism. The difference between cord blood IL-6 levels after VD and after ECS suggests that normal labour-related stress induces IL-6 production. Our data also suggest that the -174 polymorphism of the IL-6 gene participates in the regulation of IL-6 responses in both groups of neonates. Furthermore, the naive IL-6 response of stimulated neonatal cells is associated with the -174 polymorphism of the IL-6 gene. In healthy adults, the regulation of IL-6 responses differs from that of healthy neonates, since baseline and inducible IL-6 levels in adults were not associated with this polymorphism. This indicates that the genetic regulation of IL-6 production can be observed in naive cells, while in adult cells previous contact with exogenous antigens probably modifies their responses. PMID:11282548

  5. Interleukin-6 promoter polymorphism interacts with pain and life stress influencing depression phenotypes.

    PubMed

    Kovacs, David; Eszlari, Nora; Petschner, Peter; Pap, Dorottya; Vas, Szilvia; Kovacs, Peter; Gonda, Xenia; Bagdy, Gyorgy; Juhasz, Gabriella

    2016-05-01

    Interleukin-6 (IL-6) has emerged as a potent biomarker for depression as its elevated plasma levels in patients with clinical depression have been confirmed by meta-analyses. Increased plasma IL-6 concentration was associated with various psychological stress factors and physical disorders accompanied by pain. Another modulator of the IL-6 level is rs1800795, a promoter polymorphism in the IL-6 gene which is able to influence its expression rate. Therefore, we examined in a Hungarian population sample of 1053 volunteers with European origins if rs1800795 polymorphism can affect depression symptoms measured by Zung Self-rating Depression Scale (ZSDS), and Brief Symptom Inventory (BSI). We also investigated the interactions of the polymorphism with reported painful physical conditions and Recent Negative Life Events (RLE) measured by the List of Life Threatening Experiences. Rs1800795 significantly interacted with both RLE and painful condition on depressive symptoms measured by ZSDS and BSI using different heritability models, while no main effects of the polymorphism were identified. After correction for multiple testing only the rs1800795 × RLE interaction effect (recessive model) remained significant on the BSI score, while both RLE and painful conditions significantly interacted on the ZSDS. In conclusion, the functional IL-6 rs1800795 polymorphism in interaction with various stress factors increases the risk of depression and has a greater impact on symptoms measured by the ZSDS. Thus, IL-6 and other cytokines may be more relevant in the development of somatic symptoms compared to affective signs of depression, delineating a specific genotype-phenotype relationship in this heterogeneous disorder. PMID:26821321

  6. The association between sex-related interleukin-6 gene polymorphisms and the risk for cerebral palsy

    PubMed Central

    2014-01-01

    Background The relationship between genetic factors and the development of cerebral palsy (CP) has recently attracted much attention. Polymorphisms in the genes encoding proinflammatory cytokines have been shown to be associated with susceptibility to perinatal brain injury and development of CP. Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a pivotal role in neonatal brain injury, but conflicting results have been reported regarding the association between IL-6 single nucleotide polymorphisms (SNPs) and CP. The purpose of this study was to analyze IL-6 gene polymorphisms and protein expression and to explore the role of IL-6 in the Chinese CP population. Methods A total of 753 healthy controls and 713 CP patients were studied to detect the presence of five SNPs (rs1800796, rs2069837, rs2066992, rs2069840, and rs10242595) in the IL-6 locus. Of these, 77 healthy controls and 87 CP patients were selected for measurement of plasma IL-6 by Luminex assay. The SHEsis program was used to analyze the genotyping data. For all comparisons; multiple testing on each individual SNP was corrected by the SNPSpD program. Results There were no differences in allele or genotype frequencies between the overall CP patients and controls among the five genetic polymorphisms. However, subgroup analysis found significant sex-related differences in allele and genotype frequencies. Differences were found between spastic CP and controls in males for rs2069837; between CP with periventricular leukomalacia and controls in males for rs1800796 and rs2066992; and between term CP and controls in males for rs2069837. Plasma IL-6 levels were higher in CP patients than in the controls, and this difference was more robust in full-term male spastic CP patients. Furthermore, the genotype has an effect on IL-6 synthesis. Conclusions The influence of IL-6 gene polymorphisms on IL-6 synthesis and the susceptibility to CP is related to sex and gestational age. PMID:24903966

  7. 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

  8. Association of interleukin-6 polymorphisms with obesity and metabolic alterations in young Saudi population.

    PubMed

    Alharbi, Khalid Khalaf; Syed, Rabbani; Khan, Imran Ali

    2014-03-01

    Rising levels of obesity are a global problem that is being exported from affluent to developing nations through the gradual "westernization of lifestyle". Population of Saudi Arabia is going through a nutrition transition where customary and traditional food is being replaced by fast food high in fat, sugar and salt. Interleukin-6 (IL-6) is a central player in the regulation of inflammation, haematopoiesis, immune response and host defense mechanisms. During the last decade, an accumulating amount of data suggested a pivotal role for IL-6 in metabolic processes, thus fortifying the picture of IL-6 as a multifaceted, pleiotropic cytokine. The Objective is to investigate the relationship between IL-6 (rs1554606) polymorphism and the risk of obesity in young Saudi population. Totally 204 Saudi young obese subjects were involved in this study. Genotyping of IL-6 was performed by the real-time polymerase chain reaction technology, using the Taq Man 5'-allele discrimination assay. IL-6 (rs1554606) AA versus AG (p < 0.01) and AA versus GG (p < 0.01) shows significant difference between Male and female group in genotypic as well as allelic distribution differ significantly, while AG versus GG did not differ significantly (p > 0.5). We have observed significant effects for Genotyping, LDL, CHOL, AST, ALP, BILIT, BMI at 5% (0.05) significance level in the study population. Our results shown that IL-6 polymorphism have significantly differ in both male and females subjects. We have observed that some evidence of interactions of the IL-6 polymorphism and have shown statistical significant association with elevated BMI, Lipid profile and total bilurubin in the study subjects. PMID:24395296

  9. 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

  10. 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

  11. The Role of Interleukin-6 and Interleukin-8 Gene Polymorphisms in Non-Alcoholic Steatohepatitis

    PubMed Central

    Cengiz, Mustafa; Yasar, Demet Gokalp; Ergun, Mehmet Ali; Akyol, Gulen; Ozenirler, Seren

    2014-01-01

    Background: Genetic polymorphisms may play role in the pathophysiology of nonalcoholic steatohepatitis (NASH). Objectives: We purposed to assess the role of interleukin 6 (IL 6) and interleukin 8 (IL 8) gene polymorphisms in the pathogenesis of NASH. Patients and Methods: Consecutive patients with biopsy proven NASH and age- and gender-matched healthy individuals with normal liver function tests and normal ultrasonography were enrolled in the study. Histopathological findings were recorded according to nonalcoholic fatty liver disease activity score (NAS). Patients were classified according to fibrosis scores as fibrosis score < 2 (mild fibrosis group) and fibrosis score ≥ 2 (significant fibrosis group). Blood samples were collected and genomic DNA isolation kit was used to evaluate genetic polymorphisms. Results: Of thirty-eight patients, 27 (71%) were in mild fibrosis group and 11 (29%) in significant fibrosis group. Thirty-eight age- and gender-matched healthy controls were enrolled in the study. The frequencies of genotypes G/C and G/G of IL 6 among the NASH group and healthy controls were 39.5% and 60.5% vs. 53.6% and 46.4%, respectively (P = 0.32). The frequencies of the genotypes of IL 8 among the NASH group were 47.2%, 44.6%, and 8.2% for T/T, A/T, and A/A, and in healthy controls were 50%, 28.6% and 21.4%, respectively, (P = 0.568). The differences between IL 8 gene T/A and T/T genotypes were not significant statistically (P > 0.05). However, the frequency of A/A genotype in significant fibrosis group was higher than the mild fibrosis group (P = 0.0016). The differences of -251 A/T polymorphism in the IL 8 and -174 C/G polymorphism in the IL 6 were not statistically significant between fibrosis groups (P > 0.05). Conclusions: IL6 and IL8 gene polymorphisms have no role in NASH pathogenesis and liver fibrosis process, but presence of the A/A genotype in the IL8 gene is associated with disease progression. PMID:25737730

  12. Outcome of orthodontic mini-implant loss in relation to interleukin 6 polymorphisms.

    PubMed

    Reichow, A M; Melo, A C; de Souza, C M; Castilhos, B B; Olandoski, M; Alvim-Pereira, C C K; Alvim-Pereira, F; Trevilatto, P C

    2016-05-01

    Mini-implants (MIs) are used increasingly for orthodontic anchorage and their success may require some osseointegration, which is affected by the underlying host immune-inflammatory response. Interleukin 6 (IL-6) is a cytokine expressed during the host response after a trauma or infection. The aim of this study was to investigate the association of clinical characteristics and IL6 tag single nucleotide polymorphisms (which capture the information of the whole gene in terms of genetic variability) with the loss of MIs for orthodontic anchorage. A total of 487 patients were treated with orthodontic MIs between 2004 and 2010. After the application of inclusion and exclusion criteria, the sample comprised 104 patients with one or more MIs that had been in function for at least 6 months with no loss, and 31 patients who had lost one or more MIs. Allele A of rs2069843 and allele T of rs2069849 were suggestively associated with the loss of MIs for orthodontic anchorage and were in complete linkage disequilibrium, which means that one of them is sufficient to capture the same information. The location of installation (mandible) and the number of MIs installed per patient were also associated with the loss of MIs. PMID:26696139

  13. 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

  14. 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

  15. Chemically Modified DNA Aptamers Bind Interleukin-6 with High Affinity and Inhibit Signaling by Blocking Its Interaction with Interleukin-6 Receptor

    PubMed Central

    Gupta, Shashi; Hirota, Masao; Waugh, Sheela M.; Murakami, Ikuo; Suzuki, Tomoki; Muraguchi, Masahiro; Shibamori, Masafumi; Ishikawa, Yuichi; Jarvis, Thale C.; Carter, Jeffrey D.; Zhang, Chi; Gawande, Bharat; Vrkljan, Michael; Janjic, Nebojsa; Schneider, Daniel J.

    2014-01-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune and inflammatory responses, and its overproduction is a hallmark of inflammatory diseases. Inhibition of IL-6 signaling with the anti-IL-6 receptor antibody tocilizumab has provided some clinical benefit to patients; however, direct cytokine inhibition may be a more effective option. We used the systematic evolution of ligands by exponential enrichment (SELEX) process to discover slow off-rate modified aptamers (SOMAmers) with hydrophobic base modifications that inhibit IL-6 signaling in vitro. Two classes of IL-6 SOMAmers were isolated from modified DNA libraries containing 40 random positions and either 5-(N-benzylcarboxamide)-2′-deoxyuridine (Bn-dU) or 5-[N-(1-naphthylmethyl)carboxamide]-2′-deoxyuridine (Nap-dU) replacing dT. These modifications facilitate the high affinity binding interaction with IL-6 and provide resistance against degradation by serum endonucleases. Post-SELEX optimization of one Bn-dU and one Nap-dU SOMAmer led to improvements in IL-6 binding (10-fold) and inhibition activity (greater than 20-fold), resulting in lead SOMAmers with sub-nanomolar affinity (Kd = 0.2 nm) and potency (IC50 = 0.2 nm). Although similar in inhibition properties, the two SOMAmers have unique sequences and different ortholog specificities. Furthermore, these SOMAmers were stable in human serum in vitro for more than 48 h. Both SOMAmers prevented IL-6 signaling by blocking the interaction of IL-6 with its receptor and inhibited the proliferation of tumor cells in vitro as effectively as tocilizumab. This new class of IL-6 inhibitor may be an effective therapeutic alternative for patients suffering from inflammatory diseases. PMID:24415766

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

    PubMed

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

    2013-04-28

    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

  17. INTERLEUKIN 6-174C>G POLYMORPHISM IS ASSOCIATED WITH LOW BONE MINERAL DENSITY IN OLDER SUBJECTS CONSUMING LOW CALCIUM

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Interleukin 6 (IL6) is a pleiotropic proinflammtory cytokine that influences bone turnover. A common genetic variant at IL6 locus (-174C>G) has been inconsistently associated with low bone mineral density (BMD). The interaction between this polymorphism and calcium intake may account for the equivoc...

  18. 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

  19. Single nucleotide polymorphisms in interleukin-6 and their association with venous thromboembolism.

    PubMed

    Yadav, Umesh; Mahemuti, Ailiman; Hu, Xuemei; Abudureheman, Kailibinure; Xia, Yuning; Tang, Baopeng; Upur, Halmurat

    2015-06-01

    The aim of the present study was to reveal the contribution of single nucleotide polymorphisms of the interleukin‑6 (IL‑6) gene and the progression of venous thromboembolism (VTE). A case‑control study composed of 246 VTE patients, including 160 from the Han population (76 males and 84 females, mean age 57.41±13.25 years), 86 from the Uyghur population (41 males and 45 females, mean age 51.61±13.73 years) and 292 gender and ethnicity‑matched control participants, including 170 from the Han population (91 males and 79 females, mean age 55.82±11.83 years) and 122 from the Uyghur population (64 males and 58 females, mean age 53.52±13.64 years) were enrolled in the present study. The results demonstrated that the serum levels of IL‑6, C‑reactive protein (CRP), D‑dimer, fibrinogen, plasminogen activator inhibitor‑1 and leptin were significantly higher in the VTE group compared with the control group (P<0.05). The frequencies of the ‑572C/G promoter polymorphisms of the IL‑6 genotypes CC, CG and GG were identified to be 34, 48 and 18% in the Han population and 33, 47 and 20% in the Uyghur population, respectively. The allele frequency distributions of the C and G alleles were 58 and 42% in the Han population and 56 and 43% in the Uyghur population, respectively. Significant differences were identified in the ‑572C/G promoter polymorphisms between the VTE group and the control group (P<0.05). For the ‑597G/A polymorphism, all individuals carried the GG and GA genotype; AA genotypes were not detected. Logistic regression analysis was used to identify the risk factors for VTE, adjusting by confounding factors, the results of which demonstrated that the CC homozygote of the IL‑6 ‑572G/C, CRP, IL‑6 and high‑density lipoprotein‑cholesterol were independent risk factors of VTE (P<0.05). In conclusion, the ‑572G/C genotype of IL‑6 may be a genetic marker of VTE in the Han and Uyghur populations. PMID:25625484

  20. 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

  1. 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

  2. Interleukin-6 and rs1800796 locus single nucleotide polymorphisms in response to hypoxia/reoxygenation in hepatocytes

    PubMed Central

    WANG, ZHAOWEN; WU, SHAOHAN; LIAO, JIANHUA; ZHONG, LIN; XING, TONGHAI; FAN, JUNWEI; PENG, ZHIHAI

    2016-01-01

    Ischemia-reperfusion injury due to hypoxia/reoxygenation (H/R) is one of the main causes of liver damage during liver surgery. Donor interleukin-6 (IL-6) rs1800796 single nucleotide polymorphisms (SNPs) affect the metabolism of tacrolimus following liver transplantation-related hepatic H/R. This study investigated the response of IL-6 and its promoter polymorphisms to hepatic H/R in liver parenchymal cells. The association between IL-6 rs1800796 SNPs and IL-6 expression was measured in 84 disease-free liver tissues using tissue microarrays and immunohistochemistry. Subsequently, LO2G, LO2C and NC-LO2 cells were successfully constructed via stable lentivirus-mediated transfection. The effects of IL-6 and its SNPs on the biological function of LO2 cells were examined using a cell model of H/R. Our results revealed that IL-6 was mainly expressed in hepatocytes. The intermediate IL-6 expression rate in genotype CC carriers was higher than that in genotype CG/GG carriers (P=0.006), which was subsequently verified at the IL-6 mRNA level (P=0.002). The concentrations of alanine aminotransferase in the LO2G cells were significantly higher than those in the LO2C cells following H/R for 6 h and H/R for 24 h (P<0.05). The viability of the LO2C cells was higher than that of the LO2G cells (P<0.05). Furthermore, the expression of IL-6 and its downstream molecules was significantly increased in the LO2C cells compared with the LO2G cells (P<0.05). Therefore, the sequence variants of rs1800796 SNPs (G→C) exhibit an increased IL-6 transcription efficiency in liver parenchymal cells. In addition, the increased expression of IL-6 protects the hepatocytes following hepatic H/R injury. PMID:27221654

  3. 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

  4. The Effects of Gene Polymorphisms in Interleukin-4 and Interleukin-6 on the Susceptibility of Rheumatoid Arthritis in a Chinese Population

    PubMed Central

    Chai, Wei; Ni, Ming; Xu, Meng; Lian, Zijian; Shi, Lewis; Bai, Yang; Wang, Yan

    2014-01-01

    Background. Interleukin-4 (IL-4) and interleukin-6 (IL-6) have been reported to associate with pathogenesis of rheumatoid arthritis (RA); however, the role of IL-4 and IL-6 genetic polymorphisms in RA remains unknown. Method. A total of 752 unrelated Chinese patients with RA and 798 healthy Chinese volunteers with no family histories of any autoimmune diseases were recruited. The promoter IL-4-590 C/T and IL-6-174 G/C polymorphisms were genotyped. Result. The genotype distributions and allele frequencies of IL-4-590 C/T and IL-6-174 G/C polymorphisms in RA patients were significantly different from healthy volunteers. Statistically significant differences were observed in genotypes for IL-4-590 and IL-6-174. The frequencies of both the T allele on the IL-4-590 and the C on the IL-6-174 were significantly increased in RA patients. Conclusion. The IL-4-590 and IL-6-174 promoter polymorphisms may be associated with increased risk of RA and could be used as genetic marker for assessing the susceptibility and severity of RA in Chinese. PMID:24707478

  5. 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

  6. Lack of association between rs1800795 (-174 G/C) polymorphism in the promoter region of interleukin-6 gene and susceptibility to type 2 diabetes in Isfahan population

    PubMed Central

    Ghavimi, Reza; Sharifi, Mohammadreza; Mohaghegh, Mohammad Ali; Mohammadian, Hossein; Khadempar, Saedeh; Rezaei, Hamzeh

    2016-01-01

    Background: Type 2 diabetes mellitus (T2DM) is an inflammatory autoimmune disease that mostly affects older adults. The etiology of T2DM includes both genetic and environmental factors. rs1800795 (−174 G/C) single nucleotide polymorphism (SNP) linked with autoimmune disorders predispositions, identified by Genome-Wide Association Study among genes, which immunologically related is considerably over signified. The goal of this study was to evaluate the association between rs1800795 (−174 G/C) polymorphisms in the promoter of interleukin-6 (IL-6) gene with susceptibility to T2DM in a subset of the Iranian population. Materials and Methods: In this case–control study, 120 healthy subjects and 120 patients with T2DM were included. Genomic DNA obtained from whole blood samples and the polymerase chain reaction was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism method was applied for genotyping of the DNA samples with NlaIII as a restriction enzyme. SPSS for Windows software (version 18.0, SPSS, Chicago, IL, USA) was performed for statistical analysis. Results: No significant differences were found between healthy controls and T2DM patients with respect to the frequency distribution of the cytokine gene polymorphism investigated. Odds ratio, adjusted for sex, age, and smoking status has displayed similar outcomes. Conclusion: These results indicated that the rs1800795 SNP is not a susceptibility gene variant for the development of T2DM in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to T2DM. PMID:26962520

  7. Interleukin-6 expression and gene polymorphism are associated with severity of periodontal disease in a sample of Brazilian individuals

    PubMed Central

    Moreira, P R; Lima, P M A; Sathler, K O B; Imanishi, S A W; Costa, J E; Gomez, R S; Gollob, K J; Dutra, W O

    2007-01-01

    Interleukin (IL)-6 is an inflammatory mediator involved in bone resorption. G/C polymorphism at position −174 of the IL-6 gene has been reported to influence IL-6 expression, with the G allele associated with higher expression levels. The aims of this study were to investigate the expression of IL-6 as well as the incidence of IL-6 (−174) gene polymorphism and their correlation to the severity of periodontitis in Brazilians. Peripheral blood mononuclear cells were collected from 12 non-smoker individuals with periodontitis for evaluation of IL-6 expression using flow cytometry. We observed a positive correlation between the mean clinical attachment loss and intensity of expression of IL-6, in which the greater the attachment loss, the higher the expression of IL-6 (P= 0·007, R2 = 0·52). Also, patients with severe periodontitis displayed a higher intensity of IL-6 expression compared to moderate periodontitis (P= 0·04). To determine the occurrence of IL-6 gene polymorphism, DNA was obtained from oral swabs of 209 Brazilian individuals with and without periodontitis. Polymerase chain reaction, restriction endonuclease digestion and electrophoresis were performed, allowing for detection of the IL-6 (−174) polymorphism. We observed that non-smokers with moderate periodontitis (P= 0·05) and control (P= 0·04) groups displayed a higher incidence of the G– genotype when compared to severe periodontitis. This suggests that the G– genotype may represent a protective role in severity of periodontitis. Thus, the increased expression of IL-6 and IL-6 (−174) polymorphism are associated with periodontal disease severity in Brazilian individuals. PMID:17286759

  8. Estimation of volume density of interdental papilla components in patients with chronic periodontitis and interleukin-6 (-174G/C) gene polymorphisms

    PubMed Central

    Heidari, Zahra; Mahmoudzadeh-Sagheb, Hamidreza; Hashemi, Mohammad; Ansarimoghaddam, Somayeh; Sheibak, Nadia

    2016-01-01

    Background: The association between interleukin-6 (IL-6) (-174G/C) gene polymorphisms and level of tissue breakdown and periodontal disease progression is unknown. The present study investigated quantitative parameters of interdental papilla in chronic periodontitis (CP) patients with IL-6 (-174G/C) gene polymorphisms. Materials and Methods: Sixty gingival samples were studied. After determination of IL-6 (-174G/C) gene polymorphisms using a tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) technique, 45 gingival tissue samples of CP patients (GG and GC+CC genotypes) were considered as case groups. Fifteen control samples were also collected from healthy individuals. After tissue processing, interdental gingival tissues were exhaustively sectioned into 4 μm-thick sections. Ten to thirteen sections were sampled by systematic uniform random sampling and stained with Masson trichrome, and the volume density (Vv) of the gingival components was estimated using Cavalier's point counting method. Statistical analysis was performed by Student t-test to compare differences between groups. The significance level was set at P < 0.05. Results: There were statistically significant differences in the Vv of epithelium, connective tissue, collagenous and non-collagenous matrix, and blood vessels between the control and CP groups (P < 0.0001). There were no statistically significant differences in the Vv of epithelium, connective tissue of gingiva, collagenous and non-collagenous matrix, and blood vessels among GG, GC, and CC genotypes in CP patients (P > 0.05). Conclusion: Results of the current study showed that there was no association between IL-6 (-174G/C) gene polymorphisms and quantitative parameters of interdental papilla in CP patients. PMID:27076828

  9. 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. PMID:26385127

  10. Association between -174 interleukin-6 gene polymorphism and biological response to rituximab in several systemic autoimmune diseases.

    PubMed

    Robledo, Gema; Dávila-Fajardo, Cristina Lucía; Márquez, Ana; Ortego-Centeno, Norberto; Callejas Rubio, José Luis; de Ramón Garrido, Enrique; Sánchez-Román, Julio; García-Hernández, Francisco J; Ríos-Fernández, Raquel; González-Escribano, Maria Francisca; Camps García, Maria Teresa; Castillo Palma, Maria Jesús; Ayala, Maria Del Mar; Martín, Javier

    2012-09-01

    Rituximab has become a pivotal treatment for systemic autoimmune diseases. The aim of this study was to determine whether the genetic variant -174 IL-6 contributes to differences in the response to rituximab in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory myopathies, anti-neutrophil cytoplasmic antibody-mediated vasculitis, systemic sclerosis, Sjöegren's syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. DNA samples from 144 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for -174 IL-6 (rs1800795) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after the first infusion with rituximab, we evaluated the response to the drug: 60.4% of the patients showed a complete response, partial 27.8%, and 11.8% did not respond to the treatment. The CC genotype frequency was significantly increased in nonresponders with respect to responders (23.5% vs. 7.1%, respectively; p=0.049; odds ratio (OR)=4.03, 95% confidence intervals (CI) 0.78-16.97). According to the genotype distribution, rituximab was effective in 69.2% of the CC carriers, 91.9% of the CG carriers, and 88.4% of the GG carriers. A similar trend was observed when SLE patients were analyzed separately (27.3% carried CC homozygosis in nonresponders and 6.9% in responders; p=0.066; OR=5.10, 95% CI 0.65-31.73). Rituximab was effective in 62.5% of the CC carriers, 88.9% of the GC carriers, and 90% of the GG carriers. These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted. PMID:22734797

  11. 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

  12. 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.

  13. 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

  14. Body composition and -174G/C interleukin-6 promoter gene polymorphism: association with progression of insulin resistance in normal weight obese syndrome.

    PubMed

    Di Renzo, L; Bertoli, A; Bigioni, M; Del Gobbo, V; Premrov, M G; Calabrese, V; Di Daniele, N; De Lorenzo, A

    2008-01-01

    Insulin resistance and obesity are intimately related to a chronic low grade systemic inflammation. Interleukin-6 (IL-6) may influence the pathogenesis of obesity-related diseases. The aim of this study is to investigate the effect of body's fat mass on the relationships between -174G/C IL-6 promoter gene polymorphism, IL-6 circulating level and insulin resistance. A population of 150 Caucasian women was studied, subdivided according to their body composition in non-obese (NW), Normal Weight Obese (NWO) and preobese-obese (OB). The NWO subjects were found in an intermediate position between the NW and OB subjects in terms of body weight, fat mass percentage (FM%), abdominal FAT%, hs-CRP and plasma triglyceride level. Fasting plasma IL-6 concentration was positively correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) in all subjects analyzed (P=0.0014). In NWO and OB women a significantly increased IL-6 mean value was observed compared with NW subjects. In G/G population, the IL-6 plasma level of NWO and OB was significantly higher with respect to NW. No significant differences of IL-6 concentrations were observed in the three groups carrying G/C genotype. NWO and OB women homozygous for the allele C have significantly lower value of IL-6 with respect to NW subjects. IL-6 concentration was positively correlated with FM% in G/G (R(2)=0.397, P<0.001) and was negatively correlated in C/C (R(2)=0.459, P=0.002). No significant correlation was observed in G/C genotype (R(2)=0.041, P=0.173). In conclusion our study confirms that, at least in Italian Caucasian females, the FM% is a major determinant of an increase in IL-6 production and insulin resistance. -174 G/C IL-6 promoter polymorphism represents a marker which could help to identify, time in advance, "vulnerable" individuals at risk of age and obesity related diseases. PMID:18991689

  15. Interleukin 6 and rheumatoid arthritis.

    PubMed

    Yoshida, Yuji; Tanaka, Toshio

    2014-01-01

    Interleukin-6 (IL-6) is a representative cytokine featuring pleiotropic activity and redundancy. A transient synthesis of IL-6 contributes to host defense against infectious agents and tissue injuries by inducing acute phase reactions and immunological and hematopoietic responses. However, uncontrolled persistent production of IL-6 may lead to the development of several immune-mediated diseases. Rheumatoid arthritis (RA) is a chronic disease with joint and systemic inflammation resulting from immunological abnormalities and it has been found that IL-6 plays a key role in the development of this disease. Clinical trials in various parts of the world of tocilizumab, a humanized anti-IL-6 receptor antibody, have proved its efficacy and tolerable safety either as monotherapy or in combination with disease-modifying antirheumatic drugs. As a result, it is currently used as a first-line biologic for the treatment of moderate-to-severe RA in more than 100 countries. Clarification of the mechanism(s) through which tocilizumab exerts its effect on RA and of the reason(s) why IL-6 is continuously produced in RA can be expected to lead to the best use of this agent for RA patients and aid in investigations into the pathogenesis of RA. PMID:24524085

  16. Association between tumor necrosis factor-α promoter -308 A/G, -238 A/G, interleukin-6 -174 G/C and -572 G/C polymorphisms and periodontal disease: a meta-analysis.

