Interleukin-6 Promoter Research Articles

Regulation of stimulus-induced interleukin-8 gene transcription in human adrenocortical carcinoma cells – Role of AP-1 and NF-κB

Stimulation of H295R adrenocortical carcinoma cells with angiotensin II or cytokines induces the secretion of the chemokine interleukin-8 (IL-8). Here, we have analyzed the molecular mechanism of stimulus-induced IL-8 expression. IL-8 expression and IL-8 promoter activity increased in H295R cells expressing an activated Gαq-coupled designer receptor. H295R cells stimulated with either interleukin-1β (IL-1β) or phorbol ester also showed elevated IL-8 mRNA levels and higher IL-8 promoter activities. Deletion and point mutations of the IL-8 promoter revealed that the AP-1 binding site within the IL-8 promoter is essential to connect designer receptor stimulation with the transcriptional activation of the IL-8 gene. Expression of a constitutively active mutant of c-Jun, or expression of constitutively active mutants of the protein kinases MEKK1 and MKK6 confirmed that the IL-8 gene is a bona fide target of AP-1 in adrenocortical carcinoma cells. Upregulation of IL-8 expression in IL-1β-treated H295R cells required NF-κB while the phorbol ester TPA used both the AP-1 and NF-κB sites of the IL-8 gene to stimulate IL-8 expression. These data were corroborated in experiments with chromatin-embedded AP-1 or NF-κB-responsive reporter genes. While stimulation of Gαq-coupled designer receptors increased the AP-1 activity in the cells, IL-1β specifically stimulated NF-κB-regulated transcription. Stimulation of the cells with TPA increased both AP-1 and NF-κB activities. We conclude that stimulation of Gαq-coupled designer receptors or IL-1 receptors triggers distinct signaling pathways in H295R cells leading to the activation of either AP-1 or NF-κB. Nevertheless, both signaling cascades converge to the IL-8 gene, inducing IL-8 gene transcription.

IL-10 promoter hypomethylation is associated with increased IL-10 expression and poor survival in hepatocellular carcinoma

Background: Epigenetic alterations of tumor-associated genes contribute to the pathogenesis of virtually all cancer types. We evaluated the methylation status of the interleukin-10 (IL-10) gene promoter and assessed its association with IL-10 mRNA expression and clinical prognosis in hepatocellular carcinoma (HCC) patients. Methods: Methylation-specific polymerase chain reaction (MSP) and real-time polymerase chain reaction (PCR) were used to define the methylation index (MI) of the IL-10 gene and quantify IL-10 mRNA expression in 120 HCC samples and paired non-tumor tissues. Results: Mean MI was 0.47 in HCC specimens and 0.59 in non-tumor controls, and was associated with metastasis classification and serum α-fetoprotein (AFP) levels. IL-10 mRNA levels [mean –∆∆Ct of 1.678 in HCC cases with hypomethylation (∆MI ≤0) and –0.18 in HCC cases with hypermethylation (∆MI >0)] also correlated with metastasis classification and serum AFP. An association was detected between IL-10 mRNA and its gene’s MI in HCC. Also, an association was found between IL-10 hypomethylation, but not IL-10 mRNA expression and reduced postoperative HCC survival. Conclusions: These results indicate that IL-10 promoter hypomethylation is associated with increased IL-10 mRNA levels and indicative of poor survival in HCC.

IL-10 promoter hypomethylation is associated with increased IL-10 expression and poor survival in hepatocellular carcinoma.