    PubMed

    Song, Gwan Gyu; Choi, Sung Jae; Ji, Jong Dae; Lee, Young Ho

    2013-08-01

    The aim of this study was to determine whether tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) promoter polymorphisms confer susceptibility to periodontitis in ethnically different populations. A literature search was performed using PubMed and Embase and a meta-analysis of the identified studies was conducted to explore the associations between TNF-α -308 A/G, -238 A/G, IL-6 promoter -174 G/C and -572 G/C polymorphisms and periodontitis. Seventeen comparison studies for the TNF-α -308 A/G polymorphism and three studies for the TNF-α -238 A/G polymorphism were included in the meta-analysis. And 16 separate studies for the IL-6 -174 G/C polymorphism and 10 studies for the IL-6 -572 G/C polymorphism were considered in our meta-analysis. Analysis after stratification by ethnicity indicated that the TNF-α -308 A allele was associated with periodontitis in Brazilian, Asian, and Turkish populations (OR=0.637, 95% CI=0.447-0.907, p=0.013; OR=0.403, 95% CI=0.204-0.707, p=0.009; OR=1.818, 95; % CI=1.036-3.189, p=0.037). The meta-analysis showed no association between the TNF-α -238 A/G polymorphism and periodontitis. The meta-analysis indicated an association of the IL-6 -174 G/C polymorphisms with periodontitis in Brazilian populations (OR for GG+GC=2.394, 95% CI=1.081-5.302, p=0.031). Stratification by ethnicity and disease type indicated an association between the IL-6 -572 G allele and chronic periodontitis (OR=1.585, 95 % CI=1.030-2.439, p=0.036), and periodontitis in Europeans (OR=2.118, 95% CI=1.254-3.577, p=0.005). This meta-analysis demonstrates that the TNF-α -308 A/G polymorphism confers susceptibility to periodontitis in Brazilian, Asian and Turkish populations. The IL-6 -174 G/C polymorphism may confer susceptibility to periodontitis in Brazilians, and the IL-6 -572 G/C polymorphism may be associated with susceptibility to periodontitis in Europeans, and chronic periodontitis. PMID:23657600

  17. 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

  18. Genetic susceptibility to total hip arthroplasty failure: a preliminary study on the influence of matrix metalloproteinase 1, interleukin 6 polymorphisms and vitamin D receptor

    PubMed Central

    Malik, M H A; Jury, F; Bayat, A; Ollier, W E R; Kay, P R

    2007-01-01

    Background Matrix metalloproteinase (MMP)1, interleukin(IL)6 and vitamin D receptor (VDR) have been implicated in the biological cascade of events initiated by particulate wear debris and bacterial infection, resulting in periprosthetic bone loss around loosened total hip replacements (THRs). The individual responses to such stimuli may be dictated by genetic variation. Objective To study the effect of single‐nucleotide polymorphisms (SNPs) within these candidate genes. Methods A case–control study of the MMP1, IL6 and VDR genes was performed for possible association with deep sepsis or aseptic loosening. All cases included in the study were Caucasian patients with osteoarthritis who had received a cemented Charnley total hip arthroplasty (THA) and polyethylene acetabular cup. Cases consisted of 91 patients with early aseptic loosening and 71 patients with microbiological evidence of deep infection on surgery. Controls consisted of 150 patients with THAs that were clinically asymptomatic for over 10 years and showed no radiographic features of aseptic loosening. DNA samples from all individuals were genotyped using Taqman allelic discrimination. Results The C allele (p = 0.001; OR = 3.27; 95% CI 2.21 to 4.83) and C/C genotype (p = 0.001) for the MMP1 SNP were highly associated with aseptic failure when compared with controls. No statistically significant relationships were found between aseptic loosening and the MMP2, MMP4, IL6 –174 or VDRL SNPs. The T allele (p = 0.007; OR = 1.76; 95% CI 1.16 to 2.66) and T/T genotype (p = 0.028) for VDR‐T were statistically associated with osteolysis owing to deep infection as compared with controls. No statistically significant relationship was found between septic failure and any of the other SNPs examined in this study. Conclusions Aseptic loosening and possibly deep infection of THR may be due to the genetic influence of candidate susceptibility genes. SNP markers may serve as predictors of

  19. Interleukin-6, a mental cytokine.

    PubMed

    Spooren, Anneleen; Kolmus, Krzysztof; Laureys, Guy; Clinckers, Ralph; De Keyser, Jacques; Haegeman, Guy; Gerlo, Sarah

    2011-06-24

    Almost a quarter of a century ago, interleukin-6 (IL-6) was discovered as an inflammatory cytokine involved in B cell differentiation. Today, IL-6 is recognized to be a highly versatile cytokine, with pleiotropic actions not only in immune cells, but also in other cell types, such as cells of the central nervous system (CNS). The first evidence implicating IL-6 in brain-related processes originated from its dysregulated expression in several neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. In addition, IL-6 was shown to be involved in multiple physiological CNS processes such as neuron homeostasis, astrogliogenesis and neuronal differentiation. The molecular mechanisms underlying IL-6 functions in the brain have only recently started to emerge. In this review, an overview of the latest discoveries concerning the actions of IL-6 in the nervous system is provided. The central position of IL-6 in the neuroinflammatory reaction pattern, and more specifically, the role of IL-6 in specific neurodegenerative processes, which accompany Alzheimer's disease, multiple sclerosis and excitotoxicity, are discussed. It is evident that IL-6 has a dichotomic action in the CNS, displaying neurotrophic properties on the one hand, and detrimental actions on the other. This is in agreement with its central role in neuroinflammation, which evolved as a beneficial process, aimed at maintaining tissue homeostasis, but which can become malignant when exaggerated. In this perspective, it is not surprising that 'well-meant' actions of IL-6 are often causing harm instead of leading to recovery. PMID:21238488

  20. Interleukin-6, vitamin D & diabetes risk-factors modified by a short-term yoga-based lifestyle intervention in overweight/obese individuals

    PubMed Central

    Netam, Ritesh; Yadav, Raj Kumar; Khadgawat, Rajesh; Sarvottam, Kumar; Yadav, Rashmi

    2015-01-01

    Background & objectives: Several diabetes prevention programmes have demonstrated a reduction in incidence of diabetes in individuals with prediabetes through weight loss. Short-term yoga-based lifestyle intervention programmes have also been shown to be efficacious in weight loss. This study was undertaken to investigate if interleukin (IL)-6, vitamin D, neopterin, vaspin, and diabetes risk factors can be modified by a short-term yoga-based lifestyle intervention in overweight/obese subjects. Methods: In this pilot study, 34 overweight/obese [body mass index (BMI) ≥23 to <35 kg/m2 per Asian cut-off values] individuals were enrolled, and received directly supervised intervention for 10 days. Thereafter, they were advised to follow this yoga-based lifestyle at home for one month, and were reassessed for study variables at day 30. Results: There was a reduction from baseline to day 10 in weight (P<0.001), BMI (P<0.001), waist/hip-ratio (P<0.05), blood glucose (P<0.01), and a significant improvement in lipid profile. There was a decrease in median fasting insulin (P<0.05), homeostatic model assessment-insulin resistance (P<0.01), and IL-6 (P<0.05). A non-significant increase in 25-OH-vitamin D, and a decrease in neopterin and vaspin were observed. Twenty subjects returned for follow up assessments. At day 30, weight loss was sustained while systolic blood pressure also showed reduction (P<0.05). Changes in vitamin D levels were significantly and negatively correlated with changes in weight, BMI and fasting blood glucose, and positively with change in high density lipoprotein. Changes in body weight and BMI significantly and positively correlated with insulin. Changes in IL-6 levels positively and significantly correlated with change in neopterin levels. Interpretation & conclusions: The findings showed that IL-6, vitamin D, and diabetes risk factors were favourably modified by a short-term yoga-based lifestyle intervention in obesity. This study also highlighted the

  1. Stabilized Interleukin-6 receptor binding RNA aptamers

    PubMed Central

    Meyer, Cindy; Berg, Katharina; Eydeler-Haeder, Katja; Lorenzen, Inken; Grötzinger, Joachim; Rose-John, Stefan; Hahn, Ulrich

    2014-01-01

    Interleukin-6 (IL-6) is a multifunctional cytokine that is involved in the progression of various inflammatory diseases, such as rheumatoid arthritis and certain cancers; for example, multiple myeloma or hepatocellular carcinoma. To interfere with IL-6-dependent diseases, targeting IL-6 receptor (IL-6R)-presenting tumor cells using aptamers might be a valuable strategy to broaden established IL-6- or IL-6R-directed treatment regimens. Recently, we reported on the in vitro selection of RNA aptamers binding to the human IL-6 receptor (IL-6R) with nanomolar affinity. One aptamer, namely AIR-3A, was 19 nt in size and able to deliver bulky cargos into IL-6R-presenting cells. As AIR-3A is a natural RNA molecule, its use for in vivo applications might be limited due to its susceptibility to ubiquitous ribonucleases. Aiming at more robust RNA aptamers targeting IL-6R, we now report on the generation of stabilized RNA aptamers for potential in vivo applications. The new 2'-F-modified RNA aptamers bind to IL-6R via its extracellular portion with low nanomolar affinity comparable to the previously identified unmodified counterpart. Aptamers do not interfere with the IL-6 receptor complex formation. The work described here represents one further step to potentially apply stabilized IL-6R-binding RNA aptamers in IL-6R-connected diseases, like multiple myeloma and hepatocellular carcinoma. PMID:24440854

  2. Monoclonal antibodies against chicken interleukin-6

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Monoclonal antibodies (mAb) were produced against a recombinant (r) chicken interleukin-6 (IL-6). Eight mAbs that were produced were tested for isotype; ability to inhibit recombinant forms of chicken (ch), human (h) and murine (m) IL-6; and recognition of rchIL-6 by Western immunoblotting. The mA...

  3. Role of cytokine gene (interferon-γ, transforming growth factor-β1, tumor necrosis factor-α, interleukin-6, and interleukin-10) polymorphisms in the risk of oral precancerous lesions in Taiwanese.

    PubMed

    Hsu, Han-Jen; Yang, Yi-Hsin; Shieh, Tien-Yu; Chen, Chung-Ho; Kao, Yu-Hsun; Yang, Chia-Fu; Ko, Edward Cheng-Chuan

    2014-11-01

    Oral squamous cell carcinoma can be preceded by some benign oral lesions with malignant potential, including leukoplakia, erythroplakia, oral lichen planus, and oral submucous fibrosis. There are different degrees of inflammatory cells infiltration in histopathology. Inflammatory cytokines may play a pathogenic role in the development of oral precancerous lesions (OPCLs). Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. We hypothesized that the risk of OPCLs might be associated with cytokine gene polymorphisms of interferon (IFN)-γ, transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10. In the present study, 42 OPCL patients and 128 controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-γ (+874 T/A), TGF-β1 (codons 10 T/C and 25 G/C), TNF-α (-308 G/A), IL-6 (-174 G/C), and IL-10 (-1082 A/G, -819 T/C, and -592 A/C)]. Cytokine genotyping was determined by the polymerase chain reaction sequence-specific primer technique using commercial primers. Allele and genotype data were analyzed for significance of differences between cases and controls using the Chi-square (χ(2)) test. Two-sided p < 0.05 were considered to be statistically significant. A series of multivariate logistic regression models, adjusted for age, sex, betel quid chewing, alcohol consumption, and smoking, was constructed in order to access the contribution of homozygous or heterozygous variant genotypes of polymorphisms. The TNF-α (-308) polymorphism was significantly associated with OPCLs. There were significant differences in the distribution of AA, GA, and GG genotypes between OPCL patients and controls (p = 0.0004). Patients with the AA or GA genotype had a 3.63-fold increased risk of OPCLs. The TGF-β1 (codon 10 and 25) polymorphism was also significantly associated with OPCLs (p < 0.001). The IL-6 polymorphism was significantly associated with OPCLs. There are significant

  4. Interleukin-6: an emerging regulator of pathological pain.

    PubMed

    Zhou, Ya-Qun; Liu, Zheng; Liu, Zhi-Heng; Chen, Shu-Ping; Li, Man; Shahveranov, Allahverdi; Ye, Da-Wei; Tian, Yu-Ke

    2016-01-01

    Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund's adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain. PMID:27267059

  5. Targeting interleukin-6 for noninfectious uveitis

    PubMed Central

    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. PMID:26392750

  6. Combined impact of hepatitis C virus genotype 1 and interleukin-6 and tumor necrosis factor-α polymorphisms on serum levels of pro-inflammatory cytokines in Brazilian HCV-infected patients.

    PubMed

    Tarragô, Andréa Monteiro; da Costa, Allyson Guimarães; Pimentel, João Paulo Diniz; Gomes, Samara Tatielle Monteiro; Freitas, Felipe Bonfim; Lalwani, Pritesh; de Araújo, Ana Ruth S; Victória, Flamir da Silva; Victória, Marilú Barbieri; Vallinoto, Antônio Carlos Rosário; Sadahiro, Aya; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Malheiro, Adriana

    2014-11-01

    We investigated the association between hepatitis C virus (HCV) genotypes and host cytokine gene polymorphisms and serum cytokine levels in patients with chronic hepatitis C. Serum IL-6, TNF-α, IL-2, IFN-γ, IL-4, IL-10, and IL-17A levels were measured in 67 HCV patients (68.2% genotype 1 [G1]) and 47 healthy controls. The HCV patients had higher IL-6, IL-2, IFN-γ, IL-10, and IL-17A levels than the controls. HCV G1 patients had higher IL-2 and IFN-γ levels than G2 patients. The -174IL6G>C, -308TNFαG>A, and -1082IL10A>G variants were similarly distributed in both groups. However, HCV patients with the -174IL6GC variant had higher IL-2 and IFN-γ levels than patients with the GG and CC variants. Additionally, HCV patients with the -308TNFαGG genotype had higher IL-17A levels than patients with the AG genotype, whereas patients with the -1082IL10GG variant had higher IL-6 levels than patients with the AA and AG variants. A significant proportion of HCV patients had high levels of both IL-2 and IFN-γ. The subgroup of HCV patients with the G1/IL6CG/TNFαGG association displayed the highest proportions of high producers of IL-2 and IFN-γ whereas the subgroup with the G1/TNFαGG profile showed high proportions of high producers of IL-6 and IL-17A. HCV patients with other HCV/cytokine genotype associations showed no particular cytokine profile. Our results suggest that HCV genotype G1 and IL-6 and TNF-α polymorphisms have a clinically relevant influence on serum pro-inflammatory cytokine profile (IL-2 and IFN-γ) in HCV patients. PMID:25193024

  7. Recovery of CD4+ T Cells in HIV patients with a stable virologic response to antiretroviral therapy is associated with polymorphisms of interleukin-6 and central major histocompatibility complex genes.

    PubMed

    Fernandez, Sonia; Rosenow, Ann A; James, Ian R; Roberts, Steven G; Nolan, Richard C; French, Martyn A; Price, Patricia

    2006-01-01

    We investigated whether polymorphisms in genes associated with HIV disease progression and/or immune activation affect CD4+ T-cell recovery in HIV patients who began combination antiretroviral therapy (ART) with advanced immunodeficiency and achieved stable control of plasma viremia. Patients with CD4 T-cell counts <300 cells/microL (n = 33) and >400 cells/microL (n = 37) on ART were compared. A multiple case-control logistic regression associated carriage of BAT1(1,2) or interleukin (IL)6-174(2,2) with low CD4 T-cell counts (P = 0.012). BAT1*2 uniquely marks the central major histocompatibility complex region of a conserved haplotype (HLA-A1,B8,BAT1*2,TNFA-308*2,DR3,DQ2). There was no association between alleles carried at CCR5Delta32, CCR5 59029, CCR5 59353, CCR2+190 (V64I), SDF1 3'UTR, IL1A+4845, IL1B+3953, IL4-589, IL10-592, IL10-R1+536, IL10-R1+1112, IL12B 3'UTR, TNFA-308, or TNFA-1031 and CD4 T-cell counts. We suggest that immune activation and/or CD4 T-cell apoptosis in HIV patients on effective ART is influenced by genetic factors. PMID:16340466

  8. 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

  9. Establishment of swine interleukin-6 sandwich ELISA.

    PubMed

    Nuntaprasert, A; Mori, Y; Tsukiyama-Kohara, K; Kai, C

    2005-03-01

    We established a sandwich enzyme-linked immunosorbent assay (ELISA) for swine interleukin-6 (SwIL-6), which was applied for detection of SwIL-6 in vitro and in vivo. Anti-SwIL-6 rabbit- and goat-polyclonal antibodies, and monoclonal antibody (mAb) were prepared, conforming that all of the antibodies were reactive with recombinant SwIL-6 by Western blotting and indirect ELISA. A sandwich ELISA was developed using the mAb as a capture antibody and biotinylated goat-polyclonal antibody as a detection antibody. The detection limit of the sandwich ELISA for rSwIL-6 was 49pg/ml and did not show cross-reactivity with swine IL-1b, IL-4, IL-8, IL-18, IL-12, and IFN-g. Using the ELISA, SwIL-6 was detected in culture medium of the monocytes stimulated with PHA-P and PMA, and the plasma or the bronchoalveolar lavage fluid (BALF) of pigs experimentally infected with Actinobacillus pleuropneumoniae or Mycoplasma hyopneumoniae. This ELISA for SwIL-6 may be useful for understanding the role of this cytokine in various swine diseases. PMID:15582688

  10. 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

  11. 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

  12. 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

  13. 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.

  14. The role of interleukin-6 signaling in nervous tissue.

    PubMed

    Rothaug, Michelle; Becker-Pauly, Christoph; Rose-John, Stefan

    2016-06-01

    The cytokine interleukin-6 (IL-6) plays a critical role in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. Profound neuropathological changes, such as multiple sclerosis (MS), Parkinson's and Alzheimer's disease are associated with increased IL-6 expression in brain. Increased nocturnal concentrations of serum IL-6 are found in patients with impaired sleep whereas IL-6-deficient mice spend more time in rapid eye movement sleep associated with dreaming. IL-6 is crucial in the differentiation of oligodendrocytes, regeneration of peripheral nerves and acts as a neurotrophic factor. It exerts its cellular effects through two distinct pathways which include the anti-inflammatory pathway involving the membrane-bound IL-6 receptor (IL-6R) expressed on selective cells, including microglia, in a process known as classical signaling that is also critical for bacterial defense. In classical signaling binding of IL-6 to the membrane-bound IL-6R activates the β-receptor glycoprotein 130 (gp130) and subsequent down-stream signaling. The alternative, rather pro-inflammatory pathway, shown to mediate neurodegeneration in mice, termed trans-signaling, depends on a soluble form of the IL-6R that is capable of binding IL-6 to stimulate a response on distal cells that express gp130. A naturally occurring soluble form of gp130 (sgp130) has been identified that can specifically bind and neutralize the IL-6R/IL-6 complex. Thus, trans-signaling is blocked but classical signaling is completely unaffected. A modified, recombinant dimerized version of sgp130 (sgp130Fc) has successfully been used to block inflammatory processes in mice and may also be used in the clarification of IL-6 trans-signaling in neurological diseases. PMID:27016501

  15. Interleukin-6 as a Prognostic Biomarker in Ruptured Intracranial Aneurysms

    PubMed Central

    Kao, Hung-Wen; Kuo, Chen-Ling; Huang, Ching-Shan; Tseng, Wan-Min; Lin, Ching-Po

    2015-01-01

    Background Interleukin-6 (IL-6), a proinflammatory cytokine, was found to surge in the cerebral spinal fluid after aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that the plasma level of IL-6 could be an independent biomarker in predicting clinical outcome of patients with ruptured intracranial aneurysm. Methods We prospectively included 53 consecutive patients treated with platinum coil embolization of the ruptured intracranial aneurysm. Plasma IL-6 levels were measured in the blood samples at the orifices of the aneurysms and from peripheral veins. The outcome measure was the modified Rankin Scale one month after SAH. Multiple logistic regression analyses were used to evaluate the associations between the plasma IL-6 levels and the neurological outcome. Results Significant risk factors for the poor outcome were old age, low Glasgow Coma Scale (GCS) on day 0, high Fisher grades, and high aneurysmal and venous IL-6 levels in univariate analyses. Aneurysmal IL-6 levels showed modest to moderate correlations with GCS on day 0, vasospasm grade and Fisher grade. A strong correlation was found between the aneurysmal and the corresponding venous IL-6 levels (ρ = 0.721; P<0.001). In the multiple logistic regression models, the poor 30-day mRS was significantly associated with high aneurysmal IL-6 level (OR, 17.97; 95% CI, 1.51–214.33; P = 0.022) and marginally associated with high venous IL-6 level (OR, 12.71; 95% CI, 0.90–180.35; P = 0.022) after adjusting for dichotomized age, GCS on day 0, and vasospasm and Fisher grades. Conclusions The plasma level of IL-6 is an independent prognostic biomarker that could be used to aid in the identification of patients at high-risk of poor neurological outcome after rupture of the intracranial aneurysm. PMID:26176774

  16. 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. PMID:16860900

  17. Orchiectomy increases bone marrow interleukin-6 levels in mice.

    PubMed

    Zhang, J; Pugh, T D; Stebler, B; Ershler, W B; Keller, E T

    1998-03-01

    Interleukin-6 (IL-6) appears to be an important factor in disease states associated with bone resorption. There is both in vitro and in vivo evidence supporting the fact that androgens down-regulate interleukin-6 production. These observations, in combination with the fact that osteoblasts and bone marrow stromal cells produce IL-6, led us to hypothesize that orchiectomy-induced androgen loss will result in increased IL-6 expression in the bone microenvironment. To prove our hypothesis we assessed the effect of orchiectomy on IL-6 protein and mRNA expression in bone marrow and spleen. We found that orchiectomy was associated with increased serum IL-6 levels at 3 and 28 days postsurgery. Phorbol ester-stimulated IL-6 levels were also higher in supernatants from bone marrow and spleen cell cultures from orchiectomized mice compared with unoperated or sham-operated mice. Additionally, we found that steady state IL-6 mRNA levels were increased in bone marrow but not spleen cells. Finally, we found that orchiectomized mice had splenomegaly and increased bone marrow cellularity. Histopathology of the spleen revealed lymphoid hyperplasia accompanied by a marked mononuclear cell infiltration of the red pulp. We conclude that orchiectomy induces IL-6 expression in the bone marrow. These findings suggest that endocrine and cytokine interactions contribute to bone pathophysiology. PMID:9501955

  18. Rapid detection and sequencing of alleles in the 3' flanking region of the interleukin-6 gene.

    PubMed Central

    Bowcock, A M; Ray, A; Erlich, H; Sehgal, P B

    1989-01-01

    The 3' flanking region of the interleukin 6 gene is polymorphic due to insertions of different size. Within this region lies a sequence of approximately 500 base pairs that is AT rich. Based on flanking sequence information we have constructed oligonucleotides which prime the polymerase chain reaction (PCR) and amplify this AT rich region. The amplification products visualized by agarose gel electrophoresis gave fragment sizes for both homozygous and heterozygous individuals that were concordant with those observed by conventional genomic blotting techniques. Alleles that could not be typed by Southern analysis were resolved with this approach. These results illustrate the value of PCR for the rapid detection of length polymorphisms such as those due to variable numbers of tandem repeats. In contrast to RFLP analysis this procedure takes less than a day to perform, is cheaper, avoids the use of radioactivity and requires far less substrate DNA. Three different human alleles were sequenced, and differences were detected that were due to both large duplications and loss of one or two bases, suggesting that AT rich regions identify highly polymorphic loci. The same primers also amplified non-human primate DNA, allowing a comparison of the human sequence with that of the common chimpanzee and baboon. Images PMID:2789373

  19. Avoidance-related EEG asymmetry predicts circulating interleukin-6.

    PubMed

    Shields, Grant S; Moons, Wesley G

    2016-03-01

    Recent research has linked avoidance-oriented motivational states to elevated pro-inflammatory cytokine levels. According to one of many theories regarding the association between avoidance and cytokine levels, because the evolutionarily basic avoidance system may be activated when an organism is threatened or overwhelmed, an associated inflammatory response may be adaptive for dealing with potential injury in such threatening situations. To examine this hypothesis, we tested whether the neural correlate of avoidance motivation associates with baseline levels of the circulating pro-inflammatory cytokine interleukin-6 (IL-6). Controlling for covariates, greater resting neural activity in the right frontal cortex relative to the left frontal cortex-the neural correlate of avoidance motivation-was associated with baseline IL-6. These results thus support the hypothesis that the avoidance motivational system may be closely linked to systemic inflammatory activity. PMID:26461246

  20. The role of interleukin-6 in malignant mesothelioma

    PubMed Central

    Abdul Rahim, Siti N.; Ho, Gwo Y.

    2015-01-01

    Malignant mesothelioma (MM) still remains a dismal disease with a median overall survival between 9-12 months. During the past decade since the introduction of the multi-folate antagonist, pemetrexed, there have been no significant advances in its systemic treatment, particularly with novel therapeutics that have exhibited varying degrees of success in other solid tumours. In recent years, the pleiotropic proinflammatory cytokine, interleukin-6 (IL-6) has emerged as a mediator of pivotal processes such as cell proliferation and chemoresistance within the mesothelioma tumour microenvironment in addition to clinical symptoms commonly witnessed in this disease. This manuscript provides a brief summary on the pathophysiology and clinical management of MM, followed by the role of IL-6 in its tumourigenesis and the rationale for utilising anti-IL-6 therapeutics alongside standard chemotherapy and targeted agents in an attempt to prolong survival. PMID:25806346

  1. Fatigue and interleukin-6 – a multi-faceted relationship

    PubMed Central

    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. PMID:27407249

  2. 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

  3. Glucocorticoid-dependent induction of interleukin-6 receptor expression in human hepatocytes facilitates interleukin-6 stimulation of amino acid transport.

    PubMed Central

    Fischer, C P; Bode, B P; Takahashi, K; Tanabe, K K; Souba, W W

    1996-01-01

    OBJECTIVE: The authors studied the effects of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on glutamine and alanine transport in isolated human hepatocytes. They also evaluated the role of dexamethasone in modulating this response and its effects on the expression of the plasma membrane high-affinity IL-6 receptor. SUMMARY BACKGROUND DATA: Animal studies indicate that cytokines are important mediators of the increased hepatic amino acid uptake that occurs during cancer and sepsis, but studies in human tissues are lacking. The control of transport by cytokines and cytokine receptor expression in the liver may provide a mechanism by which hepatocytes can modulate amino acid availability during catabolic disease states. METHODS: Human hepatocytes were isolated from wedge biopsy specimens and plated in 24-well trays. Interleukin-6 and TNF-alpha, in combination with the synthetic glucocorticoid dexamethasone, were added to hepatocytes in culture, and the transport of radiolabeled glutamine and alanine was measured. Fluorescent-activated cell sorter (FACS) analysis was used to study the effects of dexamethasone on IL-6 receptor number in the well-differentiated human hepatoma HepG2. RESULTS: Both IL-6 and TNF-alpha exerted a small stimulatory effect on alanine and glutamine transport. Dexamethasone alone did not alter transport rates, but pretreatment of cells augmented the effects of both cytokines on carrier-mediated amino acid uptake. Dexamethasone pretreatment and a combination of IL-6 and TNF-alpha resulted in a greater than twofold increase in transport activity. Fluorescent-activated cell sorter analysis demonstrated that dexamethasone induced a threefold increase in the expression of high-affinity IL-6 receptors. CONCLUSIONS: Interleukin-6 and TNF-alpha work coordinately with glucocorticoids to stimulate amino acid uptake in human hepatocytes. Dexamethasone exerts a permissive effect on cytokine-mediated increases in transport by increasing IL

  4. The relationship between weight loss and interleukin 6 in non-small-cell lung cancer.

    PubMed

    Scott, H R; McMillan, D C; Crilly, A; McArdle, C S; Milroy, R

    1996-06-01

    Markers of the inflammatory response, interleukin 6, C-reactive protein, albumin and full blood count, were measured in non-small-cell lung cancer (NSCLC) patients (n = 21) with and without weight loss ( > 5%). There were significant increases in circulating C-reactive protein (P < 0.001), interleukin 6 (P < 0.01) and platelets (P < 0.01) in the weight-losing group. Moreover, there was a statistically significant correlation (r = 0.785, P < 0.001) between interleukin 6 and C-reactive protein concentrations. These results are consistent with interleukin 6 and the acute phase response promoting weight loss in NSCLC. PMID:8664130

  5. 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

  6. 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.

  7. Effects of interleukin-6 (IL-6) on cytotrophoblastic cells.

    PubMed

    Meisser, A; Cameo, P; Islami, D; Campana, A; Bischof, P

    1999-11-01

    Tumour invasion and trophoblastic invasion share the same biochemical mediators: the matrix metalloproteinases (MMP) and their inhibitors. In contrast to tumour invasion of a host tissue, trophoblastic invasion during implantation and placentation is stringently controlled both in tissue localization and developmental stage. The factors responsible for these important regulatory processes are unknown, but in-vitro studies point to endometrial cytokines and growth factors as possible candidates. Here we examined the possibility that interleukin-6 (IL-6), a trophoblastic and endometrial cytokine, represents such a regulatory factor. Purified first trimester cytotrophoblastic cells (CTB) were cultured for 4 days in presence or absence of increasing concentrations of IL-6. MMP-2 and MMP-9 bioactivity (zymography) and immunoactivity were measured in the culture supernatants together with total human chorionic gonadotrophin (HCG), fetal fibronectin (FFN) and leptin. IL-6 did not change the cytotrophoblastic secretion of FFN or total HCG. In contrast, this cytokine induced a dose-dependent stimulation of the leptin secretion and increased the activity, but not the immunoreactivity, of MMP-9 and MMP-2. These results indicate that IL-6 could be considered as an endometrio-trophoblastic regulator of cytotrophoblastic gelatinases. PMID:10541568

  8. Cigarette smoking decreases bioactive interleukin-6 secretion by alveolar macrophages.

    PubMed

    Soliman, D M; Twigg, H L

    1992-10-01

    Studies suggest smokers have decreased alveolar macrophage (AM) accessory cell (AC) function and a reduced incidence of immune-mediated lung diseases such as sarcoidosis. Impaired AM secretion of cytokines important in T-cell immune responses could explain this observation. We investigated production and secretion of interleukin-1 (IL-1) and interleukin-6 (IL-6) in smokers and nonsmokers. Lipopolysaccharide-induced AM IL-1 secretion in smokers was significantly reduced compared with nonsmoker AM. However, intracellular IL-1 in smoker AM was higher than in nonsmokers, suggesting that reduced IL-1 secretion was due to impaired release rather than reduced production. Smoker AM secreted significantly less bioactive IL-6 measured in a bioassay compared with nonsmoker AM. Intracellular IL-6 was virtually undetectable in both groups. In some smokers IL-6 production determined by immunoprecipitation was reduced. However, as a group antigenic IL-6 secretion determined by enzyme-linked immunoabsorbent assay was similar in smokers and nonsmokers, suggesting that smoker AM may cosecrete an inhibitor of IL-6 bioactivity. Indeed, AM supernatants from smokers inhibited B9 proliferation in response to maximal recombinant IL-6 stimulation, whereas supernatants from nonsmokers did not. We conclude that AM from smokers secrete less cytokines important in T-cell proliferation than AM from nonsmokers and suggest that for IL-6 this impairment is related to both decreased production of antigenic protein as well as cosecretion of an IL-6 inhibitor. PMID:1415725

  9. The biology and medical implications of interleukin-6.

    PubMed

    Tanaka, Toshio; Kishimoto, Tadamitsu

    2014-04-01

    Cytokines are soluble mediators, which aid cell-to-cell communication in immune responses, and interleukin-6 (IL-6) is a prototypical cytokine featuring redundant and pleiotropic activity. The complete elucidation of the IL-6-mediated signal transduction system has provided a molecular basis for the characteristic features of cytokines. When tissue damage or inflammation due to infections or injuries occurs, IL-6 synthesis is promptly induced, contributing to the host defense through the stimulation of acute-phase immune reactions and hematopoiesis. The production of IL-6 is terminated when tissue homeostasis is restored. The synthesis of IL-6 is tightly regulated transcriptionally and posttranscriptionally. However, the dysregulated continual synthesis of IL-6 has been implicated in the development of various diseases, including autoimmune and chronic inflammatory diseases and cancers. Clinical trials using the humanized anti-IL-6 receptor monoclonal antibody tocilizumab have demonstrated the efficacy of IL-6 blockade for the treatment of refractory inflammatory diseases, such as rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman disease. Moreover, favorable results from the off-label use of tocilizumab strongly suggest that it may be applicable for the treatment of other refractory immune-mediated diseases, including cancer. Therefore, the mechanisms for the dysregulated synthesis of IL-6 need to be elucidated to understand the pathogenesis of the resultant diseases and to facilitate the development of effective therapeutic strategies. PMID:24764575

  10. Therapeutic uses of anti-interleukin-6 receptor antibody.

    PubMed

    Kang, Sujin; Tanaka, Toshio; Kishimoto, Tadamitsu

    2015-01-01

    Cytokine-targeted therapy has generated a paradigm shift in the treatment of several immune-mediated diseases. Interleukin-6 (IL-6), which was initially identified as B-cell stimulatory factor 2, is a prototypical cytokine with wide-ranging biological effects on immune cells such as B and T cells, on hepatocytes, hematopoietic cells, vascular endothelial cells and on many others. IL-6 is thus crucially involved in the regulation of immune responses, hematopoiesis and inflammation. When infections and tissue injuries occur, IL-6 is promptly synthesized and performs a protective role in host defense against such stresses and traumas. However, excessive production of IL-6 during this emergent process induces potentially fatal complications, including systemic inflammatory response syndrome (SIRS), and dysregulated, persistently high expression of IL-6 causes the onset or development of various chronic immune-mediated disorders. For these reasons, IL-6 blockade was expected to become a novel therapeutic strategy for various diseases characterized by IL-6 overproduction. Indeed, worldwide clinical trials of tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, have successfully proved its outstanding efficacy against rheumatoid arthritis, juvenile idiopathic arthritis and Castleman disease, leading to the approval of tocilizumab for the treatment of these diseases. Moreover, various reports regarding off-label use of tocilizumab strongly suggest that it will be widely applicable for acute, severe complications such as SIRS and cytokine-release syndrome and other refractory chronic immune-mediated diseases. PMID:25142313

  11. 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

  12. 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

  13. Sympathetic neurons can produce and respond to interleukin 6

    PubMed Central

    März, Pia; Cheng, Jr-Gang; Gadient, Reto A.; Patterson, Paul H.; Stoyan, Tanja; Otten, Uwe; Rose-John, Stefan

    1998-01-01

    Neuronal expression of cytokines is an area of active investigation in the contexts of development, disease, and normal neural function. Although cultured rat sympathetic neurons respond very weakly to exogenous interleukin 6 (IL-6), we find that addition of soluble IL-6 receptor (sIL-6R) and IL-6 enhances neuronal survival in the absence of nerve growth factor. Neutralizing monoclonal antibodies against IL-6 block these effects. Addition of IL-6 and sIL-6R also induces a subset of neuropeptide and transmitter synthetic enzyme mRNAs identical to that demonstrated for leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Both of these effects are duplicated by addition of a highly active fusion protein of sIL-6R and IL-6, covalently linked by a flexible peptide chain, which is designated H-IL-6. In addition, we show that sympathetic neurons produce IL-6. In situ hybridization indicates a neuronal localization of IL-6 mRNA in superior cervical ganglia, and bioactive IL-6 protein is detected in ganglion culture supernatants. Interestingly, the IL-6 produced by sympathetic neurons does not lead to survival of these cells in culture unless sIL-6R is added. Thus, sympathetic neurons can produce IL-6 and may respond to it in an autocrine/paracrine manner if sIL-6R is present. Moreover, the prior findings of sIL-6R in serum and inflammatory fluids now have added interest in the context of neuro–immune interactions. PMID:9501249

  14. Interleukin-6: A Critical Cytokine in Cancer Multidrug Resistance.

    PubMed

    Ghandadi, Morteza; Sahebkar, Amirhossein

    2016-01-01

    Multidrug resistance (MDR) is a phenomenon through which tumor cells develop resistance against the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents. The most consistent feature in MDR is overexpression and/or overactivity of ATP-dependent drug efflux transporters. Other mechanisms such as overexpression of drug-detoxifying enzymes and alterations in pro-survival or pro-death signaling pathways are also responsible for MDR. Inflammatory mediators including interleukin-6 (IL-6) play important roles in various events during inflammation and are also involved in development and progression of several types of cancers. Mounting evidence has suggested a crosstalk between IL-6 and MDR in cancer, highlighting the role of IL-6 in chemotherapy response, and the potential opportunity to control MDR through modulation of IL-6 expression. Upregulation of IL-6 has been shown to promote MDR through activation of Janus kinases (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), and Ras-MAPK (mitogen-activated protein kinase) pathways. Activation of the aforementioned pathways changes the expression pattern of several genes involved in proliferation, survival and cell cycle regulation, thus facilitating MDR. Conversely, IL-6 inhibition using different strategies (antibodies, siRNA, and antisense transfection) has been shown to improve tumor responsiveness and mitigate MDR in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings on the role of IL-6 in MDR, and potential therapeutic opportunities arising from this role of IL-6. PMID:26601970

  15. 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. PMID:24076269

  16. Interleukin-6: a multifunctional targetable cytokine in human prostate cancer.

    PubMed

    Culig, Zoran; Puhr, Martin

    2012-09-01

    Several cytokines are involved in regulation of cellular events in prostate cancer. Interleukin-6 (IL-6) was frequently investigated in prostate cancer models because of its increased expression in cancer tissue at early stages of the disease. In patients with metastatic prostate cancer, it is well-known that IL-6 levels increase in serum. High levels of IL-6 were measured in the supernatants of cells which do not respond to androgenic stimulation. IL-6 expression in prostate cancer increases due to enhanced expression of transforming growth factor-beta, and members of the activating protein-1 complex, and loss of the retinoblastoma tumour suppressor. IL-6 activation of androgen receptor (AR) may contribute to progression of a subgroup of prostate cancers. Results obtained with two prostate cancer cell lines, LNCaP and MDA PCa 2b, indicate that IL-6 activation of AR may cause either stimulatory or inhibitory responses on proliferation. Interestingly, prolonged treatment with IL-6 led to establishment of an IL-6 autocrine loop, suppressed signal transducer and activator of transcription (STAT)3 activation, and increased mitogen-activated protein kinase phosphorylation. In several cell lines IL-6 acts as a survival molecule through activation of the signalling pathway of phosphotidylinositol 3-kinase. Expression of suppressors of cytokine signalling (SOCS) has been studied in prostate cancer. SOCS-3 prevents phosphorylation of STAT3 and is an important anti-apoptotic factor in AR-negative prostate cancer cells. Experimental therapy against IL-6 in prostate cancer is based on the use of the monoclonal antibody siltuximab which may be used for personalised therapy coming in the future. PMID:21664423

  17. Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir

    PubMed Central

    HIRANO, Toshio

    2010-01-01

    In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-β2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA). IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer. F759 mice, which contain a single amino-acid substitution in gp130 (Y759F) and show enhanced STAT3 activation, spontaneously develop a RA-like arthritis as they age. F759 arthritis is dependent on CD4+ T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1). Arthritis development in these mice requires that the F759 mutation is present in nonhematopoietic cells, but not in immune cells, highlighting the important role of the interaction between nonimmune tissues and the immune system in this disease. Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-κB. Ultimately, this model may represent a general etiologic process underlying other autoimmune and inflammatory diseases. More importantly, the understanding of IL-6 has paved the way for new therapeutic approaches for RA and other autoimmune and inflammatory diseases. PMID:20689230

  18. 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

  19. Expression of interleukin 6 receptors and interleukin 6 mRNA by bovine leukaemia virus-induced tumour cells.

    PubMed

    Droogmans, L; Cludts, I; Cleuter, Y; Kerkhofs, P; Adam, E; Willems, L; Kettmann, R; Burny, A

    1994-11-01

    Bovine leukaemia virus (BLV) is the aetiologic agent of bovine leucosis. The virus induces malignancies of the B-cell lineage (leukaemia/lymphoma). The role played by interleukin 6 (IL-6) in the BLV-induced leukemogenesis process was evaluated. Six cell lines derived from BLV-induced tumours were tested for the expression of IL-6 receptors. Two cell lines (LB155 and YR2) display 250-300 receptor per cell (kd = 1.7 10(-10) M and 1.4 10(-10) M, respectively) whereas the other four (LB159, LB167, YR1 and M51) do not display detectable amounts of receptors. Very low (if any) expression of IL-6 receptors has been found in the case of the B lymphocytes of animals in persistent lymphocytosis (PL). Despite the presence of IL-6 receptors on the surface of LB155 and YR2 cells, no influence of exogenous IL-6 on their growth has been observed. Northern analyses indicated the presence of IL-6 transcripts only in the case of mRNA isolated from LB155 cells. Since this cell line also expresses receptors for the cytokine, an autocrine loop may exist in these cells. Experiments in which bovine and bovine epithelial cell lines were transfected with a plasmid containing the bovine IL-6 promoter controlling the expression of the reporter cat gene failed to indicate any influence of the viral transactivator p34tax on the activity of this promoter. We conclude that IL-6 receptors and IL-6 mRNA can be found in some BLV-induced tumours, but this does not correlate with viral expression in BLV-induced leukaemia/lymphoma. PMID:7893972

  20. 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

  1. 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

  2. Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers.

    PubMed

    Shah, Tina; Zabaneh, Delilah; Gaunt, Tom; Swerdlow, Daniel I; Shah, Sonia; Talmud, Philippa J; Day, Ian N; Whittaker, John; Holmes, Michael V; Sofat, Reecha; Humphries, Steve E; Kivimaki, Mika; Kumari, Meena; Hingorani, Aroon D; Casas, Juan P

    2013-04-01

    BACKGROUND- Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. METHODS AND RESULTS- We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women's Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci (IL6R/TDRD10, HLA-DRB1, BUD13, SEZ6L, IL1RN, TRIB3, and ABO) were associated with IL-6 (P<10(-5)), although none were associated with the IL6 gene itself. With the exception of TRIB3, all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r(2)>0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration (P<10(-5)). An IL-6-specific weighted allele score explained 2% of the variance of log IL-6 levels (P=2.4410(-22)) in Whitehall II and 1% (P=1.910(-8)) in British Women's Heart and Health Studies. CONCLUSIONS- Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases. PMID:23505291

  3. 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

  4. Health Behaviors Predict Higher Interleukin-6 levels Among Patients Newly Diagnosed with Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Duffy, Sonia A.; Teknos, Theodoros; Taylor, Jeremy M.G.; Fowler, Karen E.; Islam, Mozaffarul; Wolf, Gregory T.; McLean, Scott; Ghanem, Tamer A.; Terrell, Jeffrey E.

    2013-01-01

    Background Health behaviors have been shown to be associated with recurrence risk and survival rates in cancer patients and are also associated with Interleukin-6 levels, but few epidemiologic studies have investigated the relationship of health behaviors and Interleukin-6 among cancer populations. The purpose of the study is to look at the relationship between five health behaviors: smoking, alcohol problems, body mass index (a marker of nutritional status), physical activity, and sleep and pretreatment Interleukin-6 levels in persons with head and neck cancer. Methods Patients (N=409) were recruited in otolaryngology clinic waiting rooms and invited to complete written surveys. A medical record audit was also conducted. Descriptive statistics and multivariate analyses were conducted to determine which health behaviors were associated with higher Interleukin-6 levels controlling for demographic and clinical variables among newly diagnosed head and neck cancer patients. Results While smoking, alcohol problems, body mass index, physical activity, and sleep were associated with Interleukin-6 levels in bivariate analysis, only smoking (current and former) and decreased sleep were independent predictors of higher Interleukin-6 levels in multivariate regression analysis. Covariates associated with higher Interleukin-6 levels were age and higher tumor stage, while comorbidities were marginally significant. Conclusion Health behaviors, particularly smoking and sleep disturbances, are associated with higher Interleukin-6 levels among head and neck cancer patients. Impact Treating health behavior problems, especially smoking and sleep disturbances, may be beneficial to decreasing Interleukin-6 levels which could have a beneficial effect on overall cancer treatment outcomes. PMID:23300019

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  6. 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…

  7. Interleukin 6 is a cause of flu-like symptoms in treatment with a deoxycytidine analogue.

    PubMed Central

    Masuda, N.; Negoro, S.; Takeda, K.; Kurata, N.; Kuwabara, T.; Kobayashi, S.; Fukuoka, M.

    1998-01-01

    The precise mechanism of fever and flu-like syndrome that occurs in treatment with deoxycytidine analogues remains unclear. This study demonstrated a strong correlation between plasma interleukin 6 levels and fever in treatment with oral (E)-2'-deoxy-2'(fluoromethylene)cytidine, another deoxycytidine analogue. PMID:9703288

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  9. Hypothermia increases interleukin-6 and interleukin-10 in juvenile endotoxemic mice

    PubMed Central

    Stewart, Corrine R.; Landseadel, Jessica P.; Gurka, Matthew J.; Fairchild, Karen D.

    2013-01-01

    Objective To develop a juvenile mouse model to establish effects of in vivo hypothermia on expression of the inflammation-modulating cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-10. Although induced hypothermia is neuroprotective in some patients, the mechanisms of protection are not well understood and concerns remain over potential detrimental effects, particularly in the setting of infection. We previously showed that in vitro hypothermia increases production of tumor necrosis factor-α and interleukin-1β in lipopolysaccharide-treated monocytes. Design Laboratory investigation. Setting Research laboratory. Subjects Juvenile (4-wk) male C57BL/6 mice. Interventions Mice were given chlorpromazine to suspend thermoregulation and lipopolysaccharide to stimulate cytokine production. Core temperature was maintained at 32°C or 37°C for 6 hrs by adjusting environmental temperature. In separate experiments, lipopolysaccharide-treated mice were kept in a cooling chamber without chlorpromazine treatment. Measurements and Main Results Plasma and organs were collected for cytokine quantitation. Chlorpromazine-treated hypothermic mice had 2.3-fold and 1.8-fold higher plasma interleukin-6 and interleukin-10 levels at 6 hrs compared with identically treated normothermic mice (p < .05), whereas plasma tumor necrosis factor-α and interleukin-1β were not significantly different at 2 hrs or 6 hrs. Liver tumor necrosis factor-α and interleukin-6 were significantly higher in hypothermic vs. normothermic mice, but lung and brain cytokines were not different. Lipopolysaccharide-treated mice kept in a cooling chamber without chlorpromazine treatment developed varying degrees of hypothermia with associated increases in plasma interleukin-6 and interleukin-10. A nonspecific marker of stress (plasma corticosterone) was not affected by hypothermia in lipopolysaccharide-treated mice. Conclusion Further studies are necessary to determine the

  10. Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance.

    PubMed

    Mammen, Cherry; Rupps, Rosemarie; Trnka, Peter; Boerkoel, Cornelius F

    2012-02-01

    We report a 5-year-old boy with thiazide-resistant Bartter syndrome. This is highly unusual since thiazide hypersensitivity is a common diagnostic finding in Bartter syndrome patients. Subsequent molecular testing identified compound heterozygosity for two novel mutations in KCNJ1, (c.556A > G and c.683G > A) which is associated with Bartter syndrome, and a paternally inherited polymorphism in SLC12A3 (c.791G > C). Mutations in SLC12A3 cause the thiazide-resistant tubulopathy Gitelman syndrome. Based on published studies of this polymorphism in SLC12A3 and the features of the proband's father, we postulate that this polymorphism modifies the phenotype of Bartter syndrome in the proband to thiazide resistance. PMID:22245519

  11. Serum levels of interleukin-6 are not dependent on the kidney function

    PubMed Central

    Nässberger, L.

    1992-01-01

    Interleukin-6, also named B-cell stimulatory factor, is a glycoprotein with a molecular weight of 26 kDa. Increased serum levels of interleukin-6 (IL-6) are found in several disease conditions. We investigated the importance of a deteriorated kidney function upon IL-6 serum concentrations. No relation was found between serum levels of IL-6 and s-creatinine, r = 0.004. On the other hand, the serum concentration of complement protein factor D and soluble IL-2 receptor showed a good correlation to s-creatinine, r = 0.92 and 0.79, respectively. In conclusion, serum levels of IL-6 are not dependent upon a reduced kidney function. PMID:18475461

  12. Cutaneous metallothionein induction by ultraviolet B irradiation in interleukin-6 null mice.

    PubMed

    Nishimura, N; Reeve, V E; Nishimura, H; Satoh, M; Tohyama, C

    2000-02-01

    The mediators of cutaneous metallothionein induction by ultraviolet radiation have not been defined. In this study we sought to identify cytokines that might be involved. We examined the role of interleukin-6, using the IL-6 null (IL-6-/-) mouse, which has been observed to be highly sensitive to ultraviolet radiation damage. Whereas cutaneous metallothionein concentration, measured by radioimmunoassay, began to rise in wild-type (IL-6+/+) mice by 12 h after ultraviolet irradiation, there was a significant delay in the IL-6-/- mice until 48 h after UV irradiation. Immunohistologically, metallothionein appeared in IL-6+/+ mice at 24 h in dermal fibroblasts, and then by 48 h in epidermal basal keratinocytes, with intensity increasing until 72 h, and was coincident with proliferating cell nuclear antigen-positive staining. Corresponding metallothionein expression in IL-6-/- mouse skin was significantly delayed. Serum interleukin-6 was elevated in IL-6+/+ mice following ultraviolet irradiation, with peak concentration at 4 h, but no increase in serum interleukin-1beta was found in either IL-6+/+ or IL-6-/- mice. Interestingly, tumor necrosis factor alpha concentration in serum was elevated at 12 h postirradiation in IL-6+/+ mice, but there was an earlier (at 4 and 8 h) time-dependent increase in tumor necrosis factor alpha in serum of the IL-6-/- mice. Skin zinc and copper concentrations were not altered by ultraviolet irradiation in either IL-6+/+ or IL-6-/- mice. The results suggest that interleukin-6 may be a very early mediator of cutaneous metallothionein induction by ultraviolet radiation, but that this role is possibly assumed by alternative cytokines like tumor necrosis factor alpha when interleukin-6 is deficient. PMID:10651996

  13. Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation?

    PubMed Central

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

    1996-01-01

    OBJECTIVE: The effects of interleukin (IL)-6 in the injured patient are examined in an attempt to clarify the potential pathophysiologic role of IL-6 in the response to injury. SUMMARY BACKGROUND DATA: Interleukin-6 is an integral cytokine mediator of the acute phase response to injury and infection. However, prolonged and excessive elevations of circulating IL-6 levels in patients after trauma, burns, and elective surgery have been associated with complications and mortality. The mechanistic role of IL-6 in mediating these effects is unclear. METHODS: A review of current literature is performed to summarize the origins, mechanisms of action, and biologic effects of IL-6 and to characterize the IL-6 response to injury. RESULTS: Interleukin-6 is a multifunctional cytokine expressed by a variety of cells after a multitude of stimuli, under complex regulatory control mechanisms. The IL-6 response to injury is uniquely consistent and related to the magnitude of the insult. Moreover, the early postinjury IL-6 response correlates with complications as well as mortality. CONCLUSIONS: Interleukin-6 appears to play an active role in the postinjury immune response, making it an attractive therapeutic target in attempts to control hyperinflammatory provoked organ injury. Images Figure 2. PMID:8916880

  14. Inhibition of endotoxin-induced interleukin-6 production by synthetic lipid A partial structures in human peripheral blood mononuclear cells.

    PubMed Central

    Wang, M H; Flad, H D; Feist, W; Brade, H; Kusumoto, S; Rietschel, E T; Ulmer, A J

    1991-01-01

    The effect of two synthetic lipid A partial structures, compound 406 (or LA-14-PP, identical in structure to the lipid A precursor, known as Ia or IVa) and compound 401 (lipid X), on the in vitro modulation of endotoxin (lipopolysaccharide)-induced interleukin-6 production by human blood mononuclear cells was investigated. Lipopolysaccharide of Salmonella abortus equi and synthetic Escherichia coli-type lipid A (compound 506, or LA-15-PP) had potent interleukin-6-inducing capacities. The maximum release of interleukin-6 was found after stimulation with 1 to 10 ng of lipopolysaccharide or 10 to 100 ng of synthetic E. coli-type lipid A per ml. Both synthetic lipid A partial structures (compounds 406 and 401) failed to induce interleukin-6 release. However, they inhibited lipopolysaccharide- or lipid A-induced interleukin-6 production in a dose-dependent manner. Inhibition was found not only in mononuclear cells but also in purified monocytes and was not due to a shift in the kinetics of cytokine production. Suppression was manifested in the early stage of interleukin-6 production. Inhibition was also found in the presence of recombinant gamma interferon, indicating that compound 406 and recombinant gamma interferon act in different, independent pathways. Our data, therefore, indicate that the inhibition of interleukin-6 production by lipid A partial structures may help elucidate the mechanism of interaction of the lipid A component of lipopolysaccharide with immune cells in the inflammatory reaction during gram-negative infection. PMID:1937825

  15. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis

    PubMed Central

    2012-01-01

    Summary Background A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. Methods Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. Findings In 40 studies including up to 133 449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34–10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31–9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60–1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4–8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25 458 coronary heart disease cases and 100 740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93–0·97, p=1·53×10−5). Interpretation On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to

  16. 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.

  17. Pathways to postoperative hostility in cardiac patients: mediation of coping, spiritual struggle and interleukin-6.

    PubMed

    Ai, Amy Lee; Pargament, Kenneth; Kronfol, Ziad; Tice, Terrence N; Appel, Hoa

    2010-03-01

    Using structural equation modeling, we estimated major pathways from preoperative distress, indicated by anxiety and other factors, to postoperative hostility in cardiac patients. Sequential interviews were conducted before and after surgery. Standardized medical and surgical indices were selected from a national database. Results showed that preoperative spiritual struggle mediated indirect effects of anxiety and anger coping on Interleukin-6 (IL-6) immediately before surgery. The link between spiritual struggle and IL-6 further mediated the indirect effects of anxiety and anger coping on postoperative hostility. Anger coping mediated the harmful influence of anxiety and counteracted the protection of positive religious coping on adjustment. PMID:20207662

  18. The serum level of interleukin-6 in patients with intellectual disability and refractory epilepsy.

    PubMed

    Lehtimäki, Kai A; Liimatainen, Suvi; Peltola, Jukka; Arvio, Maria

    2011-06-01

    We aimed to study the influences of active epilepsy and intellectual disability (ID) on the serum interleukin-6 (IL-6) by determining levels in 74 patients with developmental disorder with epilepsy and 63 healthy controls. The patients showed significantly higher IL-6 levels than the controls (4.1±4.5pg/ml vs. 2.1±1.0pg/ml; p<0.001). High seizure frequency and severe intellectual disability emerged as predictors for elevated serum levels of IL-6. PMID:21530175

  19. Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons.

    PubMed

    Orellana, D I; Quintanilla, R A; Gonzalez-Billault, C; Maccioni, R B

    2005-11-01

    Recent studies show that inflammation has an active role in the onset of neurodegenerative diseases. It is known that in response to extracellular insults microglia and/or astrocytes produce inflammatory agents. These contribute to the neuropathological events in the aging process and neuronal degeneration. Interleukin-6 (IL-6) has been involved in the pathogenesis of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Here, we show that IL-6 treatment of rat hippocampal neurons increases the calcium influx via NMDA-receptor, an effect that is prevented by the specific NMDA receptor antagonist MK-801 (dizocilpine). We also show that this calcium influx is mediated by the JAKs/STATs pathway, since the inhibitor of JAKs/STATs pathway, JAK 3 inhibitor, blocks calcium influx even in the presence of IL-6. This increase in calcium signal was dependent on external sources, since this signal was not observed in the presence of EGTA. Additional studies indicate that the increase in cytosolic calcium induces tau protein hyperphosphorylation, as revealed by using specific antibodies against Alzheimer phosphoepitopes. This anomalous tau hyperphosphorylation was dependent on both the JAKs/STATs pathway and NMDA receptor. These results suggest that IL-6 would induce a cascade of molecular events that produce a calcium influx through NMDA receptors, mediated by the JAKs/STATs pathway, which subsequently modifies the tau hyperphosphorylation patterns. PMID:16371324

  20. 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

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

    DOE PAGESBeta

    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 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

  2. 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.

  3. Serum interleukin-6 as a prognostic marker in neonatal calf diarrhea.

    PubMed

    Fischer, Stephani; Bauerfeind, Rolf; Czerny, Claus-Peter; Neumann, Stephan

    2016-08-01

    Neonatal calf diarrhea is still one of the most important diseases in calf rearing, and severe diarrhea has a marked effect on animal welfare. Furthermore, significant economic losses can result from this disease due to high mortality rates, high medical costs, and low weight gain. To avoid a fatal outcome of the disease, it is crucial that vulnerable calves are identified as early as possible. Interleukin-6 is described as an early and reliable prognostic marker in several diseases. In this study, 20 scouring calves were tested by ELISA for their IL-6 serum concentrations. Samples were collected twice, at the beginning of diarrhea and 7 to 10d later. Regarding the clinical outcome after 7 to 10d, calves were classified as recovered or nonrecovered. A receiver operating characteristic analysis was conducted to determine the prognostic value of IL-6 for the progress of clinical symptoms. At the beginning of diarrhea, the IL-6 concentration was significantly higher in nonrecovering calves compared with those that recover 7 to 10d after the onset of diarrhea. Interleukin-6 proved to be a useful additional parameter in the clinical examination. High initial IL-6 values can support the decision for closer monitoring and an adapted therapeutic strategy for the respective calves. This may help to prevent unnecessary animal suffering and reduce economic losses. PMID:27209135

  4. Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists

    SciTech Connect

    Zhang Songwen Liu Qiangyuan; Wang Juan; Harnish, Douglas C.