BackgroundEpigenetic alterations of tumor-associated genes contribute to the pathogenesis of virtually all cancer types. We evaluated the methylation status of the interleukin-10 (IL-10) gene promoter and assessed its association with IL-10 mRNA expression and clinical prognosis in hepatocellular carcinoma (HCC) patients.MethodsMethylation-specific polymerase chain reaction (MSP) and real-time polymerase chain reaction (PCR) were used to define the methylation index (MI) of the IL-10 gene and quantify IL-10 mRNA expression in 120 HCC samples and paired non-tumor tissues.ResultsMean MI was 0.47 in HCC specimens and 0.59 in non-tumor controls, and was associated with metastasis classification and serum α-fetoprotein (AFP) levels. IL-10 mRNA levels [mean –∆∆Ct of 1.678 in HCC cases with hypomethylation (∆MI ≤0) and –0.18 in HCC cases with hypermethylation (∆MI >0)] also correlated with metastasis classification and serum AFP. An association was detected between IL-10 mRNA and its gene’s MI in HCC. Also, an association was found between IL-10 hypomethylation, but not IL-10 mRNA expression and reduced postoperative HCC survival.ConclusionsThese results indicate that IL-10 promoter hypomethylation is associated with increased IL-10 mRNA levels and indicative of poor survival in HCC.

YAP promotes the malignancy of endometrial cancer cells via regulation of IL-6 and IL-11

BackgroundEmerging evidence shows that Hippo signal pathways can regulate the progression of various cancer. While the roles of Yes-associated protein (YAP), the key transducer of Hippo signals, in the development of endometrial cancer (EC) are rarely investigated.MethodsThe expression of YAP in endometrial cancer cells and tissues was measured. Its roles in proliferation and expression of interleukins (ILs) were investigated by use of its specific siRNA or inhibitor (verteporfin, VP).ResultsYAP was upregulated in endometrial cancer cells and tissues. Knockdown of YAP or VP can suppress the proliferation while increase its chemo-sensitivity of EC cells. We found that targeted inhibition of YAP can decrease the expression of interleukin-6 (IL-6) and IL-11 in EC cells. Recombinant IL-6 or IL-11 can attenuate si-YAP suppressed proliferation of EC cells. Chromatin immunoprecipitation (ChIP) assay suggested that YAP can directly bind with the promoter of IL-6 and induce its transcription. As to IL-11, inhibitor of NF-κB (BAY 11–7082) can significantly down regulate the mRNA expression of IL-11. Over expression of p65 abolished si-YAP suppressed transcription of IL-11. It suggested that NF-κB was involved in the YAP regulated expression of IL-11.ConclusionsYAP can regulate the proliferation and progression of EC cells. It suggested that targeted inhibition of YAP might be a potent potential approach for EC therapy.

Abstract 1510: Androgen regulated IL-8 expression in prostate cancer: Insights into tumor cell mediated immunosuppression

Abstract Androgen deprivation therapy (ADT) results in castration-resistant prostate cancer (CRPC) in a significant fraction of patients. We have previously reported that the protein levels of interleukin-8 (IL-8) were inversely correlated with disease progression in men with biochemical recurrent prostate cancer treated with Lenalidomide. Recently, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were implicated as potential drivers of CRPC. Here we show that IL-8 expression is upregulated as a consequence of ADT and mediates the recruitment of PMN-MDSCs to the tumor microenvironment. We found that IL-8 expression is regulated by both an inflammatory stimulus (NF-kβ mediated) and loss of androgen receptor (AR) signaling following ADT. We confirmed direct binding of both the p65 subunit of NF-kβ and AR to the IL-8 promoter, and their respective effects on promoter activity. The suppressive activity of AR was further supported by a reduction in active transcription markers at the chromatin level surrounding the IL-8 promoter. Accordingly, intratumoral infiltration of PMN-MDSCs correlated with IL-8 expression, and was reduced in IL-8 knockouts. Taken together, these results suggest an innate inflammatory response, loss of AR suppressive activity, and subsequent chemokine upregulation as a potential mechanism that regulates the infiltration of PMN-MDSCs to the tumor microenvironment of CRPC after ADT. These findings open a window of opportunity for therapeutic interventions aiming to improve responses to checkpoint blockade in prostate cancer. Citation Format: Zoila A. Lopez Bujanda, Michael C. Haffner, Matthew G. Chaimowitz, Nivedita Chowdhury, Paula J. Hurley, Angela M. Christiano, Charles G. Drake. Androgen regulated IL-8 expression in prostate cancer: Insights into tumor cell mediated immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1510.