    2009-02-06

    C-reactive protein (CRP), a human acute-phase protein, is a risk factor for future cardiovascular events and exerts direct pro-inflammatory and pro-atherogenic properties. The farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily, plays an essential role in the regulation of enterohepatic circulation and lipid homeostasis. In this study, we report that two synthetic FXR agonists, WAY-362450 and GW4064, suppressed interleukin-6-induced CRP expression in human Hep3B hepatoma cells. Knockdown of FXR by short interfering RNA attenuated the inhibitory effect of the FXR agonists and also increased the ability of interleukin-6 to induce CRP production. Furthermore, treatment of wild type C57BL/6 mice with the FXR agonist, WAY-362450, attenuated lipopolysaccharide-induced serum amyloid P component and serum amyloid A3 mRNA levels in the liver, whereas no effect was observed in FXR knockout mice. These data provide new evidence for direct anti-inflammatory properties of FXR.

  5. β-(1→3)-Glucan of the Southern Bracket Mushroom, Ganoderma australe (Agaricomycetes), Stimulates Phagocytosis and Interleukin-6 Production in Mouse Peritoneal Macrophages.

    PubMed

    de Melo, Renan Henrique; do Amaral, Alex Evangelista; Menolli, Rafael Andrade; Ayala, Thais Soprani; de Cassia Garcia Simao, Rita; de Santana-Filho, Arquimedes Paixao; Sassaki, Guilherme Lanzi; Kadowaki, Marina Kimiko; da Conceicao Silva, Jose Luis

    2016-01-01

    Ganoderma australe was studied to determine the composition of the cell wall, and polysaccharide fraction SK5 was obtained after freeze-thawing an aqueous 5% potassium hydroxide extraction. The monosaccharide composition of the SK5 fraction revealed by gas chromatography-mass spectrometry showed 81.3% glucose, and analyses by 13C nuclear magnetic resonance spectroscopy confirmed a β-glucan with glycosidic links of the (1→3)-β type and most likely 4-O substituted. In addition, the biological effect of the β-glucan from G. australe was evaluated via in vitro cell cultures of peritoneal macrophages isolated from Swiss mice. Biological assays were assessed for toxicity and cell activation, interleukin-6 cytokine concentrations, and the ability to stimulate phagocytic activity. There was an increase in interleukin-6 by approximately 111% with 1.0 µg/mL of polysaccharide, and phagocyte activity was increased in all concentrations examined, obtaining 52.3% with 0.25 µg/mL polysaccharide. The results indicate that a β-(1→3)-glucan isolated from G. australe can be classified as a biological response modifier. PMID:27481297

  6. Interleukin-6 induces keratin expression in intestinal epithelial cells: potential role of keratin-8 in interleukin-6-induced barrier function alterations.

    PubMed

    Wang, Lixin; Srinivasan, Shanthi; Theiss, Arianne L; Merlin, Didier; Sitaraman, Shanthi V

    2007-03-16

    Keratin 8 (K8) and keratin-18 (K18) are the major intermediate filament proteins in the intestinal epithelia. The regulation and function of keratin in the intestinal epithelia is largely unknown. In this study we addressed the role and regulation of K8 and K18 expression by interleukin 6 (IL-6). Caco2-BBE cell line and IL-6 null mice were used to study the effect of IL-6 on keratin expression. Keratin expression was studied by Northern blot, Western blot, and confocal microscopy. Paracellular permeability was assessed by apical-to-basal transport of a fluorescein isothiocyanate dextran probe (FD-4). K8 was silenced using the small interfering RNA approach. IL-6 significantly up-regulated mRNA and protein levels of K8 and K18. Confocal microscopy showed a reticular pattern of intracellular keratin localized to the subapical region after IL-6 treatment. IL-6 also induced serine phosphorylation of K8. IL-6 decreased paracellular flux of FD-4 compared with vehicle-treated monolayers. K8 silencing abolished the decrease in paracellular permeability induced by IL-6. Administration of dextran sodium sulfate (DSS) significantly increased intestinal permeability in IL-6-/- mice compared with wild type mice given DSS. Collectively, our data demonstrate that IL-6 regulates the colonic expression of K8 and K18, and K8/K18 mediates barrier protection by IL-6 under conditions where intestinal barrier is compromised. Thus, our data uncover a novel function of these abundant cytoskeletal proteins, which may have implications in intestinal disorders such as inflammatory bowel disease wherein barrier dysfunction underlies the inflammatory response. PMID:17213200

  7. Polymorphism in LEP and LEPR May Modify Leptin Levels and Represent Risk Factors for Thyroid Cancer

    PubMed Central

    Marcello, Marjory Alana; Calixto, Antonio Ramos; de Almeida, Jacqueline Fatima Martins; Cunha, Lucas Leite; Cavalari, Camila Ayume Amano; Etchebehere, Elba C. S.; da Assumpção, Ligia Vera Montalli; Geloneze, Bruno; Carvalho, Andre Lopes; Ward, Laura Sterian

    2015-01-01

    Purpose. To understand the role of polymorphisms in the LEP (rs7799039 and rs2167270) and LEPR (rs1137101 and rs1137100) genes in DTC susceptibility and their effect on leptin levels. Methods. We studied 153 patients with DTC and 234 controls through TaqMan SNP Genotyping and ELISA, comparing these data to the clinicopathological data of patients with DTC. Results. Patients with AA genotype of rs7799039 had higher levels of serum leptin (9.22 ± 0.98 ng/mL) than those with AG genotype (10.07 ± 0.60 ng/mL; P = 0.005). Individuals with AG genotype of rs2167270 also produced higher serum leptin levels (10.05 ± 0.59 ng/mL) than the subjects with GG genotype (9.52 ± 0.79 ng/mL; P < 0.05). A multivariate logistic regression adjusted for gender, age, and BMI showed that the AG genotype of rs7799039 was an independent risk for DTC (OR, 11.689; P = 0.0183; 95% CI, 1.516–90.119). Similarly, AG and GG genotypes of rs1137101 increased the susceptibility to DTC (OR, 3.747; P = 0.027; 95% CI, 1.161–12.092 and OR, 5.437; P = 0.013; 95% CI, 1.426–20.729). Conclusions. We demonstrated that rs7799039 and rs2167270 polymorphisms modify the serum leptin concentrations in patients with DTC. Furthermore, polymorphisms rs7799039 and rs1137101 increase the risk of DTC development, although they do not correlate with tumor aggressiveness. PMID:25810718

  8. Polymorphism in LEP and LEPR May Modify Leptin Levels and Represent Risk Factors for Thyroid Cancer.

    PubMed

    Marcello, Marjory Alana; Calixto, Antonio Ramos; de Almeida, Jacqueline Fatima Martins; Martins, Mariana Bonjiorno; Cunha, Lucas Leite; Cavalari, Camila Ayume Amano; Etchebehere, Elba C S; da Assumpção, Ligia Vera Montalli; Geloneze, Bruno; Carvalho, Andre Lopes; Ward, Laura Sterian

    2015-01-01

    Purpose. To understand the role of polymorphisms in the LEP (rs7799039 and rs2167270) and LEPR (rs1137101 and rs1137100) genes in DTC susceptibility and their effect on leptin levels. Methods. We studied 153 patients with DTC and 234 controls through TaqMan SNP Genotyping and ELISA, comparing these data to the clinicopathological data of patients with DTC. Results. Patients with AA genotype of rs7799039 had higher levels of serum leptin (9.22 ± 0.98 ng/mL) than those with AG genotype (10.07 ± 0.60 ng/mL; P = 0.005). Individuals with AG genotype of rs2167270 also produced higher serum leptin levels (10.05 ± 0.59 ng/mL) than the subjects with GG genotype (9.52 ± 0.79 ng/mL; P < 0.05). A multivariate logistic regression adjusted for gender, age, and BMI showed that the AG genotype of rs7799039 was an independent risk for DTC (OR, 11.689; P = 0.0183; 95% CI, 1.516-90.119). Similarly, AG and GG genotypes of rs1137101 increased the susceptibility to DTC (OR, 3.747; P = 0.027; 95% CI, 1.161-12.092 and OR, 5.437; P = 0.013; 95% CI, 1.426-20.729). Conclusions. We demonstrated that rs7799039 and rs2167270 polymorphisms modify the serum leptin concentrations in patients with DTC. Furthermore, polymorphisms rs7799039 and rs1137101 increase the risk of DTC development, although they do not correlate with tumor aggressiveness. PMID:25810718

  9. Psychiatric and cognitive symptoms in Huntington's disease are modified by polymorphisms in catecholamine regulating enzyme genes.

    PubMed

    Vinther-Jensen, T; Nielsen, T T; Budtz-Jørgensen, E; Larsen, I U; Hansen, M M; Hasholt, L; Hjermind, L E; Nielsen, J E; Nørremølle, A

    2016-03-01

    Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene but the exact pathogenesis remains unknown. Dopamine imbalance has previously been shown in HD, and furthermore dopamine is thought to be implicated in cognition, behavioral and motor disturbances. A substantiated inverse correlation between motor onset and the elongated CAG repeat in the HTT has been established. This relation does not account for the full variability of the motor onset, and efforts have been put into finding genetic modifiers of motor onset, however, mostly with unsuccessful outcome. In this study, we took an alternative approach focusing on symptom complexes and searched for modifiers of cognitive impairment and psychiatric symptoms in a well-described cohort of Danish HD gene-expansion carriers. We show that cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) genes and by the 4p16.3 B haplotype. These results support the theory of dopamine imbalance in HD, and point toward more personalized treatment modalities of HD in the future. PMID:26081309

  10. CD45 negatively regulates tumour necrosis factor and interleukin-6 production in dendritic cells.

    PubMed

    Piercy, Jenny; Petrova, Svetla; Tchilian, Elma Z; Beverley, Peter C L

    2006-06-01

    CD45 is known to regulate signalling through many different surface receptors in diverse haemopoietic cell types. Here we report for the first time that CD45-/- bone marrow dendritic cells (BMDC) are more activated than CD45+/+ cells and that tumour necrosis factor (TNF) and interleukin-6 (IL-6) production by BMDC and splenic dendritic cells (sDC), is increased following stimulation via Toll-like receptor (TLR)3 and TLR9. Nuclear factor-kappaB activation, an important downstream consequence of TLR3 and TLR9 signalling, is also increased in CD45-/- BMDC. BMDC of CD45-/- mice also produce more TNF and IL-6 following stimulation with the cytokines TNF and interferon-alpha. These results show that TLR signalling is increased in CD45-/- dendritic cells and imply that CD45 is a negative regulator of TLR and cytokine receptor signalling in dendritic cells. PMID:16771860

  11. 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

  12. 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

  13. 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

  14. Self-compassion as a predictor of interleukin-6 response to acute psychosocial stress

    PubMed Central

    Breines, Juliana G.; Thoma, Myriam V.; Gianferante, Danielle; Hanlin, Luke; Chen, Xuejie; Rohleder, Nicolas

    2015-01-01

    We examined the hypothesis that self-compassion is associated with lower levels of stress-induced inflammation. On two consecutive days, plasma concentrations of interleukin-6 (IL-6) were assessed at baseline and at 30 and 120 minutes following exposure to a standardized laboratory stressor in a sample of 41 healthy young adults. Participants who were higher in self-compassion exhibited significantly lower day 1 IL-6 responses, even when controlling for self-esteem, depressive symptoms, demographic factors, and distress. Self-compassion was not related to day 2 IL-6 response but was inversely related to day 2 baseline IL-6 levels, and to increase in baseline IL-6 from day 1 to day 2. These findings suggest that self-compassion may serve as a protective factor against stress-induced inflammation and inflammation-related disease. PMID:24239953

  15. Interleukin-6 trans signalling enhances photodynamic therapy by modulating cell cycling

    PubMed Central

    Wei, L-H; Baumann, H; Tracy, E; Wang, Y; Hutson, A; Rose-John, S; Henderson, B W

    2007-01-01

    Photodynamic therapy (PDT) of solid tumours causes tissue damage that elicits local and systemic inflammation with major involvement of interleukin-6 (IL-6). We have previously reported that PDT-treated cells lose responsiveness to IL-6 cytokines. Therefore, it is unclear whether PDT surviving tumour cells are subject to regulation by IL-6 and whether this regulation could contribute to tumour control by PDT. We demonstrate in epithelial tumour cells that while the action of IL-6 cytokines through their membrane receptors is attenuated, regulation by IL-6 via trans-signalling is established. Soluble interleukin-6 receptor-α (IL-6Rα) (sIL-6Rα) and IL-6 were released by leucocytes in the presence of conditioned medium from PDT-treated tumour cells. Cells that had lost their membrane receptor IL-6Rα due to PDT responded to treatment with the IL-6R–IL-6 complex (Hyper-IL-6) with activation of signal transducers and activator of transcription (STAT3) and ERK. Photodynamic therapy-treated cells, which were maintained during post-PDT recovery in presence of IL-6 or Hyper-IL-6, showed an enhanced suppression of proliferation. Cytokine-dependent inhibition of proliferation correlated with a decrease in cyclin E, CDK2 and Cdc25A, and enhancement of p27kip1 and hypophosphorylated Rb. The IL-6 trans-signalling-mediated attenuation of cell proliferation was also effective in vivo detectable by an improved Colon26 tumour cure by PDT combined with Hyper-IL-6 treatment. Prevention of IL-6 trans-signalling using soluble gp130 reduced curability. The data suggest that the post-PDT tumour milieu contains the necessary components to establish effective IL-6 trans-signalling, thus providing a means for more effective tumour control. PMID:17987036

  16. 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.

  17. 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

  18. Associations of Toenail Selenium Levels With Inflammatory Biomarkers of Fibrinogen, High-Sensitivity C-Reactive Protein, and Interleukin-6

    PubMed Central

    Xun, Pengcheng; Liu, Kiang; Steven Morris, J.; Daviglus, Martha L.; Stevens, June; Jacobs, David R.; He, Ka

    2010-01-01

    The authors examined the associations of toenail selenium levels with blood concentrations of fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) in an 18-year follow-up study comprising 4,032 Americans aged 20–32 years at baseline (1987) from the Coronary Artery Risk Development in Young Adults (CARDIA) Trace Element Study. Toenail samples were collected in 1987, and selenium concentrations were measured by means of instrumental neutron-activation analysis. Fibrinogen level was analyzed in 1990, 1992, and 2005; hs-CRP was assessed in 1992, 2000, and 2005; and IL-6 was measured in 2005. After adjustment for potential confounders, no statistically significant associations between toenail selenium levels and any of the 3 inflammatory biomarkers were documented. Comparing the highest quintile of toenail selenium level with the lowest, odds ratios for elevated levels of fibrinogen (>460 mg/mL), hs-CRP (>3 μg/mL), and IL-6 (>3.395 pg/mL, 80th percentile) were 1.03 (95% confidence interval (CI): 0.77, 1.38; P for trend = 0.76), 1.02 (95% CI: 0.83, 1.27; P for trend = 0.92), and 0.98 (95% CI: 0.71, 1.36; P for trend = 0.82), respectively. Gender, race/ethnicity, smoking status, and selenium supplementation did not appreciably modify these results. This study found no associations between toenail selenium and inflammation as measured by fibrinogen, hs-CRP, and IL-6. PMID:20219762

  19. 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

  20. 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. PMID:26542080

  1. 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

  2. Osteoclasts are not the major source of interleukin-6 in mouse parietal bones.

    PubMed

    Holt, I; Davie, M W; Marshall, M J

    1996-03-01

    Interleukin-6 (IL-6) is produced by bone cells and has been shown to stimulate the proliferation of osteoclast progenitors. Which cells in bone produce IL-6 is controversial. This article tests the hypothesis that tartrate-resistant acid phosphatase-positive osteoclasts (TRAP + OC) in neonatal mouse parietal bones are the major source of IL-6. Bones were preincubated with indomethacin to decrease the number of TRAP + OC and the amount of IL-6 produced. Incubation with parathyroid hormone or prostaglandin E2 increased the number of TRAP + OC and the amount of IL-6 produced. Calcitonin and 17 beta-estradiol inhibited this increase in TRAP + OC but had no effect on IL-6 production. 1,25-dihydroxy-vitamin D3 also stimulated an increase in TRAP + OC number but did not cause increased IL-6 production. Both the endocranial and ectocranial membranes of these bones produced large amounts of IL-6. TRAP activity in extracts of endocranial membranes was 14-fold that of the ectocranial membrane and, histochemically, some TRAP + cells could be detected here. However, the ectocranial membranes produced more IL-6 than the endocranial membranes. We conclude that TRAP + OC are not a major source of IL-6 in this system. PMID:8703576

  3. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130.

    PubMed Central

    Narazaki, M; Witthuhn, B A; Yoshida, K; Silvennoinen, O; Yasukawa, K; Ihle, J N; Kishimoto, T; Taga, T

    1994-01-01

    The interleukin 6 receptor-associated signal transducer, gp130, is shared by receptor complexes for leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and interleukin 11. We show here that JAK2 kinase is rapidly tyrosine phosphorylated in mouse embryonic stem cells whose pluripotentiality is maintained only by gp130-sharing cytokines after stimulation that is known to induce gp130 homodimerization. JAK1 is also tyrosine phosphorylated, but to a lesser extent, under the same conditions. Comparable results are obtained with hemopoietic lineage cells such as myeloid leukemic M1 cells and pro-B-cell line-derived transfectants expressing gp130, the former of which differentiate into macrophages after stimulation of gp130 and the latter of which initiate DNA synthesis. gp130-dimerizing stimulus upregulates kinase activity of JAK2 as revealed by immunocomplex kinase assay. Deletion or point mutation in the membrane-proximal cytoplasmic motifs in gp130 that are conserved in the hemopoietic cytokine receptor family results in the loss of tyrosine phosphorylation of JAK2, which coincides with the lack of signal transducing capability of gp130 mutants. Images PMID:8134389

  4. 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

  5. Whole-Body In Vivo Monitoring of Inflammatory Diseases Exploiting Human Interleukin 6-Luciferase Transgenic Mice.

    PubMed

    Hayashi, Makiko; Takai, Jun; Yu, Lei; Motohashi, Hozumi; Moriguchi, Takashi; Yamamoto, Masayuki

    2015-10-01

    Chronic inflammation underlies the pathological progression of various diseases, and thus many efforts have been made to quantitatively evaluate the inflammatory status of the diseases. In this study, we generated a highly sensitive inflammation-monitoring mouse system using a bacterial artificial chromosome (BAC) clone containing extended flanking sequences of the human interleukin 6 gene (hIL6) locus, in which the luciferase (Luc) reporter gene is integrated (hIL6-BAC-Luc). We successfully monitored lipopolysaccharide-induced systemic inflammation in various tissues of the hIL6-BAC-Luc mice using an in vivo bioluminescence imaging system. When two chronic inflammatory disease models, i.e., a genetic model of atopic dermatitis and a model of experimental autoimmune encephalomyelitis (EAE), were applied to the hIL6-BAC-Luc mice, luciferase bioluminescence was specifically detected in the atopic skin lesion and central nervous system, respectively. Moreover, the Luc activities correlated well with the disease severity. Nrf2 is a master transcription factor that regulates antioxidative and detoxification enzyme genes. Upon EAE induction, the Nrf2-deficient mice crossed with the hIL6-BAC-Luc mice exhibited enhanced neurological symptoms concomitantly with robust luciferase luminescence in the neuronal tissue. Thus, whole-body in vivo monitoring using the hIL6-BAC-Luc transgenic system (WIM-6 system) provides a new and powerful diagnostic tool for real-time in vivo monitoring of inflammatory status in multiple different disease models. PMID:26283726

  6. Curcumin half analog modulates interleukin-6 and tumor necrosis factor-alpha in inflammatory bowel disease

    PubMed Central

    Kondamudi, Phani Krishna; Kovelamudi, Hemalatha; Nayak, Pawan G.; Rao, Mallikarjuna Chamallamudi; Shenoy, Rekha Raghuveer

    2015-01-01

    Background: The present study was aimed at examining the effect of dehydrozingerone (DHZ), half analogue of curcumin which is the active constituent of turmeric (Curcuma longa) in the di-nitrochlorobenzene (DNCB) induced model for inflammatory bowel disease (IBD). Materials and Methods: Male Wistar rats (200–220 g) were divided into four groups (n = 6). Chemical induction of IBD was done by sensitizing with 300 µL of 20 g/L of DNCB (in acetone) onto the nape of rats for 14 days followed by intra-colonic instillation of 250 µL of DNCB (0.1% DNCB in 50% alcohol) solution on day 15. Rats in Group 1 (normal control) and Group 2 (DNCB control) were treated with vehicle. Rats in Group 3 were treated with DHZ (100 mg/kg, p.o.; 8 days) and Group 4 animals were treated with sulfasalazine (SS) (100 mg/kg, p.o.; 8 days). On 24th day, the rats were killed, colon removed and the macroscopic, biochemical, and histopathological evaluations were performed. Results: The levels of myeloperoxidase, thiobarbituric acid reactive substrate, and nitrite increased significantly (P < 0.05) in the DNCB group whereas reduced significantly in the DHZ and SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. Interleukin-6, tumor necrosis factor-alpha level was significantly high in the DNCB group. Conclusion: These findings show that DHZ can be a promising molecule for the treatment of IBD. PMID:26664018

  7. 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

  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

    2016-01-01

    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

  9. 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. PMID:26416691

  10. ARTD1 Suppresses Interleukin 6 Expression by Repressing MLL1-Dependent Histone H3 Trimethylation.

    PubMed

    Minotti, Roberta; Andersson, Anneli; Hottiger, Michael O

    2015-09-01

    ADP-ribosyltransferase diphtheria-toxin like 1/poly(ADP-ribose) polymerase 1 (ARTD1/PARP1) is a chromatin-associated protein in the nucleus and plays an important role in different cellular processes such as regulation of gene transcription. ARTD1 has been shown to coregulate the inflammatory response by modulating the activity of the transcription factor nuclear factor κB (NF-κB), the principal regulator of interleukin 6 (IL-6), an important inflammatory cytokine implicated in a variety of diseases such as cancer. However, to what extent and how ARTD1 regulates IL-6 transcription has not been clear. Here, we show that ARTD1 suppresses lipopolysaccharide (LPS)-induced IL-6 expression in macrophages, without affecting the recruitment of the NF-κB subunit RelA to the IL-6 promoter and independent of its enzymatic activity. Interestingly, knockdown of ARTD1 did not alter H3 occupancy but increased LPS-induced trimethylation of histone 3 at lysine 4 (H3K4me3), a hallmark of transcriptionally active genes. We found that ARTD1 mediates its effect through the methyltransferase MLL1, by catalyzing H3K4me3 at the IL-6 promoter and forming a complex with NF-κB. These results demonstrate that ARTD1 modulates IL-6 expression by regulating the function of an NF-κB enhanceosome complex, which involves MLL1 and does not require ADP-ribosylation. PMID:26149390

  11. Ambivalent aspects of interleukin-6 in cerebral ischemia: inflammatory versus neurotrophic aspects.

    PubMed

    Suzuki, Shigeaki; Tanaka, Kortaro; Suzuki, Norihiro

    2009-03-01

    Interleukin-6 (IL-6) is pleiotropic cytokine involved in many central nervous system disorders including stroke, and elevated serum IL-6 has been found in acute stroke patients. IL-6 is implicated in the inflammation, which contributes to both injury and repair process after cerebral ischemia. However, IL-6 is one of the neurotrophic cytokines sharing a common receptor subunit, gp130, with other neurotrophic cytokines, such as leukemia inhibitory factor (LIF) and ciliary neurotrophic factor. The expression of IL-6 is most prominently identified in neurons in the peri-ischemic regions, and LIF expression shows a similar pattern. The direct injection of these cytokines into the brain after ischemia can reduce ischemic brain injury. The cytokine receptors are localized on the neuron surface, suggesting that neurons are the cytokine target. The major IL-6 downstream signaling pathway is JAK-STAT, and Stat3 activation occurs mainly in neurons during postischemic reperfusion. Further investigation is necessary to clarify the exact role of Stat3 signaling in neuroprotection. Taken together, the information suggests that IL-6 plays a double role in cerebral ischemia, as an inflammatory mediator during the acute phase and as a neurotrophic mediator between the subacute and prolonged phases. PMID:19018268

  12. 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. PMID:25253697

  13. Are circulating cytokines interleukin-6 and tumor necrosis factor alpha involved in chlorpyrifos-induced fever?

    PubMed

    Gordon, C J; Rowsey, P J

    1999-05-01

    Oral exposure to chlorpyrifos (CHP) in the rat results in an initial hypothermic response followed by a delayed fever. Fever from infection is mediated by the release of cytokines, including interleukin-6 (IL-6) and tumor necrosis factor (TNF alpha). This study determined if the CHP-induced fever involves cytokine-mediated mechanisms similar to that of infectious fevers. Long-Evans rats were gavaged with the corn oil vehicle or CHP (10-50 mg/kg). The rats were euthanized and blood collected at various times that corresponded with the hypothermic and febrile effects of CHP. Plasma IL-6, TNF alpha, cholinesterase activity (ChE), total iron, unsaturated iron binding capacity (UIBC), and zinc were measured. ChE activity was reduced by approximately 50% 4 h after CHP. There was no effect of CHP on IL-6 when measured during the period of CHP-induced hypothermia or fever. TNF alpha levels nearly doubled in female rats 48 h after 25 mg/kg CHP. The changes in plasma cytokine levels following CHP were relatively small when compared to > 1000-fold increase in IL-6 and > 10-fold rise in TNF alpha following lipopolysaccharide (E. coli; 50 microg/kg; i.p.)-induced fever. This does not preclude a role of cytokines in CHP-induced fever. Nonetheless, the data suggest that the delayed fever from CHP is unique, involving mechanisms other than TNF alpha and IL-6 release into the circulation characteristic of infectious fevers. PMID:10413184

  14. Low serum levels of interleukin-6 in children with post-infective acute thrombocytopenic purpura.

    PubMed

    Gangarossa, S; Romano, V; Munda, S E; Sciotto, A; Schilirò, G

    1995-08-01

    Interleukin-6 plays an important role in host defense mechanisms and it appears to be a major mediator of the acute-phase response. IL-6 is also an important thrombocytopoietic factor. High serum levels of IL-6 are present in reactive thrombocytosis. The number and function of circulating platelets are the major factors that affect megakaryocytopoiesis by thrombopoietin. High levels of thrombopoietin have been observed in patients with thrombocytopenic purpura. To evaluate a possible thrombopoietin-like function of IL-6, we measured IL-6 levels in the serum of patients affected by post-infective acute thrombocytopenic purpura using a sensitive ELISSA assay. As controls, we studied normal subjects and patients with reactive thrombocytosis. No significant difference was observed between thrombocytopenic patients and normal controls. High IL-6 levels were present in patients with reactive thrombocytosis. In conclusion, we had not observed high levels of IL-6 in acute thrombocytopenic purpura and, very probably, IL-6 is not involved in the regulation of platelet mass for the hemostatic function. The thrombocytopoietic activity of IL-6 is another acute-phase response and it is consistent with the other functions of this cytokine. This suggests an active participation of platelets in host defense mechanisms. PMID:7628586

  15. Muscle-derived interleukin-6: lipolytic, anti-inflammatory and immune regulatory effects.

    PubMed

    Pedersen, Bente Klarlund; Steensberg, Adam; Keller, Pernille; Keller, Charlotte; Fischer, Christian; Hiscock, Natalie; van Hall, Gerrit; Plomgaard, Peter; Febbraio, Mark A

    2003-04-01

    Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the exercise-induced increase in plasma IL-6. The transcription rate for IL-6 in muscle nuclei isolated from muscle biopsies during exercise is very high and is enhanced further when muscle glycogen content is low. Furthermore, cultured human primary muscle cells can increase IL-6 mRNA when incubated with the calcium ionophore ionomycin and it is likely that myocytes produce IL-6 in response to muscle contraction. The biological roles of muscle-derived IL-6 have been investigated in studies in which human recombinant IL-6 was infused in healthy volunteers to mimic closely the IL-6 concentrations observed during prolonged exercise. Using stable isotopes, we have demonstrated that physiological concentrations of IL-6 induce lipolysis. Although we have yet to determine the precise biological action of muscle-derived IL-6, our data support the hypothesis that the role of IL-6 released from contracting muscle during exercise is to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery during exercise. In addition, IL-6 inhibits low-level TNF-alpha production, and IL-6 produced during exercise probably inhibits TNF-alpha-induced insulin resistance in peripheral tissues. Hence, IL-6 produced by skeletal muscle during contraction may play an important role in the beneficial health effects of exercise PMID:12690457

  16. 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

  17. 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

  18. Differential Control of Interleukin-6 mRNA Levels by Cellular Distribution of YB-1

    PubMed Central

    Kang, Sujin; Lee, Taeyun A.; Ra, Eun A.; Lee, Eunhye; Choi, Hyun jin; Lee, Sungwook; Park, Boyoun

    2014-01-01

    Cytokine production is essential for innate and adaptive immunity against microbial invaders and must be tightly controlled. Cytokine messenger RNA (mRNA) is in constant flux between the nucleus and the cytoplasm and in transcription, splicing, or decay; such processes must be tightly controlled. Here, we report a novel function of Y-box-binding protein 1 (YB-1) in modulating interleukin-6 (IL-6) mRNA levels in a cell type-specific manner. In lipopolysaccharide (LPS)-stimulated macrophages, YB-1 interacts with IL-6 mRNA and actively transports it to the extracellular space by YB-1-enriched vesicles, resulting in the proper maintenance of intracellular IL-6 mRNA levels. YB-1 secretion occurs in a cell type-specific manner. Whereas macrophages actively secret YB-1, dendritic cells maintain it predominantly in the cytoplasm even in response to LPS. Intracellular YB-1 has the distinct function of regulating IL-6 mRNA stability in dendritic cells. Moreover, because LPS differentially regulates the expression of histone deacetylase 6 (HDAC6) in macrophages and dendritic cells, this stimulus might control YB-1 acetylation differentially in both cell types. Taken together, these results suggest a unique feature of YB-1 in controlling intracellular IL-6 mRNA levels in a cell type-specific manner, thereby leading to functions that are dependent on the extracellular and intracellular distribution of YB-1. PMID:25398005

  19. 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. ?? 2007 American Society of Mammalogists.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26251044

  1. Gender Difference in the Prognostic Role of Interleukin 6 in Oral Squamous Cell Carcinoma

    PubMed Central

    Chen, Chih-Jung; Sung, Wen-Wei; Lin, Yueh-Min; Chen, Mu-Kuan; Lee, Ching-Hsiao

    2012-01-01

    Background Interleukin 6 (IL6) plays an important role in immunoregulation and tumorigenesis in human cancers. Oral squamous cell carcinoma (OSCC) is a malignant tumor of the oral cavity with a male predominant tendency and a poor clinical prognosis. Due to the relatively few cases in females, the gender difference of prognostic markers for OSCC is seldom discussed. Methods In this study, we used immunohistochemical staining methods to investigate the associations between IL6 expression and the clinicopathological characteristics of OSCC. In addition, we collected 74 female and 263 male OSCC patients for evaluation. Results High IL6 expression in tumor cells was significantly associated OSCC patient characteristics including female gender (P<0.001), high lymph node metastatic rate (P = 0.007), and poor tumor differentiation (P = 0.008). Tumor-expressed IL6 had prognostic role in male OSCC patients as defined by the log-rank test (P = 0.014), but not in female patients (P = 0.959). In male OSCC patients, high IL6 expression in tumor cells was associated with poor prognosis (P = 0.025) and a 1.454-fold higher death risk, as determined by Cox regression. Conclusions High IL6 expression in tumor cells was therefore significantly associated with aggressive clinical manifestations and might be an independent survival predictor, particularly in male OSCC patients. PMID:23185547

  2. Endothelial interleukin-6 defines the tumorigenic potential of primary human cancer stem cells.

    PubMed

    Krishnamurthy, Sudha; Warner, Kristy A; Dong, Zhihong; Imai, Atsushi; Nör, Carolina; Ward, Brent B; Helman, Joseph I; Taichman, Russell S; Bellile, Emily L; McCauley, Laurie K; Polverini, Peter J; Prince, Mark E; Wicha, Max S; Nör, Jacques E

    2014-11-01

    Head and neck squamous cell carcinomas (HNSCC) contain a small subpopulation of stem cells endowed with unique capacity to generate tumors. These cancer stem cells (CSC) are localized in perivascular niches and rely on crosstalk with endothelial cells for survival and self-renewal, but the mechanisms involved are unknown. Here, we report that stromal interleukin (IL)-6 defines the tumorigenic capacity of CSC sorted from primary human HNSCC and transplanted into mice. In search for the cellular source of Interleukin-6 (IL-6), we observed a direct correlation between IL-6 levels in tumor-associated endothelial cells and the tumorigenicity of CSC. In vitro, endothelial cell-IL-6 enhanced orosphere formation, p-STAT3 activation, survival, and self-renewal of human CSC. Notably, a humanized anti-IL-6R antibody (tocilizumab) inhibited primary human CSC-mediated tumor initiation. Collectively, these data demonstrate that endothelial cell-secreted IL-6 defines the tumorigenic potential of CSC, and suggest that HNSCC patients might benefit from therapeutic inhibition of IL-6/IL-6R signaling. PMID:25078284

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

    PubMed Central

    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

    2016-01-01

    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 Phe229 and Phe279 of IL-6R. In the first antibody, a HCDR3 tryptophan binds similarly to hot spot residue Phe279. 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 Phe279. In the second antibody, the side chain of HCDR3 valine ties into site I like IL-6R Phe279, whereas a LCDR1 tyrosine side chain occupies a second cavity within site I and mimics the interactions of IL-6R Phe229. PMID:27129274

  4. 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

  5. Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene.

    PubMed Central

    Weinhold, B; Rüther, U

    1997-01-01

    We have investigated the function of different mediators of the regulation of the human C-reactive protein (hCRP) gene in transgenic mice. hCRP was induced by lipopolysaccharide and wounding in interleukin-6 (IL-6) +/+ mice, but not in IL-6 -/- mice. This finding suggested that IL-6 is necessary for the induction of hCRP. However, injection of IL-6 did not induce the hCRP gene. Thus, the induction of hCRP by IL-6 seems to require an additional cofactor. Therefore, we screened different cytokines for their activity in IL-6 +/+ and IL-6 -/- mice. Surprisingly, interleukin-1beta, as well as oncostatin M or leukaemia inhibitory factor, led to an induction of hCRP in both genetic backgrounds. These results indicate an IL-6-dependent and -independent regulation of hCRP. These hCRP transgenic mice therefore represent a novel model system for defining the cytokine network involved in the regulation of acute-phase genes during the course of inflammation. PMID:9359411

  6. Sex differences in the association between level of childhood interleukin-6 and insulin resistance in adolescence.

    PubMed

    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 (VO(2peak)) moderate this relationship. Methods. 292 nine-year-old children (n = 292) were followed for 4 years. Anthropometrics and VO(2peak) 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

  7. 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

  8. Regulatory effects of interleukin-6 in immunoglobulin G immune-complex-induced lung injury.

    PubMed Central

    Shanley, T. P.; Foreback, J. L.; Remick, D. G.; Ulich, T. R.; Kunkel, S. L.; Ward, P. A.

    1997-01-01

    Interleukin-6 (IL-6) is a cytokine produced in response to a variety of inflammatory stimuli. Although IL-6 is often observed in increased amounts in acute respiratory distress syndrome, its role in the development of lung injury is unclear. The role of IL-6 was studied in the rat model of lung injury induced by the intra-alveolar deposition of IgG immune complexes. IL-6 induction, as determined by Northern blot analysis and bioactivity, was found as a function of time during the course of development of injury. Recombinant IL-6 instilled intratracheally at commencement of injury led to substantial reductions in lung vascular permeability, neutrophil accumulation, and levels of tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 in bronchoalveolar lavage fluids. Conversely, blocking of intrinsic IL-6 by a neutralizing antibody resulted in increases in lung vascular permeability, neutrophil content, and TNF-alpha levels in bronchoalveolar lavage fluids. Rat alveolar macrophages stimulated in vitro with lipopolysaccharide in the presence of IL-6 showed a significant reduction in TNF-alpha expression. Together, these findings suggest that IL-6 acts as an intrinsic regulator of lung inflammatory injury after deposition of IgG immune complexes and that the protective effects of exogenously administered IL-6 may be in part linked to suppressed TNF-alpha production. Images Figure 1 Figure 4 PMID:9212745

  9. Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer

    PubMed Central

    Johnson, Christopher; Han, Yuyan; Hughart, Nathan; McCarra, Jennifer; Alpini, Gianfranco; Meng, Fanyin

    2012-01-01

    In recent years, the relationship between interleukin-6 (IL-6), hepatobiliary inflammation, and cancer has been studied. It is becoming clear that this cytokine plays an important role in the pathogenesis of both cholangiocarcinoma (CCA, cancer of the bile ducts) and hepatocellular carcinoma (HCC, cancer arising from the liver parenchyma). Inflammation due to various chronic hepatobiliary diseases including hepatitis B, hepatitis C, alcoholic liver injury, and primary sclerosing cholangitis (PSC) has been associated with increased levels of IL-6 and with increased rates of malignancy. In this review, we will summarize the current knowledge linking inflammation to hepatobiliary cancer, and discuss the key role of IL-6 and its signaling pathways in mediating this link. We will first review the major signaling pathways that are triggered when IL-6 engages its receptor. These include PI3 kinase, JAK/STAT, p38 MAP kinase and others that ultimately lead to cell proliferation, protection from apoptosis and increased metastatic potential. We will then discuss data linking IL-6 and hepatobiliary cancer, namely HCC and CCA. PMID:22724089

  10. 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

  11. Simvastatin prevents the induction of interleukin-6 gene expression by titanium particles in human osteoblastic cells.

    PubMed

    Vallés, Gema; Pérez, Concepción; Boré, Alba; Martín-Saavedra, Francisco; Saldaña, Laura; Vilaboa, Nuria

    2013-01-01

    One of the most important complications of total joint arthroplasty is failure associated with periprosthetic osteolysis, a process mainly initiated by the biological response to wear-derived products from the biomaterials in service. The inflammatory mediator interleukin-6 (IL-6) plays a key role in the establishment and progression of aseptic loosening. Metal particles specifically up-regulate IL-6 production in bone-forming cells and implant-bone interfacial tissues. The use of statins has been recently associated with a significantly reduced risk of revision in patients that undergo total hip arthroplasty. We hypothesized that simvastatin (Simv) could modulate the osteoblastic response to titanium particles (Ti) by attenuating the production of IL-6. Pre-treatment of human osteoblastic cells with Simv down-regulated Ti particle-induced IL-6 gene expression at mRNA and protein levels. The effect of Simv on Ti-induced IL-6 production in osteoblastic cells could not be explained by inhibition of the internalization of metal particles. The mechanism involved in this down-regulation is based in the inhibition of the HMG-CoA/GGPP/RhoA/ROCK pathway, independently of Simv effects in the cholesterol synthesis. The cytokine-lowering property of Simv has been observed in Saos-2 cells and human primary osteoblasts (hOBs) exposed to Ti particles, and was further enhanced when hOBs were co-cultured with macrophages. PMID:22922248

  12. Interleukin-1 beta induces synthesis and secretion of interleukin-6 in human chondrocytes.

    PubMed

    Bender, S; Haubeck, H D; Van de Leur, E; Dufhues, G; Schiel, X; Lauwerijns, J; Greiling, H; Heinrich, P C

    1990-04-24

    Increased concentrations of interleukin-6 (IL-6) have been found in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and crystal-related joint diseases. It is therefore of great interest to identify the cells responsible for the production of IL-6, and to investigate whether IL-6 plays a role in the pathogenesis of degenerative or inflammatory joint diseases. Here we show that human interleukin-1 beta (IL-1 beta) induces IL-6 synthesis and secretion in differentiated human chondrocytes. In organ cultures resembling closely the in vivo system 10(6) chondrocytes incubated with 100 units of interleukin-1 beta per ml of medium led to the release of 6 X 10(3) units of IL-6 within 24 h. Chondrocytes cultured in agarose or as monolayers similarly incubated with IL-1 beta produced even higher amounts of IL-6: 70 X 10(3) units per 10(6) cells within 24 h. The induction of IL-6 synthesis by IL-1 beta was also shown at the mRNA level. IL-6 secreted by stimulated chondrocytes showed heterogeneity upon Western blot analysis. PMID:2335234

  13. 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. PMID:19041259

  14. Upregulated interleukin-6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma.

    PubMed

    Stanam, Aditya; Love-Homan, Laurie; Joseph, Tisha S; Espinosa-Cotton, Madelyn; Simons, Andrean L

    2015-08-01

    Despite the role of epidermal growth factor receptor (EGFR) signaling in head and neck squamous cell carcinoma (HNSCC) development and progression, clinical trials involving EGFR tyrosine kinase inhibitors (TKIs) have yielded poor results in HNSCC patients. Mechanisms of acquired resistance to the EGFR TKI erlotinib was investigated by developing erlotinib-resistant HNSCC cell lines and comparing their gene expression profiles with their parental erlotinib-sensitive HNSCC cell lines using microarray analyses and subsequent pathway and network analyses. Erlotinib-resistant HNSCC cells displayed a significant upregulation in immune response and inflammatory pathways compared to parental cells. Interleukin-6 (IL-6) was one of thirteen genes that was significantly differentially expressed in all erlotinib-resistant HNSCC cell lines, which was validated using RT-PCR and ELISA. Blockade of IL-6 signaling using the IL-6 receptor antagonist tocilizumab, was able to overcome erlotinib-resistance in erlotinib-resistant SQ20B tumors in vivo. Overall, erlotinib-resistant HNSCC cells display elevated IL-6 expression levels compared to erlotinib-sensitive HNSCC cells and blockade of the IL-6 signaling pathway may be an effective strategy to overcome resistance to erlotinib and possibly other EGFR TKIs for HNSCC therapy. PMID:25888065

  15. 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

  16. 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

  17. Interleukin-6 is required for pristane-induced plasma cell hyperplasia in mice.

    PubMed

    Dedera, D A; Urashima, M; Chauhan, D; LeBrun, D P; Bronson, R T; Anderson, K C

    1996-07-01

    Intraperitoneal injection of pristane induces production of interleukin-6 (IL-6) and either plasmacytosis or plasmacytoma in mice, depending upon the genetic background. Pristane does not induce plasmacytoma in IL-6 knockout (IL-6-/-) mice, suggesting that IL-6 is required for this process. In the present study we determined whether IL-6 is also required for pristane-induced hyperplasia of normal plasma cells. Pristane was injected intraperitoneally into IL-6-/- and IL-6 wild-type (IL-6+/+) mice. Overall there were more deaths in IL-6+/+ mice (85%) than in IL-6-/- mice (40%), P = 0.024. Hyperplastic lymph node and spleen weight did not differ (P = 0.82 and P = 0.15, respectively) in IL-6-/- versus IL-6+/+ mice. Lymphocytosis with similar patterns of expression of B-cell (B220) and T-cell (Thy-1) antigens was noted in both IL-6-/- and IL-6+/+ mice. However, morphological studies, dual fluorescent staining for Syn-1 and B220 antigens (syn-1+ B220+ cells), and intracytoplasmic Ig staining revealed plasma cell hyperplasia in lymph node and spleen from IL-6+/+, but not IL-6-/-, mice. These plasma cells from IL-6+/+ mice were polyclonal and unable to induce tumour formation in severe combined immunodeficient mice. These data demonstrate that IL-6 is required for pristane-induced hyperplasia of polyclonal plasma cells in mice. PMID:8757508

  18. 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). PMID:27129274

  19. 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

  20. 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

  1. The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation.

    PubMed

    Brasier, Allan R

    2010-05-01

    Vascular inflammation is a common pathophysiological response to diverse cardiovascular disease processes, including atherosclerosis, myocardial infarction, congestive heart failure, and aortic aneurysms/dissection. Inflammation is an ordered process initiated by vascular injury that produces enhanced leucocyte adherence, chemotaxis, and finally activation in situ. This process is coordinated by local secretion of adhesion molecules, chemotactic factors, and cytokines whose expression is the result of vascular injury-induced signal transduction networks. A wide variety of mediators of the vascular injury response have been identified; these factors include vasoactive peptides (angiotensin II, Ang II), CD40 ligands, oxidized cholesterol, and advanced glycation end-products. Downstream, the nuclear factor-kappaB (NF-kappaB) transcription factor performs an important signal integration step, responding to mediators of vascular injury in a stimulus-dependent and cell type-specific manner. The ultimate consequence of NF-kappaB signalling is the activation of inflammatory genes including adhesion molecules and chemotaxins. However, clinically, the hallmark of vascular NF-kappaB activation is the production of interleukin-6 (IL-6), whose local role in vascular inflammation is relatively unknown. The recent elucidation for the role of the IL-6 signalling pathway in Ang II-induced vascular inflammation as one that controls monocyte activation as well as its diverse signalling mechanism will be reviewed. These new discoveries further our understanding for the important role of the NF-kappaB-IL-6 signalling pathway in the process of vascular inflammation. PMID:20202975

  2. 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

  3. Effects of serotonin and catecholamine depletion on interleukin-6 activation and mood in human volunteers.

    PubMed

    Harrison, Ben J; Olver, James S; Norman, Trevor R; Nathan, Pradeep J

    2002-08-01

    There is increasing evidence that depression and related neurotic illnesses are associated with alterations in immune function that may contribute to their pathogenesis. For example, clinical and experimental studies have shown that abnormal HPA-axis activation and monoamine neurotransmission may be related to an increased release of proinflammatory cytokines from stimulated lymphocytes in the periphery and brain. In the present investigation, the effects of tryptophan depletion (TD) on unstimulated plasma interleukin-6 (IL-6) concentrations were investigated in order to determine whether acute changes in serotonin (5-HT) neurotransmission would induce a proinflammatory response in healthy individuals. The effects of TD were compared with the analogous procedure of tyrosine depletion (TPD), which reduces catecholamine metabolism in humans. Thirteen female participants completed three experimental sessions: TD, TPD and a balanced-control condition (B). Mood-ratings and blood sampling were performed at baseline and 5 h after the administration of the mixtures. Analyses revealed that TD and TPD markedly reduced tryptophan and tyrosine/phenylalanine levels, respectively. No changes in plasma IL-6 production or ratings of lowered mood were observed, however, subjects did report feeling more fatigued after TD. These findings indicate that a transient disruption in global monoamine function does not stimulate a proinflammatory response of IL-6 in normal volunteers. PMID:12404674

  4. 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

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

    PubMed

    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

  6. 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. PMID:24594001

  7. Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway.

    PubMed

    Jang, Yeong-Su; Kang, Ju-Hee; Woo, Jong Kyu; Kim, Hwan Mook; Hwang, Jong-Ik; Lee, Sang-Jin; Lee, Ho-Young; Oh, Seung Hyun

    2016-07-15

    Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell surface molecule that can mediate homophilic adhesion and promote neurite outgrowth from cultured dorsal root ganglion (DRG) neurons. Interestingly, Ninj1 overexpressed in human cancer; however, its role in metastasis is not clear. This study showed that inhibition of Ninj1 promotes lung cancer metastasis through interleukin 6 (IL-6)/STAT3 signaling. Ninj1 levels were relatively low in highly motile lung cancer cells. While inhibition of Ninj1 enhanced cell migration in lung cancer cells, overexpression of Ninj1 significantly suppressed it. We found that inhibition of Ninj1 significantly increased expression and secretion of IL-6 in A549 cells. We also found that inhibition of IL-6 decreased intercellular adhesion molecule 1 (ICAM-1) expression. In addition, inhibition of Ninj1 significantly increased cell motility and invasiveness of lung cancer cells. In an in vivo model, we found that Ninj1 suppression did not affect tumor growth but induced significant increase in incidence of lung metastasis, and sizes and number of tumor nodules. Taken together, our data clearly demonstrate that Ninj1 suppresses migration, invasion and metastasis of lung cancer via inhibition of the IL-6 signaling pathway in vitro and in vivo. PMID:26815582

  8. 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

  9. A Ribonucleoprotein Complex Protects the Interleukin-6 mRNA from Degradation by Distinct Herpesviral Endonucleases

    PubMed Central

    Muller, Mandy; Hutin, Stephanie; Marigold, Oliver; Li, Kathy H.; Burlingame, Al; Glaunsinger, Britt A.

    2015-01-01

    During lytic Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs escape SOX-induced cleavage and remain robustly expressed. Prominent among these is interleukin-6 (IL-6), a growth factor important for survival of KSHV infected B cells. IL-6 escape is notable because it contains a sequence within its 3’ untranslated region (UTR) that can confer protection when transferred to a SOX-targeted mRNA, and thus overrides the endonuclease targeting mechanism. Here, we pursued how this protective RNA element functions to maintain mRNA stability. Using affinity purification and mass spectrometry, we identified a set of proteins that associate specifically with the protective element. Although multiple proteins contributed to the escape mechanism, depletion of nucleolin (NCL) most severely impacted protection. NCL was re-localized out of the nucleolus during lytic KSHV infection, and its presence in the cytoplasm was required for protection. After loading onto the IL-6 3’ UTR, NCL differentially bound to the translation initiation factor eIF4H. Disrupting this interaction, or depleting eIF4H, reinstated SOX targeting of the RNA, suggesting that interactions between proteins bound to distant regions of the mRNA are important for escape. Finally, we found that the IL-6 3’ UTR was also protected against mRNA degradation by the vhs endonuclease encoded by herpes simplex virus, despite the fact that its mechanism of mRNA targeting is distinct from SOX. These findings highlight how a multitude of RNA-protein interactions can impact endonuclease targeting, and identify new features underlying the regulation of the IL-6 mRNA. PMID:25965334

  10. Prostaglandin E2 stimulates the production of interleukin-6 by neonatal mouse parietal bones.

    PubMed

    Holt, I; Davie, M W; Braidman, I P; Marshall, M J

    1994-04-01

    The pleiotropic cytokine interleukin-6 (IL-6) is thought to be involved in bone homeostasis. A number of bone resorbing agents have been shown to induce the release of IL-6 from bone. We wished to determine whether prostaglandin E2 (PGE2), which is a mediator of bone resorption, can elicit the production of IL-6. IL-6 was measured by the proliferative response of B9 hybridoma cells and could be completely neutralised by an anti-IL-6 antibody. Parietal bones from neonatal mice were maintained in culture in the presence of indomethacin (10(-6) M) with or without PGE2. The time course and dose-response to PGE2 of IL-6 production were determined. After 6 h in culture, 10(-8) M PGE2 produced significantly more IL-6 than the controls (P < 0.005). PGE2 (10(-6) M) stimulated the production of a mean of 12.8 ng/ml IL-6 over 6 h. Preincubating bones with indomethacin for 20 h prior to a 6 h culture with indomethacin led to a lowering of the production of IL-6 (mean 1.8 ng/ml) compared to bones cultured without the preincubation period (5.8 ng/ml). When the indomethacin preincubation period was used, a significant increase in IL-6 production was found with 10(-9) M PGE2 (P < 0.005), and 10(-6) M PGE2 caused the production of 39.9 ng/ml IL-6 over 6 h. Stripping endocranial and ectocranial membranes from bones demonstrated the membranes to be the major site of IL-6 production. However, intact bones were required for maximal stimulated IL-6 production. PMID:8061551

  11. A ribonucleoprotein complex protects the interleukin-6 mRNA from degradation by distinct herpesviral endonucleases.

    PubMed

    Muller, Mandy; Hutin, Stephanie; Marigold, Oliver; Li, Kathy H; Burlingame, Al; Glaunsinger, Britt A

    2015-05-01

    During lytic Kaposi's sarcoma-associated herpesvirus (KSHV) infection, the viral endonuclease SOX promotes widespread degradation of cytoplasmic messenger RNA (mRNA). However, select mRNAs escape SOX-induced cleavage and remain robustly expressed. Prominent among these is interleukin-6 (IL-6), a growth factor important for survival of KSHV infected B cells. IL-6 escape is notable because it contains a sequence within its 3' untranslated region (UTR) that can confer protection when transferred to a SOX-targeted mRNA, and thus overrides the endonuclease targeting mechanism. Here, we pursued how this protective RNA element functions to maintain mRNA stability. Using affinity purification and mass spectrometry, we identified a set of proteins that associate specifically with the protective element. Although multiple proteins contributed to the escape mechanism, depletion of nucleolin (NCL) most severely impacted protection. NCL was re-localized out of the nucleolus during lytic KSHV infection, and its presence in the cytoplasm was required for protection. After loading onto the IL-6 3' UTR, NCL differentially bound to the translation initiation factor eIF4H. Disrupting this interaction, or depleting eIF4H, reinstated SOX targeting of the RNA, suggesting that interactions between proteins bound to distant regions of the mRNA are important for escape. Finally, we found that the IL-6 3' UTR was also protected against mRNA degradation by the vhs endonuclease encoded by herpes simplex virus, despite the fact that its mechanism of mRNA targeting is distinct from SOX. These findings highlight how a multitude of RNA-protein interactions can impact endonuclease targeting, and identify new features underlying the regulation of the IL-6 mRNA. PMID:25965334

  12. High-level transient expression of ER-targeted human interleukin 6 in Nicotiana benthamiana.

    PubMed

    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 T(0) 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 T(2) 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

  13. Effects of interleukin-6 on cellular function in UMR-106-01 osteoblastlike cells

    SciTech Connect

    Fang, M.A.; Hahn, T.J. )

    1991-02-01

    High levels of interleukin-6 (IL-6) have been detected in synovial fluid from patients with inflammatory arthropathies associated with local bone resorption, suggesting a role for IL-6 as a local regulator of bone resorption and remodeling. In the present study we examined the effects of IL-6 on ({sup 3}H)thymidine (({sup 3}H)TdR) incorporation, collagen synthesis, and alkaline phosphatase activity in UMR-106-01 rat osteoblastic osteosarcoma cells. IL-6 stimulated a dose-dependent increase in ({sup 3}H)TdR incorporation that was maximal at 1000 U/ml (- 147% of basal, p less than 0.005) in osteoblastlike cells that were in a logarithmic phase of growth. The increase in ({sup 3}H)TdR incorporation was maximal between 12 and 24 h and was neutralized by pretreatment with the polyclonal rabbit antibody to IL-6. IL-6 also increased cell number and the secretion of prostaglandin E2 in UMR-106-01 cells in logarithmic growth phase. The stimulation of ({sup 3}H)TdR incorporation and release of PGE2 into the culture medium by IL-6 was inhibited by indomethacin. A 24 h exposure of the osteoblastlike cells to 1000 U/ml of IL-6 reduced ({sup 3}H)proline incorporation into collagenase-digestible (CDP) protein to 73% of control values (p less than 0.01). Noncollagen protein (NCP) synthesis was inhibited to 80% of control values (p less than 0.01) by 1000 U/ml of IL-6. The inhibitory effect was relatively greater on CDP than on NCP and consequently resulted in a decrease in the percentage of collagen synthesis. Alkaline phosphatase activity was not altered in these cells after a 24 h exposure to 1-1000 U/ml of IL-6.

  14. Inhibition of interleukin-6 expression by the V protein of parainfluenza virus 5

    SciTech Connect

    Lin Yuan; Sun Minghao; Fuentes, Sandra M.; Keim, Celia D.; Rothermel, Terri; He Biao

    2007-11-25

    The V protein of parainfluenza virus 5 (PIV5) plays an important role in the evasion of host immune responses. The V protein blocks interferon (IFN) signaling in human cells by causing degradation of the STAT1 protein, a key component of IFN signaling, and blocks IFN-{beta} production by preventing nuclear translocation of IRF3, a key transcription factor for activating IFN-{beta} promoter. Interleukin-6 (IL-6), along with tumor necrosis factor (TNF)-{alpha} and IL-1{beta}, is a major proinflammatory cytokine that plays important roles in clearing virus infection through inflammatory responses. Many viruses have developed strategies to block IL-6 expression. Wild-type PIV5 infection induces little, if any, expression of cytokines such as IL-6 or TNF-{alpha}, whereas infection by a mutant PIV5 lacking the conserved C-terminal cysteine rich domain (rPIV5V{delta}C) induced high levels of IL-6 expression. Examination of mRNA levels of IL-6 indicated that the transcription activation of IL-6 played an important role in the increased IL-6 expression. Co-infection with wild-type PIV5 prevented the activation of IL-6 transcription by rPIV5V{delta}C, and a plasmid encoding the full-length PIV5 V protein prevented the activation of IL-6 promoter-driven reporter gene expression by rPIV5V{delta}C, indicating that the V protein played a role in inhibiting IL-6 transcription. The activation of IL-6 was independent of IFN-{beta} even though rPIV5V{delta}C-infected cells produced IFN-{beta}. Using reporter gene assays and chromatin immunoprecipitation (ChIP), it was found that NF-{kappa}B played an important role in activating expression of IL-6. We have proposed a model of activating and inhibiting IL-6 transcription by PIV5.