Regulation of platelet-activating factor-mediated interleukin-6 promoter activation by the 48\xa0kDa but not the 45\xa0kDa isoform of protein tyrosine phosphatase non-receptor type 2

BackgroundAn underlying state of inflammation is thought to be an important cause of cardiovascular disease. Among cells involved in the early steps of atherosclerosis, monocyte-derived dendritic cells (Mo-DCs) respond to inflammatory stimuli, including platelet-activating factor (PAF), by the induction of various cytokines, such as interleukin 6 (IL-6). PAF is a potent phospholipid mediator involved in both the onset and progression of atherosclerosis. It mediates its effects by binding to its cognate G-protein coupled receptor, PAFR. Activation of PAFR-induced signaling pathways is tightly coordinated to ensure specific cell responses.ResultsHere, we report that PAF stimulated the phosphatase activity of both the 45 and 48 kDa isoforms of the protein tyrosine phosphatase non-receptor type 2 (PTPN2). However, we found that only the 48 kDa PTPN2 isoform has a role in PAFR-induced signal transduction, leading to activation of the IL-6 promoter. In luciferase reporter assays, expression of the 48 kDa, but not the 45 kDa, PTPN2 isoform increased human IL-6 (hIL-6) promoter activity by 40% after PAF stimulation of HEK-293 cells, stably transfected with PAFR (HEK-PAFR). Our results suggest that the differential localization of the PTPN2 isoforms and the differences in PAF-induced phosphatase activation may contribute to the divergent modulation of PAF-induced IL-6 promoter activation. The involvement of PTPN2 in PAF-induced IL-6 expression was confirmed in immature Mo-DCs (iMo-DCs), using siRNAs targeting the two isoforms of PTPN2, where siRNAs against the 48 kDa PTPN2 significantly inhibited PAF-stimulated IL-6 mRNA expression. Pharmacological inhibition of several signaling pathways suggested a role for PTPN2 in early signaling events. Results obtained by Western blot confirmed that PTPN2 increased the activation of the PI3K/Akt pathway via the modulation of protein kinase D (PKD) activity. WT PKD expression counteracted the effect of PTPN2 on PAF-induced IL-6 promoter transactivation and phosphorylation of Akt. Using siRNAs targeting the individual isoforms of PTPN2, we confirmed that these pathways were also active in iMo-DCs.ConclusionTaken together, our data suggest that PTPN2, in an isoform-specific manner, could be involved in the positive regulation of PI3K/Akt activation, via the modulation of PKD activity, allowing for the maximal induction of PAF-stimulated IL-6 mRNA expression.

Tet3 enhances IL-6 expression through up-regulation of 5-hmC in IL-6 promoter in chronic hypoxia induced atherosclerosis in offspring rats

AimsTet1, Tet2, and interleukin-6 (IL-6) have been linked to atherosclerosis. Whether Tet3 has a relationship with atherosclerosis and IL-6 was unknown. This study aims to determine the link between Tet3 and IL-6, and the role of Tet3 in prenatal hypoxia-induced atherosclerosis in offspring rats. Main methodsPregnant rats were divided into hypoxia and control group. Their male offspring were tested at 20 months old. Hematoxylin-eosin staining and transmission electron microscopic staining were used. Gene mRNA and protein levels were measured with q-PCR or Western blotting. Cell viability and migration was tested with MTT or cell scratch assay. 5-hmC and 5-mC expression were obtained by qGlucMS-PCR; 5-hmC and 5-mC activity were obtained by dot blotting. Key findingsChronic prenatal hypoxia increased Tet3 and IL-6 expression, and decreased Tet3 activity in offspring rats. GlucMS-qPCR showed the percentage of 5-hmC was significantly up-regulated in the promoter of IL-6 in both the rats and cells. Moreover, 5-hmC percentage also was increased in the A7r5 cells transfected with Tet3. Furthermore, Tet3 promoted proliferation and migration of A7r5 cells. However, Tet3 was not sensitive to acute hypoxia, while influenced by HIF-1α DNA element. SignificanceTet3 enhanced IL-6 expression though up-regulating 5-hmC percentage in the IL-6 promoter.