  15. Role of serum interleukin-6 in deciding therapy for multidrug resistant oral lichen planus

    PubMed Central

    Marwah, Akanksha; Kaushik, Smita; Garg, Vijay K.; Gupta, Sunita

    2015-01-01

    Background Oral lichen planus (OLP) is a T cell mediated immune response. T cells locally present in the involved tissues release cytokines like interleukin-6 (IL-6), which contributes to pathogenesis of OLP. Also IL-6 has been associated with multidrug resistance protein (MRP) expression by keratinocytes. Correspondingly, upregulation of MRP was found in OLP. We conducted this study to evaluate the effects of various drugs on serum IL-6 in OLP; and correlation of these effects with the nature of clinical response and resistance pattern seen in OLP lesions with various therapeutic modalities. Thus we evaluated the role of serum IL-6 in deciding therapy for multidrug resistant OLP. Material and Methods Serum IL-6 was evaluated in 42 erosive OLP (EOLP) patients and 10 normal mucosa and 10 oral squamous cell carcinoma cases using ELISA technique. OLP patients were randomly divided into 3 groups of 14 patients each and were subjected to Pimecrolimus local application, oral Mycophenolate Mofetil (MMF) and Methotrexate (MTX) alongwith Pimecrolimus local application. IL-6 levels were evaluated before and after treatment. Results Serum IL-6 levels were raised above 3pg/ml in 26.19% erosive OLP (EOLP) cases (mean- 3.72±8.14). EOLP (5%) cases with IL-6 levels above 5pg/ml were resistant in MTX group. However significant decrease in serum IL-6 corresponding with the clinical resolution was seen in MMF group. Conclusions Significantly raised IL-6 levels in EOLP reflect the chronic inflammatory nature of the disease. As serum IL-6 levels significantly decreased in MMF group, correspondingly no resistance to treatment was noted. However with MTX there was no significant decrease in IL-6 and resistance to treatment was noted in some, especially plaque type lesions. Thus IL-6 can be a possible biomarker in deciding the best possible therapy for treatment resistant OLP. Key words:Lichen planus, biological markers, cytokines, enzyme-linked immunosorbent assay, immunosuppressive

  16. Cloning, characterization and mRNA expression of interleukin-6 in blunt snout bream (Megalobrama amblycephala).

    PubMed

    Zhang, Chun-Nuan; Zhang, Ji-Liang; Liu, Wen-Bin; Wu, Qiu-Jue; Gao, Xiao-Chan; Ren, Hong-Tao

    2016-07-01

    In the present study, the interleukin-6 gene (IL-6) cDNA in blunt snout bream (Megalobrama amblycephala) was identified and its expression profiles under ammonia stress and bacterial challenge were investigated. The IL-6 sequence consisted of 1045 bp, including a 696 bp ORF which translated into a 232 amino acid (AA) protein. The protein contained a putative signal peptide of 24 AA in length. IL-6 expression analysis showed that the it is differentially expressed in various tissues under normal conditions and the highest IL-6 level was observed in the intestine tissue, followed by the liver, and then in the gills. Under ammonia stress, the IL-6 mRNA level both in spleens and intestine increased significantly (P < 0.05), with the maximum levels attained at 6 h, 12 h (72, 10-fold, respectively). Thereafter, they all significantly decreased (P < 0.01) and returned to the basal value within 48 h. Whereas, in livers it slightly decreased at 3 h firstly (0.5-fold), and then significantly (P < 0.05) increased with the maximum level attained 12 h (3-fold). Further expression analysis showed that the mRNA level of IL-6 in spleens, intestine and livers of blunt snout bream all increased significantly (P < 0.05), with maximum values attained at 6 h, 3 h, 6 h (10, 6, 18-fold, respectively) after Aeromonas hydrophila (A. hydrophila) injection, and then decreased to the basal value within 24 h which suggested that IL-6 was involved in the immune response to A. hydrophila. The cloning and expression analysis of the IL-6 provide theoretical basis to further study the mechanism of anti-adverseness and expression characteristics under stress conditions in blunt snout bream. PMID:26965748

  17. Activation of AMP-Activated Protein Kinase by Interleukin-6 in Rat Skeletal Muscle

    PubMed Central

    Kelly, Meghan; Gauthier, Marie-Soleil; Saha, Asish K.; Ruderman, Neil B.

    2009-01-01

    OBJECTIVE Interleukin-6 (IL-6) directly activates AMP-activated protein kinase (AMPK) in vivo and in vitro; however, the mechanism by which it does so is unknown. RESEARCH DESIGN AND METHODS We examined this question in skeletal muscle using an incubated rat extensor digitorum longus (EDL) muscle preparation as a tool. RESULTS AMPK activation by IL-6 coincided temporally with a nearly threefold increase in the AMP:ATP ratio in the EDL. The effects of IL-6 on both AMPK activity and energy state were inhibited by coincubation with propranolol, suggesting involvement of β-adrenergic signaling. In keeping with this notion, IL-6 concurrently induced a transient increase in cAMP, and its ability to activate AMPK was blocked by the adenyl cyclase inhibitor 2′5′-dideoxyadenosine. In addition, like other β-adrenergic stimuli, IL-6 increased glycogen breakdown and lipolysis in the EDL. Similar effects of IL-6 on AMPK, energy state, and cAMP content were observed in C2C12 myotubes and gastrocnemius muscle in vivo, indicating that they were not unique to the incubated EDL. CONCLUSIONS These studies demonstrate that IL-6 activates AMPK in skeletal muscle by increasing the concentration of cAMP and, secondarily, the AMP:ATP ratio. They also suggest that substantial increases in IL-6 concentrations, such as those that can result from its synthesis by muscles during exercise, may play a role in the mobilization of fuel stores within skeletal muscle as an added means of restoring energy balance. PMID:19502419

  18. Interleukin-6 as a potential molecular target in esophageal squamous cell carcinoma

    PubMed Central

    ZHAO, ZHI-FEI; LI, JIAN-XIONG; YE, RUI; WU, XUAN; GAO, LING-LING; NIU, BAO-LONG

    2016-01-01

    Knowledge of potential tumor markers may improve chemotherapeutic efficacy. Interleukin-6 (IL-6) expression in local tumor tissues is associated with cancer progression and poor prognosis in variety of cancer types. The aim of the present study was to investigate the role and potential application of IL-6 in determining the prognosis of esophageal carcinoma. KYSE170 and TE13 esophageal cancer cell lines were used to conduct cell- and animal-based experiments investigating biological changes and tumor behavior. Immunohistochemical analysis revealed that 70–80% of cancer cells exhibited positive staining for IL-6, compared with <15% of non-malignant epithelial cells. These immunohistochemical results were consistent with the mRNA expression levels detetced. The IL-6 silencing vector significantly reduced invasion and proliferation of the two cell lines and attenuated tumor growth in xenograft mouse models (P<0.05). The IL-6 silencing vector markedly reduced the presence of Ki-67 (a typical proliferation marker) and microvessel density, indicating that downregulation of IL-6 levels may greatly affect tumor growth and inhibition. The IL-6 silencing vector increased E-cadherin and matrix metalloproteinase (MMP)-9 expression levels in the two esophageal carcinoma cell lines. This vector also regulated the release of IL-6 in cell supernatant and serum in KYSE170- and TE13-tumor-bearing mice. The secretion of vascular endothelial growth factor and cluster of differentiation 31 (a nuclear protein) immunoreactive molecules were also reduced by the IL-6 silencing vector. Therefore, IL-6 may be an important trigger in the progression of angiogenesis and endothelial tube formation within the tumor, and targeting IL-6 may be a promising strategy for the treatment of esophageal cancer. PMID:26893670

  19. Interleukin-6 gene knockout antagonizes high-fat-induced trabecular bone loss.

    PubMed

    Wang, Chunyu; Tian, Li; Zhang, Kun; Chen, Yaxi; Chen, Xiang; Xie, Ying; Zhao, Qian; Yu, Xijie

    2016-10-01

    The purpose of the study was to determine the roles of interleukin-6 (IL6) in fat and bone communication. Male wild-type (WT) mice and IL6 knockout (IL6(-/-)) mice were fed with either regular diet (RD) or high-fat diet (HFD) for 12 weeks. Bone mass and bone microstructure were evaluated by micro-computed tomography. Gene expression related to lipid and bone metabolisms was assayed with real-time quantitative polymerase chain reaction. Bone marrow cells from both genotypes were induced to differentiate into osteoblasts or osteoclasts, and treated with palmitic acid (PA). HFD increased the body weight and fat pad weight, and impaired lipid metabolism in both WT and IL6(-/-) mice. The dysregulation of lipid metabolism was more serious in IL6(-/-) mice. Trabecular bone volume fraction, trabecular bone number and trabecular bone thickness were significantly downregulated in WT mice after HFD than those in the RD (P < 0.05). However, these bone microstructural parameters were increased by 53%, 34% and 40%, respectively, in IL6(-/-) mice than those in WT mice on the HFD (P < 0.05). IL6(-/-) osteoblasts displayed higher alkaline phosphatase (ALP) activity and higher mRNA levels of Runx2 and Colla1 than those in WT osteoblasts both in the control and PA treatment group (P < 0.05). IL6(-/-) mice showed significantly lower mRNA levels of PPARγ and leptin and higher mRNA levels of adiponectin in comparison with WT mice on HFD. In conclusion, these findings suggested that IL6 gene deficiency antagonized HFD-induced bone loss. IL6 might bridge lipid and bone metabolisms and could be a new potential therapeutic target for lipid metabolism disturbance-related bone loss. PMID:27493246

  20. Expression of the interleukin 6 receptor in primary renal cell carcinoma.

    PubMed Central

    Costes, V; Liautard, J; Picot, M C; Robert, M; Lequeux, N; Brochier, J; Baldet, P; Rossi, J F

    1997-01-01

    AIMS: Interleukin 6 (IL-6) is expressed in the majority of renal cell carcinomas and has an important role in the proliferation of some renal cell carcinoma cell lines. This action is mediated by two membrane proteins, gp80 (the IL-6 receptor; IL-6R), which binds IL-6, and gp130, which transduces the signal. The soluble form of gp80 (sIL-6R) is able to activate gp130 when complexed to the IL-6 molecule. These considerations prompted an investigation of IL-6R expression in this malignancy. IL-6, C reactive protein (CRP), and sIL-6R were also measured in serum and correlated to clinical and pathological features. METHODS: Immunostaining was performed on cryostat sections from renal cell carcinoma tumours with M91, an anti-IL-6R monoclonal antibody, using the alkaline phosphatase antialkaline phosphatase technique. The proliferation index was measured using the KI-67 monoclonal antibody. CRP, IL-6, and sIL-6R were measured in serum before nephrectomy, using an immunoenzymatic or immunoradiometric assay. RESULTS: There were significant differences in survival in patients with tumours larger than 8 cm, metastasis at diagnosis, high nuclear grade tumours, detectable serum concentrations of IL-6 (correlated to CRP serum concentration), more than 4% proliferating cells, and the presence of the IL-6R in situ. Furthermore, the serum IL-6 concentration correlated with tumour size and stage. The mean serum sIL-6R concentration was not significantly different from that observed in 40 normal subjects. Tumour IL-6R expression was present in 10 samples. There was a significant association between the presence of the IL-6 receptor in tumours and tumour stage, nuclear grade, proliferation index, and serum IL-6. CONCLUSIONS: This study revealed the importance of IL-6/CRP and IL-6R expression in situ as potential new prognostic factors and opens the way to new therapeutic strategies in renal cell carcinoma. Images PMID:9462266

  1. Gene-specific regulation of hepatic selenoprotein expression by interleukin-6.

    PubMed

    Martitz, J; Becker, N-P; Renko, K; Stoedter, M; Hybsier, S; Schomburg, L

    2015-11-01

    Sepsis is a severe inflammatory disease resulting in excessive production of pro-inflammatory cytokines including interleukin-6 (IL-6), causing oxidative stress, tissue damage and organ dysfunction. Health benefits have been observed upon selenium (Se) supplementation in severe sepsis. Selenium is incorporated into selenoproteins implicated in anti-oxidative defence, thyroid hormone metabolism and immunoregulation. Selenium metabolism is controlled by hepatocytes synthesizing and secreting the Se transporter selenoprotein P (SePP). The circulating SePP declines in sepsis causing low serum Se levels. Dysregulation of the hepatic selenoenzyme deiodinase type 1 (DIO1) potentially contributes to the low T3 (thyroid hormone) syndrome observed in severe diseases. We hypothesized that IL-6 affects hepatic selenoprotein biosynthesis directly. Testing human hepatocytes in culture, IL-6 reduced the concentrations of SePP mRNA and secreted SePP in a dose-dependent manner. In parallel, expression of DIO1 declined at the mRNA, protein and enzyme activity level. The effects of IL-6 on glutathione peroxidase (GPX) expression were isozyme-specific; GPX1 remained unaffected, while transcript concentrations of GPX2 increased and those of GPX4 decreased. This pattern of IL-6-dependent effects was mirrored in reporter gene experiments with SePP, DIO1, GPX1, and GPX2 promoter constructs pointing to direct transcriptional effects of IL-6. The redirection of hepatic selenoprotein biosynthesis by IL-6 may represent a central regulatory circuit responsible for the decline of serum Se and low T3 concentrations in sepsis. Accordingly, therapeutic IL-6 targeting may be effective for improving the Se and thyroid hormone status, adjuvant Se supplementation success and survival in sepsis. PMID:26399395

  2. Interleukin-6 Levels in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis

    PubMed Central

    Peng, Zheng; Sun, Yifan; Lv, Xiaolan; Zhang, Hongyu; Liu, Chunming; Dai, Shengming

    2016-01-01

    Background The change of serum interleukin-6(IL-6) levels in women with polycystic ovary syndrome (PCOS), as well as the relations between IL-6 levels and body mass index (BMI), insulin resistance(IR) and androgen status of PCOS patients, are not fully understood. Methods A literature search was performed in October 2015 using PubMed, Embase and the Cochrane Library databases to identify studies. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs). Results Twenty articles with 25 case-control studies included 1618 women (922 PCOS patients and 696 controls) were included in this study. IL-6 levels in controls were significantly lower than that of PCOS patients (SMD = 0.78, 95%CI = 0.41–1.16, P<0.001), with significant heterogeneity across studies (I2 = 91% and P<0.001). Meta-regression analysis model indicated IR status was the main source of heterogeneity (P = 0.005). Results from group analysis suggested that high IL-6 levels in PCOS were significantly associated with Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR) ratio and total testosterone ratio (T ratio), and was found in both lean and obese women with PCOS. Cumulative meta-analysis results indicated the total effect size (SMD) had tend to be stable since 2012(0.79 to 0.92). Conclusions A high IL-6 level is not an intrinsic characteristic of PCOS, but may be a useful monitoring biomarker for the treatment of PCOS. PMID:26849353

  3. 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. PMID:25921605

  4. 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

  5. Role of Procalcitonin and Interleukin-6 in Predicting Cancer, and Its Progression Independent of Infection.

    PubMed

    Chaftari, Anne-Marie; Hachem, Ray; Reitzel, Ruth; Jordan, Mary; Jiang, Ying; Yousif, Ammar; Garoge, Kumait; Deshmukh, Poonam; Al Hamal, Zanaib; Jabbour, Joseph; Hanania, Alexander; Raad, Sammy; Jamal, Mohamed; Raad, Issam

    2015-01-01

    Procalcitonin (PCT) and Interleukin-6 (IL-6) have emerged as biomarkers for different inflammatory conditions. The purpose of the study was to evaluate the role of PCT and IL-6 as biomarkers of cancer and its progression in a large cohort of patients. This cross-sectional study included residual plasma samples collected from cancer patients, and control subjects without cancer. Levels of PCT and IL-6 were determined by Kryptor compact bioanalyzer. We identified 575 febrile cancer patients, 410 non-febrile cancer patients, and 79 non-cancer individuals. The median PCT level was lower in control subjects (0.029 ng/ml) compared to cancer patients with stage I-III disease (0.127 ng/ml) (p<0.0001) and stage IV disease (0.190 ng/ml) (p<0.0001). It was also higher in febrile cancer patients (0.310 ng/ml) compared to non-febrile cancer patients (0.1 ng/ml) (p<0.0001). Median IL-6 level was significantly lower in the control group (0 pg/ml) than in non-febrile cancer patients with stages I-III (7.376 pg/ml) or stage IV (9.635 pg/ml) (p<0.0001). Our results suggest a potential role for PCT and IL-6 in predicting cancer in non-febrile patients. In addition, PCT is useful in detecting progression of cancer and predicting bacteremia or sepsis in febrile cancer patients. PMID:26148092

  6. Role of Procalcitonin and Interleukin-6 in Predicting Cancer, and Its Progression Independent of Infection

    PubMed Central

    Chaftari, Anne-Marie; Hachem, Ray; Reitzel, Ruth; Jordan, Mary; Jiang, Ying; Yousif, Ammar; Garoge, Kumait; Deshmukh, Poonam; Al Hamal, Zanaib; Jabbour, Joseph; Hanania, Alexander; Raad, Sammy; Jamal, Mohamed; Raad, Issam

    2015-01-01

    Procalcitonin (PCT) and Interleukin-6 (IL-6) have emerged as biomarkers for different inflammatory conditions. The purpose of the study was to evaluate the role of PCT and IL-6 as biomarkers of cancer and its progression in a large cohort of patients. This cross-sectional study included residual plasma samples collected from cancer patients, and control subjects without cancer. Levels of PCT and IL-6 were determined by Kryptor compact bioanalyzer. We identified 575 febrile cancer patients, 410 non-febrile cancer patients, and 79 non-cancer individuals. The median PCT level was lower in control subjects (0.029 ng/ml) compared to cancer patients with stage I-III disease (0.127 ng/ml) (p<0.0001) and stage IV disease (0.190 ng/ml) (p<0.0001). It was also higher in febrile cancer patients (0.310 ng/ml) compared to non-febrile cancer patients (0.1 ng/ml) (p<0.0001). Median IL-6 level was significantly lower in the control group (0 pg/ml) than in non-febrile cancer patients with stages I-III (7.376 pg/ml) or stage IV (9.635 pg/ml) (p<0.0001). Our results suggest a potential role for PCT and IL-6 in predicting cancer in non-febrile patients. In addition, PCT is useful in detecting progression of cancer and predicting bacteremia or sepsis in febrile cancer patients. PMID:26148092

  7. 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. PMID:10762353

  8. 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

  9. 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

  10. 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

  11. Modulation of Kaposi's Sarcoma-Associated Herpesvirus Interleukin-6 Function by Hypoxia-Upregulated Protein 1

    PubMed Central

    Giffin, Louise; Yan, Feng; Major, M. Ben

    2014-01-01

    ABSTRACT 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. IMPORTANCE 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. PMID:24920810

  12. Ovariectomy does not induce osteopenia through interleukin-6 in rhesus monkeys (Macaca mulatta).

    PubMed

    Keller, E T; Binkley, N C; Stebler, B A; Hall, D M; Johnston, G M; Zhang, J; Ershler, W B

    2000-01-01

    To characterize the role of interleukin-6 (IL-6) in estrogen (E2)-depletion bone loss, we utilized a nonhuman primate model of human skeletal physiology. Adult female rhesus monkeys were sham-operated (S; n = 5), ovariectomized (ovx; n = 10), or ovx followed by E2 replacement (ovx + E2; n = 10) and evaluated for the indicated parameters at 0, 3, 6, and 9 months post-ovx. Lumbar spine bone mineral density (BMD) decreased by 3 months and continued to decline through 9 months in the ovx, but not in the ovx + E2 or S groups. Middle and distal radius BMD was decreased at 9 months in the ovx, but not in the ovx + E2 or S groups. The S group had marked fluctuations in bone remodeling parameters, and cytokine levels in S animals were consistent with menstrual cycling, and therefore only those values in the ovx and ovx + E2 groups are reported. Serum osteocalcin and skeletal-specific alkaline phosphatase were elevated in the ovx group compared with the ovx + E2 group. There was no difference in serum or bone marrow plasma IL-6 levels between the ovx and ovx + E2 groups. Similarly, there was no difference in basal or phorbol ester-stimulated IL-6 levels of peripheral blood mononuclear cell or bone marrow cell culture supernatants between groups. There was no difference in serum or bone marrow soluble IL-6 receptor between groups. However, the bone marrow plasma soluble IL-6 receptor levels were transiently increased from baseline at 3 months in the ovx but not in the ovx + E2 group. In summary, there was no bone loss in the ovx + E2 group, although the serum and bone marrow IL-6 levels were similar to those of the ovx group. These data suggest that modulation of IL-6 is not the key mechanism through which estrogen deprivation mediates bone loss in rhesus monkeys. PMID:10617157

  13. Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism

    PubMed Central

    Frampton, Gabriel; Invernizzi, Pietro; Bernuzzi, Francesca; Pae, Hae Yong; Quinn, Matthew; Horvat, Darijana; Galindo, Cheryl; Huang, Li; McMillin, Matthew; Cooper, Brandon; Rimassa, Lorenza; DeMorrow, Sharon

    2015-01-01

    Background and objectives Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth. Methods The expression and secretion of progranulin were evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated signalling in the expression of progranulin was assessed using a combination of specific inhibitors and shRNA knockdown techniques. The effect of progranulin on proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation were assessed in vitro. Progranulin knockdown cell lines were established, and the effects on cholangiocarcinoma growth were determined. Results Progranulin expression and secretion were upregulated in cholangiocarcinoma cell lines and tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBPβ pathway. Blocking any of these signalling molecules, by either pharmacological inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin expression. Treatment of cholangiocarcinoma cells with recombinant progranulin increased cell proliferation in vitro by a mechanism involving Akt phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1. Knockdown of progranulin expression in cholangiocarcinoma cells decreased the expression of proliferating cellular nuclear antigen, a marker of proliferative capacity, and slowed tumour growth in vivo. Conclusions Evidence is presented for a role for progranulin as a novel growth factor regulating cholangiocarcinoma growth. Specific targeting of progranulin may represent an alternative for the development of therapeutic strategies. PMID:22068162

  14. Interleukin-6 inhibition attenuates hypertension and associated renal damage in Dahl salt-sensitive rats.

    PubMed

    Hashmat, Shireen; Rudemiller, Nathan; Lund, Hayley; Abais-Battad, Justine M; Van Why, Scott; Mattson, David L

    2016-09-01

    Immune cells in the kidney are implicated in the development of hypertension and renal damage in the Dahl salt-sensitive (SS) rat. Interestingly, interleukin 6 (IL-6) mRNA is 54-fold higher in T-lymphocytes isolated from the kidney compared with circulating T-lymphocytes. The present experiments assessed the role of IL-6 in the development of SS hypertension by treating rats (n = 13-14/group) with an IL-6 neutralizing antibody or normal IgG during an 11-day period of high-salt (4.0% NaCl chow) intake. The mean arterial pressure (MAP) and urine albumin excretion rates (Ualb) were not different between the groups fed low salt (0.4% NaCl). Following 11 days of drug treatment and high salt, however, the rats receiving anti-IL-6 demonstrated a 47% reduction of IL-6 in the renal medulla compared with control SS. Moreover, the increase in MAP following 11 days of high-NaCl intake was significantly attenuated in SS administered anti-IL-6 compared with the control group (138 ± 3 vs. 149 ± 3 mmHg) as was the salt-induced increase in Ualb and glomerular and tubular damage. To investigate potential mechanisms of action, a flow cytometric analysis of immune cells in the kidney (n = 8-9/group) demonstrated that the total number of monocytes and macrophages was significantly lower in the treatment vs. the control group. The total number of T- and B-lymphocytes in the kidneys was not different between groups. These studies indicate that IL-6 production may participate in the development of SS hypertension and end-organ damage by mediating increased infiltration or proliferation of macrophages into the kidney. PMID:27279492

  15. Mesenchymal stem cells and Interleukin-6 attenuate liver fibrosis in mice

    PubMed Central

    2013-01-01

    Background Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for liver fibrosis. Issues concerning poor MSC survival and engraftment in the fibrotic liver still persist and warrant development of a strategy to increase MSC potency for liver repair. The present study was designed to examine a synergistic role for Interleukin-6 (IL-6) and MSCs therapy in the recovery of carbon tetrachloride (CCl4) induced injured hepatocytes in vitro and in vivo. Methods Injury was induced through 3 mM and 5 mM CCl4 treatment of cultured hepatocytes while fibrotic mouse model was established by injecting 0.5 ml/kg CCl4 followed by treatment with IL-6 and MSCs. Effect of MSCs and IL-6 treatment on injured hepatocytes was determined by lactate dehydrogenase release, RT-PCR for (Bax, Bcl-xl, Caspase3, Cytokeratin 8, NFκB, TNF-α) and annexin V apoptotic detection. Analysis of MSC and IL-6 treatment on liver fibrosis was measured by histopathology, PAS, TUNEL and Sirius red staining, RT-PCR, and liver function tests for Bilirubin and Alkaline Phosphatase (ALP). Results A significant reduction in LDH release and apoptosis was observed in hepatocytes treated with a combination of MSCs and IL-6 concomitant with upregulation of anti-apoptotic gene Bcl-xl expression and down regulation of bax, caspase3, NFκB and TNF-α. Adoptive transfer of MSCs in fibrotic liver pretreated with IL-6 resulted increased MSCs homing and reduced fibrosis and apoptosis. Hepatic functional assessment demonstrated reduced serum levels of Bilirubin and ALP. Conclusion Pretreatment of fibrotic liver with IL-6 improves hepatic microenvironment and primes it for MSC transplantation leading to enhanced reduction of liver injury after fibrosis. Synergistic effect of IL-6 and MSCs seems a favored therapeutic option in attenuation of liver apoptosis and fibrosis accompanied by improved liver function. PMID:23531302

  16. Protection of intestinal injury during heat stroke in mice by interleukin-6 pretreatment

    PubMed Central

    Phillips, Neil A; Welc, Steven S; Wallet, Shannon M; King, Michelle A; Clanton, Thomas L

    2015-01-01

    The role of interleukin-6 (IL-6) in hyperthermia and heat stroke is poorly understood. Plasma IL-6 is elevated following hyperthermia in animals and humans, and IL-6 knockout mice are more intolerant of severe hyperthermia. We evaluated the effect of IL-6 supplementation on organ injury following severe hyperthermia exposure in anaesthetized mice. Two hours prior to hyperthermia, mice were treated with 0.6 μg intraperitoneal IL-6, or identical volumes of saline in controls. Mice were anaesthetized, gavaged with FITC–dextran for measures of gastrointestinal permeability, and exposed to incremental (0.5°C every 30 min) increases in temperature. Heating stopped when maximum core temperature (Tc) of 42.4°C was attained (Tc,max). The mice recovered at room temperature (≈22°C) for 30 or 120 min, at which time plasma and tissues were collected. IL-6-treated mice, on average, required ≈25 min longer to attain Tc,max. Injury and swelling of the villi in the duodenum was present in untreated mice after 30 min of recovery. These changes were blocked by IL-6 treatment. IL-6 also reduced gastrointestinal permeability, assayed by the accumulation of FITC–dextran in plasma. Plasma cytokines were also attenuated in IL-6-treated animals, including significant reductions in TNFα, MCP-1 (CXCL2), RANTES (CCL5) and KC (CCL5). The results demonstrate that IL-6 has a protective influence on the pattern of physiological responses to severe hyperthermia, suggesting that early endogenous expression of IL-6 may provide a protection from the development of organ damage and inflammation. PMID:25433073

  17. Air Pollution and Inflammation (Interleukin-6, C-Reactive Protein, Fibrinogen) in Myocardial Infarction Survivors

    PubMed Central

    Rückerl, Regina; Greven, Sonja; Ljungman, Petter; Aalto, Pasi; Antoniades, Charalambos; Bellander, Tom; Berglind, Niklas; Chrysohoou, Christina; Forastiere, Francesco; Jacquemin, Bénédicte; von Klot, Stephanie; Koenig, Wolfgang; Küchenhoff, Helmut; Lanki, Timo; Pekkanen, Juha; Perucci, Carlo A.; Schneider, Alexandra; Sunyer, Jordi; Peters, Annette

    2007-01-01

    Background Numerous studies have found that ambient air pollution has been associated with cardiovascular disease exacerbation. Objectives Given previous findings, we hypothesized that particulate air pollution might induce systemic inflammation in myocardial infarction (MI) survivors, contributing to an increased vulnerability to elevated concentrations of ambient particles. Methods A prospective longitudinal study of 1,003 MI survivors was performed in six European cities between May 2003 and July 2004. We compared repeated measurements of interleukin 6 (IL-6), fibrinogen, and C-reactive protein (CRP) with concurrent levels of air pollution. We collected hourly data on particle number concentrations (PNC), mass concentrations of particulate matter (PM) < 10 μm (PM10) and < 2.5 μm (PM2.5), gaseous pollutants, and meteorologic data at central monitoring sites in each city. City-specific confounder models were built for each blood marker separately, adjusting for meteorology and time-varying and time-invariant covariates. Data were analyzed with mixed-effects models. Results Pooled results show an increase in IL-6 when concentrations of PNC were elevated 12–17 hr before blood withdrawal [percent change of geometric mean, 2.7; 95% confidence interval (CI), 1.0–4.6]. Five day cumulative exposure to PM10 was associated with increased fibrinogen concentrations (percent change of arithmetic mean, 0.6; 95% CI, 0.1–1.1). Results remained stable for smokers, diabetics, and patients with heart failure. No consistent associations were found for CRP. Conclusions Results indicate an immediate response to PNC on the IL-6 level, possibly leading to the production of acute-phase proteins, as seen in increased fibrinogen levels. This might provide a link between air pollution and adverse cardiac events. PMID:17637925

  18. Interleukin-6 and interleukin-8 production by mononuclear cells of chronic alcoholics during treatment.

    PubMed

    Martinez, F; Thomas, N M; Darban, H; Cox, T J; Wood, S; Watson, R R

    1993-12-01

    Chronic alcohol consumption has been associated with suppression of a number of immune parameters. This study was designed to investigate the relationship between chronic alcohol ingestion and cessation with respect to release of interleukin-6 (IL-6) and interleukin-8 (IL-8) using highly specific and sensitive ELISA assays, as well as a functional assay, natural killer cell cytotoxic activity. ELISAs were developed to determine the amount of IL-6 and IL-8 release by peripheral blood mononuclear cells (PBMCs). Two groups of subjects were recruited: young (18-22 years old), nonalcoholic users (controls) and long-term alcoholics (35-55 years old). Blood samples were collected at time 0 from all subjects and from alcoholics 28 days after treatment had begun and alcohol use had ceased. Then mitogen-stimulated release of cytokines by peripheral blood cells was determined. The abstaining controls, and the alcoholics, after 30 days of abstinence, tended to produce lower amounts of IL-6 and IL-8, although these differences were not statistically significant. Natural killer cell activity was not statistically different between the young groups, yet appeared to increase once alcohol use discontinued. Some of the cells from the controls (abstainers) were incubated with ethanol (EtOH). Its content in sealed wells was measured after the time of incubation of PBMCs. When EtOH was serially diluted in plates, some well-well diffusion was noted, but the maximum concentration of EtOH never fell below 0.3% from an initial concentration of 0.5%, and at no time was the EtOH concentration gradient completely lost, even after 66 hr of incubation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8116830

  19. Measures of Adiposity Predict Interleukin-6 Responses to Repeated Psychosocial Stress

    PubMed Central

    McInnis, Christine M.; Thoma, Myriam V.; Gianferante, Danielle; Hanlin, Luke; Chen, Xuejie; Breines, Juliana G.; Hong, Suzi; Rohleder, Nicolas

    2014-01-01

    Objective Overweight and obese individuals, who comprise approximately two-thirds of the U.S. population, are at increased risk for developing a range of diseases. This increased risk may be due in part to maladaptive stress responses within this group, including heightened low-grade inflammation and HPA axis non-habituation. In this study we tested the relationship between adiposity, plasma interleukin-6 (IL-6) and HPA axis responses to repeated stress. Methods Sixty-seven healthy participants were exposed to the Trier Social Stress Test (TSST) on two consecutive days. We collected saliva for cortisol measurements at baseline and at 1, 10, 30, 60 and 120 minutes post-TSST, and blood for plasma IL-6 measurements at baseline and 30 and 120 minutes post-TSST. Results Stress exposure induced significant increases of cortisol and IL-6 on both days (cortisol: F=38, p<0.001; IL-6: F=90.8; p<0.001), and repeated exposure was related with cortisol habituation (F=8.2; p<0.001) and IL-6 sensitization (F=5.2; p=0.022). BMI and body fat were related with higher cortisol responses to repeated stress (BMI: beta=0.34; p=0.014; body fat: beta=0.29; p=0.045), and with higher IL-6 responses to repeated stress (BMI: beta=0.27, p=0.044; body fat: beta=0.37; p=0.006). Conclusions Taken together, individuals with higher measures of adiposity showed less efficient HPA axis habituation as well as sensitization of IL-6 responses to repeated acute stress. These findings point to maladaptive stress response patterns in overweight humans, which, through exposure to higher levels of inflammatory mediators, might partially explain diseases related with overweight and/or obesity. PMID:25107874

  20. 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

  1. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

    PubMed Central

    Savale, Laurent; Tu, Ly; Rideau, Dominique; Izziki, Mohamed; Maitre, Bernard; Adnot, Serge; Eddahibi, Saadia

    2009-01-01

    Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH). Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6). Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/-) and wild-type (IL-6+/+) mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer) mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice. PMID:19173740

  2. Serum Levels of Interleukin-6 and Interleukin-10 as Biomarkers for Hepatocellular Carcinoma in Egyptian Patients

    PubMed Central

    Othman, Mohamed S.; Aref, Ahmed M.; Mohamed, Amal A.; Ibrahim, Wesam A.

    2013-01-01

    Interleukin-10 (IL-10) and interleukin-6 (IL-6) have been reported to be related to hepatocellular carcinoma (HCC) prognosis. This study aimed to investigate the clinical usefulness of serum levels of IL-6 and IL-10 as biomarkers for HCC among high-risk patients. Materials and Methods. 80 individuals were enrolled in this study; they were categorized into 4 groups: group 1 healthy individuals (NC) (n = 20), group 2 chronic hepatitis C virus (HCV) patients (n = 20), group 3 cirrhotic patients (LC) (n = 20), and HCC group (n = 20). Using ELISA technique serum levels of IL-6, IL-10, and alpha fetoprotein (AFP) were evaluated in all groups. Results. The mean serum levels of IL-6 were significantly higher in HCC than in LC, HCV, and NC groups (13.99 ± 1.80, 7.49 ± 0.43, 5.78 ± 0.74, and 2.57 ± 0.31), respectively (P < 0.05); also the serum levels of IL-10 were significantly higher in HCC compared with LC, HCV, and NC groups (13.69 ± 1.89, 7.37 ± 0.53, 5.18 ± 0.6, and 3.31 ± 0.42) (P < 0.05). We also found that the tumor size is correlated strongly with IL-6 and IL-10 levels (r = 0.925, P < 0.001; r = 0.821, P < 0.001), respectively. Conclusion. The combination of those markers may help to identify a group of HCC patients with low AFP.

  3. 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. PMID:26144889

  4. Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo.

    PubMed

    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

  5. CHRNA3 polymorphism modifies lung adenocarcinoma risk in the Chinese Han population.

    PubMed

    He, Ping; Yang, Xue-Xi; He, Xuan-Qiu; Chen, Jun; Li, Fen-Xia; Gu, Xia; Jiang, Ju-Hong; Liang, Hui-Ying; Yao, Guang-Yu; He, Jian-Xing

    2014-01-01

    Recent genome-wide association studies (GWASs) have identified 15q25.1 as a lung cancer susceptibility locus. Here, we sought to explore the direct carcinogenic effects of genetic variants in this region on the risk of developing lung adenocarcinoma (ADC). Five common SNPs (rs8034191, rs16969968, rs1051730, rs938682, and rs8042374) spanning the 15q25.1 locus were assayed in a case-control study examining a cohort of 301 lung ADCs and 318 healthy controls. Stratification analysis by gender, smoking status, and tumor, node, metastasis (TNM) classification, was performed. In addition, sections from ADC tissue and normal tissue adjacent to tumors were stained with an anti-CHRNA3 (cholinergic receptor nicotinic α3) antibody by immunohistochemistry in 81 cases. Our results demonstrate that rs8042374, a variant of the CHRNA3 gene, is associated with an increased risk of ADC with an OR of 1.76 (95% CI: 1.17-2.65, p=0.024). This variant was linked to a greater risk of ADC in female nonsmokers (OR (95% CI): 1.81 (1.05-3.12), p=0.032) and female stage I+II cases (OR (95% CI): 1.92 (1.03-3.57), p=0.039). Although located within the same gene, rs938682 showed protective effects for smokers, stage III+IV cases, and male stage III+IV cases. Additionally, the CHRNA3 protein level in ADC tissue was slightly higher than in the surrounding normal lung tissue, based on immunohistochemical analysis. Our results suggest that the CHRNA3 polymorphism functions as a genetic modifier of the risk of developing lung ADC in the Chinese population, particularly in nonsmoking females. PMID:24686516

  6. 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

  7. 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

  8. Diagnostic and Prognostic Value of Serum Interleukin-6 in Colorectal Cancer

    PubMed Central

    Xu, Jinming; Ye, Yao; Zhang, Honghe; Szmitkowski, Maciej; Mäkinen, MJ; Li, Peiwei; Xia, Dajing; Yang, Jun; Wu, Yihua; Wu, Han

    2016-01-01

    Abstract The application of serum interleukin-6 (IL-6) in the diagnosis and prognosis of colorectal cancer (CRC) has been evaluated in many studies, whereas the results were contradictive. The aim of this study was to systematically evaluate this issue. An original study was conducted to explore the diagnostic value of serum IL-6 in CRC. Pubmed, Embase, and Cochrane library databases were searched for eligible studies. For diagnostic meta-analysis, aggregate data (AD) and individual participant data (IPD) meta-analyses were both adopted. The sensitivity and specificity were pooled and a summary receiver-operating characteristic (ROC) curve was constructed. For prognostic meta-analysis, study-specific hazard ratios (HRs) of IL-6 for survival were summarized. Secondary analysis of survival data was performed to synthesize the Kaplan–Meier curves. Total 17 studies (including our study) were included in this meta-analysis. The pooled sensitivity, specificity, and area under curve (AUC) of serum IL-6 were 0.72 (95% CI: 0.46–0.88), 0.74 (95% CI: 0.56–0.86), and 0.79 (95% CI: 0.75–0.82) in CRC diagnosis, respectively. Further, IPD meta-analysis strengthened the diagnostic value of serum IL-6 (the AUC, sensitivity, and specificity were 0.794, 0.606, and 0.839, respectively). For prognostic analysis, the high serum level of IL-6 was inversely associated with overall survival (OS) (pooled HR = 1.76, 95% CI: 1.42–2.19, P < 0.001) and disease-free survival (DFS) (pooled HR = 2.97, 95% CI: 1.76–5.01, P < 0.001). The synthesized Kaplan–Meier curves indicated that CRC patients with higher serum IL-6 level had a worse OS (P = 0.0027) and DFS (P < 0.001), which further support the prognostic value of serum IL-6 in CRC patients. The present study confirmed that serum IL-6 may be a potential biomarker for CRC diagnosis, and the high serum IL-6 level was associated with poor prognosis for both CRC overall survival and disease-free survival. The

  9. Interleukin 6 and lipopolysaccharide binding protein - markers of inflammation in acute appendicitis.

    PubMed

    Brănescu, C; Serban, D; Dascălu, A M; Oprescu, S M; Savlovschi, C

    2013-01-01

    The rate of incidence of acute appendicitis is 12% in the case of male patients and 25% in case of women, which represents about 7% of the world population. The appendectomy rate has remained constant (i.e. 10 out of 10,000 patients per year). Appendicitis most often occurs in patients aged between 11-40 years, on the threshold between the third and fourth decades, the average age being 31.3 years. Since the first appendectomy performed by Claudius Amyand (1681/6 -1740), on December, 6th, 1735 to our days, i.e., 270 years later, time has confirmed the efficiency of both the therapy method and the surgical solution. The surgical cure in case of acute appendicitis has proved to be acceptable within the most widely practised techniques in general surgery. The variety of clinical forms has reached all age ranges, which in its turn has resulted in a large number of semiotic signs. In the case of acute appendicitis, interdisciplinarity has allowed the transfer of concept and methodology transfer among many areas of expertise, aimed at a better, minute understanding of the inflammatory event itself. Acute appendicitis illustrates inflammation development at digestive level and provides for a diagnostic and paraclinical exploration which continually upgrades. The recent inclusion in the studies of the Lipopolysaccharide binding protein (LBP)- type inflammation markers has laid the foundation of the latter's documented presence in the case of acute appendicitis-related inflammation. Proof of the correlation between the histopathological, clinical and evolutive forms can be found by identifying and quantifying these inflammation markers. The importance of studying inflammation markers allows us to conduct studies going beyond the prognosis of the various stages in which these markers were identified. The present article shows the results of a 1-year monitoring of the inflammation markers' values for Interleukin-6 and Lipopolysaccharide binding protein (LBP)-types, both pre

  10. Interleukin-6 protects cerebellar granule neurons from NMDA-induced neurotoxicity.

    PubMed

    Wang, Xiao-Chun; Qiu, Yi-Hua; Peng, Yu-Ping

    2007-04-25

    Interleukin-6 (IL-6) is an important cytokine that participates in inflammation reaction and cell growth and differentiation in the immune and nervous systems. However, the neuroprotection of IL-6 against N-methyl-D-aspartate (NMDA)-induced neurotoxicity and the related underlying mechanisms are still not identified. In the present study, the cultured cerebellar granule neurons (CGNs) from postnatal (8-day) infant rats were chronically exposed to IL-6 for 8 d, and then NMDA (100 micromol/L) was applied to the cultured CGNs for 30 min. Methyl-thiazole-tetrazolium (MTT) assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and confocal laser scanning microscope (CLSM) were used to detect neuronal vitality, apoptosis and dynamic changes of intracellular Ca(2+) levels in the neurons, respectively. Anti-gp130 monoclonal antibody (75 ng/mL) was employed to the cultured CGNs with IL-6 to inhibit IL-6 activity so as to evaluate the role of gp130 (a 130 kDa glucoprotein transducing IL-6 signal) in mediating IL-6 neuroprotection. Western blot was used to measure the expressions of phospho-signal transducer and activator of transcription 3 (STAT3) and phospho-extracellular signal regulated kinase 1/2 (ERK1/2) in the cultured CGNs. The NMDA stimulation of the cultured CGNs without IL-6 pretreatment resulted in a significant reduction of the neuronal vitality, notable enhancement of the neuronal apoptosis and intracellular Ca(2+) overload in the neurons. The NMDA stimulation of the CGNs chronically pretreated with IL-6 caused a remarkable increase in the neuronal vitality, marked suppression of neuronal apoptosis and intracellular Ca(2+) overload in the neurons, compared with that in the control neurons without IL-6 pretreatment. Furthermore, anti-gp130 antibody blocked the inhibitory effect of IL-6 on NMDA-induced intracellular Ca(2+) overload in the neurons. The levels of phospho-STAT3 and phospho-ERK1/2 were significantly higher in IL-6

  11. Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth.

    PubMed

    Culig, Zoran; Bartsch, Georg; Hobisch, Alfred

    2002-11-29

    Interleukin-6 (IL-6) is a multifunctional cytokine which is involved in regulation of growth of various malignant tumors. IL-6 binds to its receptor, which is composed of a ligand-binding and a signal-transducing subunit and activates pathways of signal transducers and activators of transcription and mitogen-activated protein kinases (MAPKs). In prostate cancer cells, IL-6 induces divergent proliferative responses. Serum levels of IL-6 are elevated in patients with therapy-resistant carcinoma of the prostate. We have investigated whether IL-6 interacts with the androgen signaling pathway in prostate cancer cells. In DU-145 cells, transiently transfected with androgen receptor (AR) cDNA, IL-6 caused ligand-independent and synergistic activation of the AR. Nonsteroidal antagonists of the AR down-regulated AR activity induced by IL-6. In LNCaP cells, IL-6-induced expression of the AR-regulated prostate-specific antigen gene. Inhibitors of protein kinase A and C and MAPK down-regulated IL-6-induced AR activity. IL-6 expression in human prostate tissue was studied by immunohistochemistry. In benign prostatic tissue, IL-6 immunoreactivity was confined to basal cells. In prostate intraepithelial neoplasia and in cancer tissue, atypical intraluminal and cancer cells expressed IL-6. The expression of IL-6 receptor was demonstrated in benign and malignant tissue in both epithelium and stroma. In the authors' laboratory, IL-6-inhibited proliferation of parental LNCaP cells. A new LNCaP subline was generated to investigate changes in signal transduction which might occur after prolonged treatment with IL-6. In the subline LNCaP-IL-6+, IL-6 neither reduced a number of cells nor caused G1 growth arrest. IL-6 receptor expression declined during long-term IL-6 treatment. However, IL-6-up-regulated AR expression and was capable of inducing AR activity in LNCaP-IL-6+ cells. Parental LNCaP cells do not express IL-6. In contrast, IL-6 mRNA and protein expression were detectable in

  12. Intraalveolar TNF-α in combined burn and inhalation injury compared with intraalveolar interleukin-6.

    PubMed

    Stromps, Jan-Philipp; Fuchs, Paul; Demir, Erhan; Grieb, Gerrit; Reuber, Kai; Pallua, Norbert

    2015-01-01

    The objective of this study was to evaluate the role of intraalveolar tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in a combination of skin burn and smoke inhalation injuries because this combined trauma is associated with an increased morbidity and mortality compared with either of these traumas alone. We used a standardized small animal model (rats n = 84) to investigate the early intraalveolar excretion of TNF-α during the first one, three, and six hours after a singular skin burn injury, singular smoke inhalation injury, and a combination involving both the traumas. The data were compared with the data from control rats that only received preparation and mechanical ventilation. The TNF-α serum levels and intraalveolar IL-6 concentrations were also measured. One hour after trauma, there was a significant difference in the TNF-α concentration between the controls and both the singular traumas (control vs burn P < .0444 and control vs smoke P < .005) and between the inhalation injury and the combined trauma (smoke vs burn + smoke P < .0084). After three and six hours, no significant differences among the groups were observed. Compared with the controls, both the singular skin burn and smoke inhalation injuries led to increased intraalveolar TNF-α excretion, whereas the combined trauma showed the least intraalveolar TNF-α levels at three and six hours post-trauma. These findings differed from the serum TNF-α levels. Compared with the IL-6 levels, we observed a negative correlation within the intraalveolar cytokine concentrations after one hour (r = -.809), three hours (r = -.627), and six hours (r = -.746). This study confirms the importance of the intraalveolar cytokine reaction in the early posttraumatic stage after a combined burn and inhalation injury. The differences between the combined and singular traumas indicate that TNF-α plays a role in the immunologic hyporesponsiveness of the lung and therefore in the systemic pathophysiological

  13. Effects of antipsychotics on cortisol, interleukin-6 and hippocampal perfusion in healthy volunteers.

    PubMed

    Handley, Rowena; Mondelli, Valeria; Zelaya, Fernando; Marques, Tiago; Taylor, Heather; Reinders, Antje A T S; Chaddock, Christopher; McQueen, Grant; Hubbard, Kathryn; Papadopoulos, Andrew; Williams, Steve; McGuire, Philip; Pariante, Carmine; Dazzan, Paola

    2016-07-01

    This randomized within-subject, double blind study aimed to compare the effects of a single dose of two different antipsychotics (haloperidol and aripiprazole) on cortisol, interleukin (IL)-6 and hippocampal regional Cerebral Blood Flow (rCBF) in the same 17 healthy male individuals. Subjects received a single dose of haloperidol (3mg), aripiprazole (10mg) and placebo, in a randomized order on three study appointments. We measured salivary cortisol levels at multiple time points, IL-6 levels from plasma samples, and resting cerebral blood flow (rCBF), using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T). We found significantly lower cortisol levels in the haloperidol condition (F(2,32)=5.78, p=0.007), than in either placebo (p=0.013; CI=0.45, 0.406) or aripiprazole (p=0.037; CI=-0.520, -0.014). Interleukin-6 levels were also lower following haloperidol (F(2,22)=4.19, p=0.048) in comparison with placebo (p=0.02; CI=0.14, 1.8), but not with aripiprazole. Finally, we found a greater rCBF in the right (peak voxel: T=6.47, p<0.0001) and left (peak voxel T=5.17, p<0.01) hippocampus following haloperidol compared with placebo, and at trend level also in the left hippocampus following aripiprazole compared with placebo (T=4.07, p=0.057). These differences in hippocampal rCBF after both antipsychotics were no longer evident (haloperidol) or present at trend level (aripiprazole), after controlling for cortisol and IL-6 levels. Our findings suggest that haloperidol can directly regulate the hypothalamic-pituitary-adrenal (HPA) axis and immune system through a pharmacological action via D2 receptor antagonism. Finally, our data suggest that the increased hippocampal rCBF is a manifestation of the reduction in IL-6 and cortisol which follows the administration of haloperidol. PMID:27112637

  14. Role of the C-terminus in the activity, conformation, and stability of interleukin-6.

    PubMed Central

    Ward, L. D.; Hammacher, A.; Zhang, J. G.; Weinstock, J.; Yasukawa, K.; Morton, C. J.; Norton, R. S.; Simpson, R. J.

    1993-01-01

    Two murine interleukin-6 (mIL-6) variants were constructed using the polymerase chain reaction (PCR), one lacking the last five residues (183-187) at the C-terminus (pMC5) and another with the last five residues of mIL-6 substituted by the corresponding residues of human IL-6 (pMC5H). The growth stimulatory activity of pMC5 on the mouse hybridoma cell line 7TD1 was < 0.05% of mIL-6, whereas pMC5H and mIL-6 were equipotent. The loss of biological activity of pMC5 correlated with its negligible receptor binding affinity on 7TD1 cells, while the binding of pMC5H was comparable to that of mIL-6. Both pMC5 and pMC5H, like mIL-6, failed to interact with recombinant soluble human IL-6 receptor when assayed by surface plasmon resonance-based biosensor analysis. These studies suggest that the C-terminal seven amino acids of human IL-6, alone, do not define species specificity for receptor binding. A variety of biophysical techniques, as well as the binding of a conformational-specific monoclonal antibody, indicated that the global fold of the mIL-6 variants was similar to that of mIL-6, although small changes in the NMR spectra, particularly for pMC5, were observed. Some of these changes involved residues widely separated in the primary structure. For instance, interactions involving Tyr-22 were influenced by the C-terminal amino acids suggesting that the N- and C-termini of mIL-6 are in close proximity. Equilibrium unfolding experiments indicated that pMC5 was 0.8 kcal/mol less stable than mIL-6, whereas pMC5H was 1.4 kcal/mol more stable. These studies emphasize the structural importance of the C-terminal amino acids of IL-6 and suggest that truncation or mutation of this region could lead to small but significant alterations in other regions of the molecule. PMID:8401231

  15. Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage.

    PubMed Central

    Bruunsgaard, H; Galbo, H; Halkjaer-Kristensen, J; Johansen, T L; MacLean, D A; Pedersen, B K

    1997-01-01

    1. This study was performed to test the hypothesis that the exercise-induced increase in circulating cytokine levels is associated with muscle damage. Nine healthy young male subjects performed two high-intensity bicycle exercise trials separated by two weeks. The first trial consisted of 30 min of normal bicycle exercise (concentric exercise), whereas the second consisted of 30 min of braking with reversed revolution (eccentric exercise). The work loads were chosen to give the same increases in heart rate and catecholamine levels in the blood during each trial. 2. Significant increases (P < 0.05) in plasma concentration of creatine kinase (CK), aspartate aminotransferase and alanine aminotransferase were observed only after the eccentric exercise. Furthermore, the level of interleukin-6 (IL-6) in serum increased significantly after the eccentric exercise and was significantly correlated to CK concentration in the following days, whereas no significant changes were found after the concentric exercise. 3. The total concentration of lymphocytes increased significantly (P < 0.05) as a result of eccentric compared with concentric exercise. This was mainly due to a significantly more pronounced recruitment of natural killer (NK) cells and CD8 positive cells (CD8+ cells) during the eccentric trial. However, no significant differences between the two types of work were found in regard to the circulating concentration of monocytes. The concentration of neutrophils was only significantly increased 2 h after the concentric exercise. 4. The finding that high-intensity eccentric exercise caused a more pronounced increase in the plasma level of IL-6, compared with concentric exercise, supports the hypothesis that the post-exercise cytokine production is related to skeletal muscle damage. The fact that no differences between eccentric and concentric exercise were found in the recruitment of most blood mononuclear cell subsets to the blood supports the hypothesis that the

  16. 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

  17. 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

  18. Circulating interleukin-6 and rheumatoid arthritis: A Mendelian randomization meta-analysis.

    PubMed

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

    2016-06-01

    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

  19. An Interleukin-6 Neutralizing Antibody Prevents Cyclosporine Induced Nephrotoxicity in Mice

    PubMed Central

    LaSpina, Mark; Tripathi, Sudipta; Gatto, Louis A.; Bruch, David; Maier, Kristopher G.; Kittur, Dilip S.

    2008-01-01

    Introduction 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 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. Methods Male mice C57B/6 mice from JAX Laboratories at 6–8 weeks were subjected to a low salt diet throughout the trial. After one week on a low salt diet, the mice were injected daily with treatments in 50µL vehicle composed of 75% cremaphor and Ethanol for five weeks. A vehicle alone group was also set aside. Mice were weighed and 25mg/kg/day cyclosporine was injected daily. Apocynin 20mg/kg were injected either alone or concomitantly with CyA. Another group of mice were administered IL-6 Antibody at 2µg/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 ten 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 ten blocks, and the number of blocks that contained necrotic tubules per photo was recorded. Results 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 observed to have 15% (6/40) damage. Comparing imaging analysis, there was no difference between mice treated with CyA alone and with CyA with apocynin. However

  20. GSTM1 and GSTP1 Polymorphisms as Potential Factors for Modifying the Effect of Smoking on Inflammatory Response

    PubMed Central

    Kim, Jin-Hee; Park, Shin-Goo; Lee, Kwan-Hee; Choi, Ji-Ho; Ha, Eun-Hee; Myung, Seung-Kwon

    2006-01-01

    Inflammation has been known to be an important underlying condition for development of various diseases including cancer. The aims of this study were to investigate whether tobacco smoke exposure increases the level of inflammation biomarkers and the GSTM1 and GSTP1 gene polymorphisms are associated with inflammatory response due to tobacco smoke exposure. We measured urinary cotinine level in 300 healthy university students. Total serum TNF-α levels and blood WBC counts were determined to evaluate inflammatory response. Allelic loss of the GSTM1 and the GSTP1 (Ile105Val) polymorphism were determined by PCR and RFLP. Tobacco smoke exposure was found to be associated with increase of both TNF-α level and WBC count. Particularly, smokers with combination of GSTM1 null and GSTP1 AG or GG genotypes showed higher TNF-α level than those with the other genotype combinations (p=0.07). This result suggests that smoking may induce inflammation measured as TNF-α level or WBC count and combinations of the GSTM1 and GSTP1 polymorphisms may modify the effect of smoking on serum TNF-α level. PMID:17179680

  1. 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

  2. Vitamin D receptor gene polymorphism as an important modifier of positive family history related breast cancer risk.

    PubMed

    Sillanpää, Pia; Hirvonen, Ari; Kataja, Vesa; Eskelinen, Matti; Kosma, Veli-Matti; Uusitupa, Matti; Vainio, Harri; Mitrunen, Katja

    2004-04-01

    The association between vitamin D receptor (VDR) gene polymorphisms and diseases such as breast cancer, prostate cancer and osteoporosis has been extensively investigated during recent years. To date, several polymorphisms have been found in the VDR gene. In this Finnish case-control study, comprising 483 breast cancer patients and 482 healthy population controls, we investigated the association between altered breast cancer risk and two polymorphisms in the 3' end of the gene detectable with ApaI and TaqI restriction enzymes. A statistically significant difference was observed in the ApaI genotype distribution between cases and controls. Women with the VDR variant a allele containing genotypes showed a decreased risk for breast cancer [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.54-0.98] compared to women with the AA genotype. This association was especially strong among women with a positive family history of breast cancer (OR 0.14, 95% CI 0.03-0.76). Moreover, there was a trend (P for trend = 0.0007) for decreased risk with increasing number of variant alleles. The lowest risk of breast cancer was seen for the women with the aa genotype (OR 0.03, 95% CI 0.003-0.31) compared to women with the AA genotype. A tendency of decreased risk of breast cancer was also observed for the TaqI T allele containing genotypes (Tt and TT) (OR 0.68, 95% CI 0.41-1.12), but because the distribution of Taql alleles in the controls missed the Hardy-Weinberg equilibrium (P = 0.01), we were unable to properly assess the potential impact of the TaqI polymorphism in breast cancer susceptibility. In conclusion, our results suggest that the VDR ApaI genotype may be an important modifier of individual breast cancer risk among Finnish women, especially if they have a positive family history of breast cancer. PMID:15083068

  3. 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. PMID:11201682

  4. Mndal, a new interferon-inducible family member, is highly polymorphic, suppresses cell growth, and may modify plasmacytoma susceptibility.