Interleukin-18 Polymorphisms Deficiency Association with Asthma Risk: An Update Meta-analysis.

Growing evidence indicated conflicting results that Interleukin-18 (IL-18) promoter polymorphisms rs1946518 (A-607C), rs187238 (G-137C) and rs549908 (A-105C) were associated with asthma risk. The aim of this study is to comprehensively evaluate the IL-18 polymorphisms and asthma by a systematic review and meta-analysis. A total of 12 studies testing the association between these polymorphisms and asthma were examined (8 studies for A-607C, 8 studies for G-137C, and 4 studies for A-105C) in the update meta-analysis, up to Dec 30, 2017. Summary odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate the strength of association between each polymorphism and asthma using fixed- and random-effects models when appropriate. Heterogeneity and publication bias were evaluated. The meta-analysis results indicated that any allele frequencies of the IL-18 polymorphisms (A-607C, G-137C and A-105C) was not associated with asthma risk (p>0.05). And no statistically significant association was observed between genotype frequencies of these polymorphisms and asthma under different genetic models (p>0.05). Subgroup analysis results were similar to the main analysis by ethnicity, sample size, genotyping methods, matching criteria and quality score. There was no evidence of publication bias. The present meta-analysis suggests that IL-18 polymorphisms (A-607C, G-137C and A-105C) were unlikely to be associated with asthma risk.

Association of A-197G polymorphism in interleukin-17 gene with chronic periodontitis: Evidence from six case-control studies with a computational biology approach.

The aim of the present study was to evaluate the association of interleukin-17 (IL-17) A-197G gene polymorphism with chronic periodontitis (CP) in a case-control study, a meta-analysis, and an in silico approach. In the case-control study, 122 cases with CP and 126 healthy controls were recruited; IL-17 A-197G genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. In the meta-analysis, comprehensive literature retrieval was performed on valid databases to identify relevant studies. Bioinformatics tools were employed to investigate the effects of A-197G transition on the promoter region of IL-17. Our case-control study revealed a significant association between IL-17 A-197G transition and CP. The overall meta-analysis revealed significant associations between the IL-17 A-197G polymorphism and CP risk in homozygote co-dominant and recessive models. The stratified analysis also showed a statistically significant association between the mentioned transition and CP risk in the Caucasian population. The in silico analysis revealed that the A-197G polymorphism could make changes in protein-binding sites of the IL-17 promoter region. Our study supports that IL-17 A-197G transition could be a genetic risk factor for CP. However, further studies with a larger sample size among different ethnicities are required to obtain a more accurate conclusion.

Occurrence of Interleukin-2 (330 G/T) Promoter Polymorphism in ARV associated hepatotoxicity.