    PubMed

    Zhang, Ke; Kagan, Daniel; DuBois, Wendy; Robinson, Richard; Bliskovsky, Valery; Vass, William C; Zhang, Shuling; Mock, Beverly A

    2009-10-01

    The human HIN-200 gene cluster and its mouse counterpart, the interferon inducible-200 (Ifi200) family, both on Chr 1, are associated with several diseases, including solid tumors and lupus. Our study was initiated to identify the modifier gene(s) encoded by the Pctm locus, in which mouse B-cell plasmacytomas induced by pristane are associated with heterozygosity of Chr 1 genes near the Ifi200 cluster. A screen for differentially expressed genes in granulomatous tissues induced by pristane in resistant and susceptible strains identified a new Ifi200 member whose expression was 1000-fold higher in the strain carrying the resistant allele of Pctm and was the most highly expressed Ifi200 gene. The gene, designated Mndal (for MNDA-like, myeloid nuclear differentiation antigen-like), was absent in the susceptible genome, as were genomic sequences upstream of Ifi203, the gene adjacent to Mndal. Ectopic expression of MNDAL suppressed cell growth, which, together with the disease susceptibility of heterozygotes at the Pctm locus, suggests that Mndal, perhaps with Ifi203, acts as a tumor suppressor and display(s) haploinsufficiency. Mndal is highly polymorphic among inbred mouse strains, because it is absent in 10 of 24 strains. This polymorphism may have implications for other disease modifiers mapping to the same region. PMID:19654412

  5. Identification of a KCNQ1 Polymorphism Acting as a Protective Modifier against Arrhythmic Risk in Long QT Syndrome

    PubMed Central

    Duchatelet, Sabine; Crotti, Lia; Peat, Rachel A.; Denjoy, Isabelle; Itoh, Hideki; Berthet, Myriam; Ohno, Seiko; Fressart, Véronique; Monti, Maria Cristina; Crocamo, Cristina; Pedrazzini, Matteo; Dagradi, Federica; Vicentini, Alessandro; Klug, Didier; Brink, Paul A.; Goosen, Althea; Swan, Heikki; Toivonen, Lauri; Lahtinen, Annukka M.; Kontula, Kimmo; Shimizu, Wataru; Horie, Minoru; George, Alfred L.; Trégouët, David-Alexandre; Guicheney, Pascale; Schwartz, Peter J.

    2013-01-01

    Background Long-QT Syndrome (LQTS) is characterized by such striking clinical heterogeneity, that even among family members carrying the same mutation, clinical outcome can range between sudden death to no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in LQTS patients. Methods and Results In a matched case-control study including 112 LQTS patient duos from France, Italy and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of two relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation; one with cardiac events and one asymptomatic and untreated. The findings were then validated in two independent founder populations totaling 174 symptomatic and 162 asymptomatic LQTS patients, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 [0.19 – 0.61] (p<0.0002) and with shorter QTc (p<0.0001) in the combined discovery and replication cohorts. Conclusions We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in LQTS patients. This finding is a step toward a novel approach for risk stratification in LQTS patients. PMID:23856471

  6. Promoter variants in interleukin-6 and tumor necrosis factor alpha and risk of coronary artery disease in a population from Western India

    PubMed Central

    Bhanushali, Aparna A; Das, B R

    2013-01-01

    INTRODUCTION: A central component of the atherosclerotic process is inflammation. Single nucleotide polymorphisms (SNPs) present in the promoter region of various cytokines can lead to altered levels of the transcript and a state of low-grade inflammation exacerbating the risk of coronary artery disease (CAD). The present work tries to understand the role of permissive promoter variants in the interleukin-6 gene (IL-6-174G/C) and the tumor necrosis factor alpha (TNFα-308G/A) in the causation of CAD and also dyslipidemia. MATERIALS AND METHODS: Genotyping was conducted on 100 cases of CAD and 150 controls by the allele termination assay SNaPshot. Biochemical parameters were determined by routine enzymatic endpoint methods. The results were analyzed by appropriate statistical methods. RESULTS: No differences in the minor allele frequency IL-6-174G/C SNP were seen between cases and controls (0.13 vs. 0.12). The differences in the allele frequency of TNFα-308A between cases (6%) and controls (2%) have led to an odds ratio, 3.370; 95% confidence interval, 1.039-11.543; P=0.033 in the univariate analysis. In the final logistic regression analysis, however none of the variants were associated with an increased risk of CAD. CONCLUSIONS: In summary, no association of the permissive promoter variants in the IL-6 gene and the TNFα gene were seen with an increased CAD risk. These and other studies highlight the importance of doing population specific studies. PMID:24497708

  7. Common interleukin-6 promoter variants associate with the more severe forms of distal interphalangeal osteoarthritis

    PubMed Central

    Kämäräinen, Olli-Pekka; Solovieva, Svetlana; Vehmas, Tapio; Luoma, Katariina; Riihimäki, Hilkka; Ala-Kokko, Leena; Männikkö, Minna; Leino-Arjas, Päivi

    2008-01-01

    Introduction The objective of this study was to investigate the relationship of the IL-6 promoter variants G-597A, G-572C and G-174C (rs1800797, rs1800796 and rs1800795, respectively), which have been shown to affect both the transcription and secretion of IL-6, to symptomatic distal interphalangeal (DIP) osteoarthritis (OA). Methods A total of 535 women aged 45 to 63 years were included. Radiographs of both hands were taken and each DIP joint was evaluated (grade 0 to 4) for the presence of OA. Information on symptoms (pain, tenderness) in each joint was collected by using a self-administered questionnaire. Symptomatic DIP OA was defined by the presence of both radiographic findings of grade 2 or more and symptoms in at least two DIP joints, and symmetrical DIP OA by the presence of radiographic findings of grade 2 or more in at least one symmetrical pair of DIP joints. Common polymorphic loci in the IL-6 gene were amplified and the promoter haplotypes were reconstructed from genotype data with the PHASE program. Logistic regression analysis was used to examine the association between the IL-6 genotypes/diplotypes and the DIP OA outcome. Results The G alleles of two promoter single nucleotide polymorphisms (SNPs) G-597A and G-174C were more common among the subjects with symptomatic DIP OA than among those with no disease (P = 0.020 and 0.024, corrected for multiple testing). In addition, the carriage of at least one G allele in these positions increased the risk of disease (P = 0.006 and P = 0.008, respectively). Carrying a haplotype with the G allele in all three promoter SNPs increased the risk of symptomatic DIP OA more than fourfold (odds ratio (OR) 4.45, P = 0.001). Carriage of the G-G diplotype indicated an increased risk of both symmetrical DIP OA (OR 1.52, 95% confidence interval 1.01 to 2.28) and symptomatic DIP OA (OR 3.67, 95% confidence interval 1.50 to 9.00). Conclusion The present study showed that the presence of G alleles at common IL-6

  8. 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.

  9. 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

  10. 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

  11. Ixodes ricinus Salivary Serpin IRS-2 Affects Th17 Differentiation via Inhibition of the Interleukin-6/STAT-3 Signaling Pathway

    PubMed Central

    Páleníková, Jana; Lieskovská, Jaroslava; Langhansová, Helena; Kotsyfakis, Michalis; Chmelař, Jindřich

    2015-01-01

    Th17 cells constitute a subset of CD4+ T lymphocytes that play a crucial role in protection against extracellular bacteria and fungi. They are also associated with tissue injury in autoimmune and inflammatory diseases. Here, we report that serpin from the tick Ixodes ricinus, IRS-2, inhibits Th17 differentiation by impairment of the interleukin-6 (IL-6)/STAT-3 signaling pathway. Following activation, mature dendritic cells produce an array of cytokines, including the pleiotropic cytokine IL-6, which triggers the IL-6 signaling pathway. The major transcription factor activated by IL-6 is STAT-3. We show that IRS-2 selectively inhibits production of IL-6 in dendritic cells stimulated with Borrelia spirochetes, which leads to attenuated STAT-3 phosphorylation and finally to impaired Th17 differentiation. The results presented extend the knowledge about the effect of tick salivary serpins on innate immunity cells and their function in driving adaptive immune responses. PMID:25712932

  12. Colorectal cancer cell-derived interleukin-6 enhances the phagocytic capacity and migration of THP-1 cells.

    PubMed

    Yeh, Kun-Yun; Wu, Tsung-Han; Wu, Tai-Ling

    2016-03-01

    Macrophages perform a versatile range of functions in response to environmental stimuli. In the present study, we evaluated whether interleukin-6 (IL-6), a cytokine released from colorectal cancer (CRC) cells and associated with CRC pathogenesis and metastasis, modulates the phagocytic capacity and migratory ability of macrophages, using a monocyte-macrophage THP-1 cell model and human peripheral monocytes. We found that CRC cells enhanced the phagocytic capacity and migration of THP-1 cells and human peripheral monocytes. CRC cell culture supernatants and recombinant IL-6 neutralized with anti-IL-6 and anti-gp130 antibodies considerably decreased IL-6-mediated phagocytosis by and migration of THP-1 cells and human peripheral monocytes, via the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Our data suggest that CRC cells secreting IL-6 via STAT3 phosphorylation can enhance the phagocytic capacity and migration of macrophages in the tumor microenvironment. PMID:26775116

  13. INTERLEUKIN 6 MEDIATES NEUROINFLAMMATION AND MOTOR COORDINATION DEFICITS AFTER MILD TRAUMATIC BRAIN INJURY AND BRIEF HYPOXIA IN MICE

    PubMed Central

    Yang, Sung H.; Gangidine, Matt; Pritts, Timothy A.; Goodman, Michael D.; Lentsch, Alex B.

    2014-01-01

    Traumatic brain injury (TBI) is a leading cause of mortality and disability. Acute postinjury insults after TBI, such as hypoxia, contribute to secondary brain injury and worse clinical outcomes. The functional and neuroinflammatory effects of brief episodes of hypoxia experienced following TBI have not been evaluated. Our previous studies have identified interleukin 6 (IL-6) as a potential mediator of mild TBI–induced pathology. In the present study, we sought to determine the effects of brief hypoxia on mild TBI and whether IL-6 played a role in the neuroinflammatory and functional deficits after injury. A murine model of mild TBI was induced by a weight drop (500 g from 1.5 cm). After injury, mice were exposed to immediate hypoxia (Fio2 = 15.1%) or normoxia (Fio2 = 21%) for 30 min. Serum and brain samples were analyzed for inflammatory cytokines 24 h after TBI. Neuron-specific enolase was measured as a serum biomarker of brain injury. Evaluation of motor coordination was performed for 5 days after TBI using a rotarod device. In some animals, anti–IL-6 was administered following TBI and hypoxia to neutralize systemic IL-6. Mice undergoing TBI had significant increases in brain injury. Exposure to brief hypoxia after TBI resulted in a more than 5-fold increase in serum neuron-specific enolase. This increase was associated with increases in serum and brain cytokine expression, suggesting that brief hypoxia exacerbates systemic and brain inflammation. Neutralization of IL-6 suppressed postinjury neuroinflammation and neuronal injury. In addition, TBI and hypoxia induced significant motor coordination deficits that were completely abrogated by IL-6 blockade. Exposure to hypoxia after TBI induces neuroinflammation and brain injury. These changes can be mitigated by neutralization of systemic IL-6. Interleukin 6 blockade also corrected the TBI-induced deficit in motor coordination. These data suggest that systemic IL-6 modulates the degree of neuroinflammation and

  14. 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. PMID:23894380

  15. 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

  16. 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

  17. Interleukin-6 and risk of colorectal cancer: results from the CLUE II cohort and a meta-analysis of prospective studies

    PubMed Central

    Kakourou, Artemisia; Koutsioumpa, Charalampia; Lopez, David S.; Hoffman-Bolton, Judith; Bradwin, Gary; Rifai, Nader; Helzlsouer, Kathy J.; Platz, Elizabeth A.

    2016-01-01

    Purpose The association between prediagnostic inter-leukin-6 (IL-6) concentrations and risk of colorectal cancer was evaluated in a nested case–control study and a meta-analysis of prospective studies. Methods 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. Results 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; I2 46 %). An inverse association was noted for rectal cancer (RR 0.69; 95 % CI 0.54–0.88; I2 0 %), but there was evidence for small-study effects (p 0.02). Conclusion 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. PMID:26220152

  18. 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

  19. DNA polymorphism sensitive impedimetric detection on gold-nanoislands modified electrodes.

    PubMed

    Bonanni, Alessandra; Pividori, Maria Isabel; del Valle, Manel

    2015-05-01

    Nanocomposite materials are being increasingly used in biosensing applications as they can significantly improve biosensor performance. Here we report the use of a novel impedimetric genosensor based on gold nanoparticles graphite-epoxy nanocomposite (nanoAu-GEC) for the detection of triple base mutation deletion in a cystic-fibrosis (CF) related human DNA sequence. The developed platform consists of chemisorbing gold nano-islands surrounded by rigid, non-chemisorbing, and conducting graphite-epoxy composite. The ratio of the gold nanoparticles in the composite was carefully optimized by electrochemical and microscopy studies. Such platform allows the very fast and stable thiol immobilization of DNA probes on the gold islands, thus minimizing the steric and electrostatic repulsion among the DNA probes and improving the detection of DNA polymorphism down to 2.25fmol by using electrochemical impedance spectroscopy. These findings are very important in order to develop new and renewable platforms to be used in point-of-care devices for the detection of biomolecules. PMID:25702990

  20. Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists.

    PubMed

    Rajaraman, Preetha; Bhatti, Parveen; Doody, Michele Morin; Simon, Steven L; Weinstock, Robert M; Linet, Martha S; Rosenstein, Marvin; Stovall, Marilyn; Alexander, Bruce H; Preston, Dale L; Sigurdson, Alice J

    2008-12-01

    Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case-control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (OR(GC) = 1.1, OR(CC) = 1.3; p-trend = 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/Gy(GG) = 1.0, 95% CI = <0, 6.0; EOR/Gy(GC/CC) = 5.9, 95% CI = 0.9, 14.4; p(het) = 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/Gy(AA) = 9.1, 95% CI = 2.1-21.3; EOR/Gy(AC/CC) = 0.6, 95% CI = <0, 4.6; p(het) = 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk. PMID:18767034

  1. Genetic polymorphisms in DNA repair and oxidative stress pathways may modify the association between body size and postmenopausal breast cancer

    PubMed Central

    McCullough, Lauren E.; Eng, Sybil M.; Bradshaw, Patrick T.; Cleveland, Rebecca J.; Steck, Susan E.; Terry, Mary Beth; Shen, Jing; Crew, Katherine D.; Rossner, Pavel; Ahn, Jiyoung; Ambrosone, Christine B.; Teitelbaum, Susan L.; Neugut, Alfred I.; Santella, Regina M.; Gammon, Marilie D.

    2015-01-01

    Purpose Obesity is associated with increased bioavailability of estrogen, hyperinsulemia and chronic inflammation, all of which may promote tumor growth. Given DNA repair and oxidative stress pathways may work together with these mechanisms to influence carcinogenesis, we hypothesized that genetic variation in these pathways may modify the obesity-postmenopausal breast cancer association. Methods Resources from a population-based case-control study (990 cases/970 controls) were used to construct logistic regression models. Body mass index (BMI, weight kg/height m2) was assessed 1-year prior to reference date. We characterized interactions between BMI and 29 genetic polymorphisms in oxidative stress and DNA repair pathways. Results Age-adjusted odds ratios (95% confidence intervals) for postmenopausal breast cancer were 1.24 (1.00–1.52) and 1.35 (1.09–1.71) for 25≥BMI<30 and BMI≥30, respectively. We observed multiplicative interactions (p≤0.05) for eight gene polymorphisms in DNA repair and oxidative stress pathways. For example, among MPO variant allele carriers, obesity was associated with a two-fold increased risk of postmenopausal breast cancer [2.13 (1.35–3.36)]; however in wild-type homozygotes, the relationship was less pronounced [1.33 (0.93–1.89)]. Our findings were no longer significant after Bonferroni correction. Conclusions Obesity may be particularly deleterious for postmenopausal breast cancer development in the presence of biologically plausible DNA repair or oxidative stress genotypes. PMID:25703993

  2. Carotid Intima-Media Thickness Is Associated With Allelic Variants of Stromelysin-1, Interleukin-6, and Hepatic Lipase Genes The Northern Manhattan Prospective Cohort Study

    PubMed Central

    Rundek, Tanja; Elkind, Mitchell S.; Pittman, John; Boden-Albala, Bernadette; Martin, Steve; Humphries, Steve E.; Juo, Suh-Hang Hank; Sacco, Ralph L.

    2009-01-01

    Background and Purpose Atherosclerosis is a complex disorder with hereditary and environmental causes. Carotid artery intima-media wall thickness (IMT) is a useful measure of atherosclerosis. The objective of this study was to determine the association between carotid IMT and functional promoter variants of stromelysin-1 (MMP3: −1612 5A>6A), interleukin-6 (IL6: −174G>C), and hepatic lipase (HL: −480C>T) genes. Methods B-mode carotid ultrasound was performed among 87 subjects (mean age, 70 ± 12 years; 55% women; 60% Caribbean-Hispanic, 25% black, and 13% white) from the Northern Manhattan Prospective Cohort Study. Carotid IMT was calculated as a composite measure (mean of the maximum IMT in the bifurcation, the common carotid artery, and the internal carotid artery). Results For all polymorphisms, genotype distribution was not significantly different from Hardy-Weinberg equilibrium. The frequencies of the rare alleles were as follows: MMP3 −1612 5A>6A, 0.31 (95% CI, 0.25 to 0.39); IL6 −174 G>C, 0.20 (95% CI, 0.13 to 0.25); and HL −480 C>T, 0.45 (95% CI, 0.35 to 0.50). Carotid IMT in the sample was 0.78±0.18 mm. Subjects with the MMP3 genotype 6A6A had 8% greater mean carotid IMT than the other MMP3 genotypes combined (0.95±0.17 versus 0.87±0.15 mm; P=0.04). Subjects with the IL6 genotype GG had 11% greater IMT (0.85±0.17 versus 0.76±0.16 mm; P=0.03), and those with the HL genotype CC had 13% greater IMT (0.87±20 versus 0.76±0.18 mm; P=0.02) than the other genotypes combined. Adjustment for other risk factors did not change these associations. Conclusions Carotid IMT is higher among subjects homozygous for functional variants in genes related to matrix deposition (MMP3 −16126A), inflammation (IL6 −174G), and lipid metabolism (HL −480C). These associations were independent of race-ethnicity and some environmental exposures. Further studies are needed to confirm these genotype-phenotype associations. PMID:11988625

  3. Clinical Relevance of Transforming Growth Factor-β1, Interleukin-6 and Haptoglobin for Prediction of Obesity Complications in Prepubertal Egyptian Children

    PubMed Central

    El-Alameey, Inas R.; Fadl, Nevein N.; Hameed, Enas R. Abdel; Sherif, Lobna S.; Ahmed, Hanaa H.

    2015-01-01

    BACKGROUND: The rate of obesity is increasing throughout the world. Obesity in adults’ research is characterized by chronic inflammation, associated with type 2 Diabetes and cardiovascular risk. The degree to which these changes occur in childhood obesity is not fully defined. AIM: This study was designed to explore the relation between circulating levels of pro-inflammatory cytokines, and obesity. PATIENTS AND METHODS: This cross sectional case control study was carried out in 50 randomly selected pre-pubertal overweight and obese children compared with fifty apparently healthy children of matched age and sex. Serum levels of transforming growth factor-β1, interleukin-6, and haptoglobin were quantified by ELISA technique. RESULTS: ANOVA test followed by Post Hoc test showed highly significant increase in the serum levels of the transforming growth factor-β1, interleukin-6 and haptoglobin among obese children compared to overweight and healthy children respectively. The body weight, BMI and BMI z-score were significantly positively correlated with serum levels of the three pro-inflammatory cytokines. Serum levels of interleukin-6, and haptoglobin were found to be strong predictors of complications in severe obesity by linear regression analysis. CONCLUSIONS: Obesity is associated with chronic low-grade inflammation. High levels of interleukin-6 and haptoglobin are considered to be early biomarkers of inflammation associated with severe obesity with subsequent cardiovascular and type 2 diabetes risk.

  4. Stearidonic and eicosapentaenoic acids inhibit interleukin-6 expression in ob/ob mouse adipose stem cells via toll-like receptor-2-mediated pathways

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Increases in adipose tissue weight positively correlates with increased circulating inflammatory cytokines such as interleukin-6 (IL-6). We previously have shown that adipose stem cell produce significantly higher levels of IL-6 when compared to other cell types in the adipose tissue in genetically ...

  5. The role of interleukin-6 in pulmonary and systemic manifestations in a murine model of chronic obstructive pulmonary disease.

    PubMed

    Pauwels, Nele S; Bracke, Ken R; Maes, Tania; Pilette, Charles; Joos, Guy F; Brusselle, Guy G

    2010-10-01

    Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary and extrapulmonary manifestations including systemic inflammation and weight loss. Increased levels of interleukin-6 (IL-6) have been demonstrated in sputum and serum of COPD patients. Therefore, the authors investigated the in vivo role of IL-6 in a murine model of COPD. Wild-type (WT) and IL-6 knockout (KO) mice were exposed subacutely (4 weeks) and chronically (24 weeks) to air or cigarette smoke (CS). Subacute and chronic CS exposure significantly increased pulmonary IL-6 mRNA expression in lung tissue and IL-6 protein levels in bronchoalveolar lavage fluid of WT mice. However, CS-induced accumulation of inflammatory cells at both time points and lymphoid aggregate formation upon chronic CS exposure were independent of IL-6. Chonic CS exposure was associated with a significant failure to gain weight in both WT mice and IL-6 KO mice. Remarkably, air-exposed IL-6 KO mice have lower body weight, serum leptin levels, and adipose tissue mass compared to air-exposed WT mice. In conclusion, IL-6 is of minor importance in CS-induced pulmonary and systemic manifestations in mice, but this study confirms the role for IL-6 as regulator of body weight and body composition. PMID:20939756

  6. Increased interleukin-6 expression is associated with poor prognosis and acquired cisplatin resistance in head and neck squamous cell carcinoma

    PubMed Central

    GAO, JIAN; ZHAO, SEN; HALSTENSEN, TROND S.

    2016-01-01

    Increased expression of interleukin 6 (IL-6) is associated with poor prognosis and chemoresistance in many different carcinomas, but its role in head and neck squamous cell carcinoma (HNSCC) is still unsettled. Analyzing tumorous mRNA expression data from 399 HNSCC patients revealed that high IL-6 expression predicted poor prognosis. Similar tendency was observed in platinum treated patients, suggesting an IL-6 associated cisplatin resistance. IL-6 increase was also found in two in-house acquired cisplatin-resistant HNSCC cell lines (both basaloid and conventional squamous cell carcinoma) by using microarray analysis. However, although the in-house acquired cisplatin-resistant cell lines had higher basal and markedly increased cisplatin-induced IL-6 expression, IL-6 did not mediate the cisplatin resistance as neither exogenous IL-6 nor IL-6R/gp130 inhibitors affected cisplatin sensitivity. Moreover, the IL-6/STAT3 pathway was impaired in the resistant cell lines, partly due to decreased IL-6R expression. Thus, high IL-6 expression correlated to poor prognosis and acquired cisplatin resistance, but it did not mediate cisplatin resistance in the HNSCC cell lines. PMID:27108527

  7. Immune challenge induces differential corticosterone and interleukin-6 responsiveness in rats bred for extremes in anxiety-related behavior.

    PubMed

    Salome, N; Tasiemski, A; Dutriez, I; Wigger, A; Landgraf, R; Viltart, O

    2008-02-19

    Disturbances in mood such as anxiety and depression are often associated with altered hypothalamo-pituitary-adrenal (HPA) axis reactivity, but also with changes in cytokine production, such as interleukin-6 (IL-6), an essential immune factor produced by macrophages and lymphocytes during inflammatory processes. The reciprocal relationship between the HPA axis and the immune system is now well established. In order to understand better the endocrine reactivity of anxious individuals faced with an immune challenge, a model of innate anxiety-related behavior, HAB and LAB rats (HABs, high and LABs, low anxiety-related behavior) was used in this study. We sought to determine whether injection of lipopolysaccharide (LPS) induced a differential HPA axis reactivity and plasma IL-6 release in HABs and LABs. After LPS injection, the plasma adrenal corticotrophic hormone increase did not differ between HABs and LABs, whereas a larger increase in plasma corticosterone levels occurred in HABs than in LABs at 2 h after injection. Moreover, basal IL-6 levels were lower in HABs than in LABs, leading to a higher IL-6 2 h/basal ratio in HABs. In conclusion, we propose for the first time a link between the endocrine and immune systems of HABs and LABs and suggest that IL-6 could be a neuroendocrine correlate of trait anxiety in HABs. PMID:18207648

  8. Inhibition effect of cypermethrin mediated by co-regulators SRC-1 and SMRT in interleukin-6-induced androgen receptor activation.

    PubMed

    Wang, Qi; Zhou, Ji-Long; Wang, Hui; Ju, Qiang; Ding, Zhen; Zhou, Xiao-Long; Ge, Xing; Shi, Qiao-Mei; Pan, Chen; Zhang, Jin-Peng; Zhang, Mei-Rong; Yu, Hong-Min; Xu, Li-Chun

    2016-09-01

    It is hypothesized that the pesticide cypermethrin may induce androgen receptor (AR) antagonism via ligand-independent mechanisms. The Real-Time Cell Analysis (RTCA) iCELLigence system was used to investigate the inhibitory effect of cypermethrin on interleukin-6 (IL-6)-induced ligand-independent LNCaP cell growth. Then, the mammalian two-hybrid assays were applied to clarify whether the mechanism of IL-6-induced AR antagonism of cypermethrin was associated with the interactions of the AR and co-activator steroid receptor co-activator-1 (SRC-1) and co-repressor silencing mediator for retinoid and thyroid hormone receptors (SMRT). Cypermethrin inhibited the LNCaP cell growth induced by IL-6. The interactions of AR-SRC-1 and AR-SMRT mediated by IL-6 were suppressed by cypermethrin. The results indicate that the IL-6-mediated AR antagonism induced by cypermethrin is related to repress the recruitment of co-regulators SRC-1 and SMRT to the AR in a ligand-independent manner. Inhibition of the interactions of AR-SRC-1 and AR-SMRT mediated by IL-6 contributes to the AR antagonism induced by cypermethrin. PMID:27239967

  9. Reciprocal Association of Plasma IGF-1 and Interleukin-6 Levels With Cardiometabolic Risk Factors in Nondiabetic Subjects

    PubMed Central

    Succurro, Elena; Andreozzi, Francesco; Sciaqua, Angela; Hribal, Marta Letizia; Perticone, Francesco; Sesti, Giorgio

    2008-01-01

    OBJECTIVE—To examine the relationship between plasma IGF-1 and interleukin-6 (IL-6) levels in Caucasian nondiabetic subjects and evaluate the association of IGF-1 and IL-6 with the cardiometabolic risk factors characterizing metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS—The study group consisted of 186 Caucasian nondiabetic subjects who underwent an oral glucose tolerance test and an euglycemic-hyperinsulinemic clamp. A logistic regression analysis, adjusted for age and sex, was used to determine the association between tertiles of IGF-1 and IL-6 and the MetS and its components. RESULTS—After adjusting for age and sex, both IGF-1 and IL-6 were correlated with insulin resistance and individual components of MetS, but in opposite directions. In the logistic regression model adjusted for age and sex, higher IL-6 and lower IGF-1 levels confer increased risk of having MetS and its two underlying pathophysiological abnormalities, i.e., visceral obesity and insulin resistance. CONCLUSIONS—The present results raise the possibility that lowered protection against inflammation, i.e., lower IGF-1 levels, may have a role in the development of MetS and its features, resulting in an imbalance between proinflammatory and anti-inflammatory proteins. PMID:18535190

  10. Oxidized Low-Density Lipoprotein Is Present in Astrocytes Surrounding Cerebral Infarcts and Stimulates Astrocyte Interleukin-6 Secretion

    PubMed Central

    Shie, Feng-Shiun; Neely, M. Diana; Maezawa, Izumi; Wu, Hope; Olson, Sandy J.; Jürgens, Günther; Montine, Kathleen S.; Montine, Thomas J.

    2004-01-01

    Ischemic injury to brain is associated with both disruption of the blood-brain barrier and increased oxidative stress. Given the neurotoxicity associated with exposure to oxidized low-density lipoprotein (oxLDL) in vitro, we tested the hypothesis that oxLDL may be present in parenchymal cells of cerebrum after infarction and that oxLDL may influence the pathophysiology of cerebral infarction. Our results showed that the subacute phase of cerebral infarction in patients was characterized by the appearance of oxLDL epitopes in astrocytes, but not neurons or microglia, in the perinecrotic zone. We further demonstrated that minimally oxLDL was most effectively internalized by primary cultures of rat astrocytes, and that exposure to minimal oxLDL stimulated astrocyte interleukin-6 secretion but did not alter nitric oxide production. These results demonstrate for the first time that oxLDL is present in brain parenchyma of patients with ischemic infarction and suggest a potential mechanism by which oxLDL may activate innate immunity and thereby indirectly influence neuronal survival. PMID:15039206