IL-2 cytokine is involved in HIV replication and is also known to cause hepatic injury. Polymorphisms in the IL-2 gene are associated with altered interleukin-2 production. Hence, we assessed the prevalence of IL-2-303G/T polymorphism in 165 HIV patients (34 with and 131without hepatotoxicity) and 155 healthy controls using the PCR-RFLP method. In patients with hepatotoxicity, IL-2-303GT, -303GT+TT genotypes were less prevalent as compared to without hepatotoxicity and healthy controls (29.4% vs. 42.7%, 58.8% vs. 69.5%; 29.4% vs. 40.6%, 58.8% vs. 66.5%, respectively). In patients with hepatotoxicity using tobacco and alcohol, IL-2-303GT,-303TT genotypes were distributed higher as compared to non-users (42.9% vs. 25.9%, OR=8.52, 42.9% vs. 25.9%, OR=9.09, and 28.6% vs. 29.6%, OR=1.63, 42.9% vs. 25.9%, OR=2.93), while IL-2-303TT genotype occurred more often in HIV patients consuming alcohol (34.1% vs. 23.0%). Nevirapine users with hepatotoxicity overrepresented the IL-2-303GT,-303TT genotypes as compared to efavirenz (34.8% vs. 18.2%, OR=4.64, 34.8% vs. 18.2%, OR=3.88). Among nevirapine users, IL-2-303GT genotype was associated with susceptibility to the acquisition of hepatotoxicity with borderline significance (OR=4.24, P=0.06). HIV patients using nevirapine majorly represented the IL-2-303TT genotype (26.9% vs. 25.0%, OR=2.35) while HIV patients with nevirapine + alcohol usage presented the IL-2 -330TT genotype at a higher frequency (34.2%% vs. 23.5%, OR=1.51). In patients with hepatotoxicity using nevirapine + alcohol, the genotype IL-2 - 330TT was predominant (60.0% vs. 27.8%, OR=3.16). Thus, IL-2-303G/T polymorphism did not confer the susceptibility to ARV associated hepatotoxicity. However, IL-2-303G/T polymorphism with nevirapine usage may facilitate the risk for acquisition of ARV associated hepatotoxicity.

Expression of IL-17 and its gene promoter methylation status are associated with the progression of chronic hepatitis B virus infection.

To explore interleukin-17 (IL-17) and its epigenetic regulation during the progression of chronic hepatitis B virus (HBV) infection.A total of 162 patients with chronic HBV infection, including 75 with chronic hepatitis B (CHB), 54 with hepatitis B-associated liver cirrhosis and 33 with hepatitis B-associated hepatocellular carcinoma (HBV-HCC), were enrolled in this study. Thirty healthy adults of the same ethnicity were enrolled in the control group. Whole venous blood was obtained from the patients and normal controls (n = 30). Clinical and laboratory parameters were assessed, and we performed enzyme-linked immunosorbent assay and quantitative real-time PCR to measure the serum levels and relative mRNA expression of IL-17, respectively. IL-17 promoter methylation in peripheral blood mononuclear cells was assessed by methylation-specific PCR. We analyzed the serum and mRNA levels of IL-17 and IL-17 promoter methylation in the 4 groups as well as the effect of methylation on serum IL-17 levels. Correlations between the IL-17 promoter methylation status and clinical parameters were analyzed by Spearman correlation analysis.Compared to the normal control group, the patient groups exhibited significantly higher serum and relative mRNA levels of IL-17. The methylation distribution among the patients was significantly lower than that among the normal controls (P < .05), with the HBV-HCC group showing the lowest IL-17 gene methylation frequency. The average IL-17 promoter CG methylation level was negatively correlated with IL-17 mRNA expression (r = −0.39, P = .03), and negative correlations between IL-17 promoter methylation and prothrombin time activity (r = −0.585, P = .035), alanine aminotransferase (r = −0.522, P < .01), aspartate aminotransferase (r = −0.315, P < .05), and the model for end-stage liver disease score (r = −0.461, P < .05) were observed. IL-17 serum levels in the methylated-promoter groups were significantly lower than those in the unmethylated-promoter groups.IL-17 expression and promoter methylation were associated with chronic HBV infection progression, especially in the HBV-HCC group. The IL-17 promoter status may help clinicians initiate the correct treatment strategy at the CHB stage.

Association between interleukin-10 gene polymorphisms and severe chronic periodontitis.

Periodontitis is an inflammatory disease that is a result of the interaction between pathogenic bacteria and host immune response. Genetic alterations in interleukin-10 (IL-10) gene may be associated with the increased risk of periodontitis. We investigated the association between genotype and haplotype frequencies of IL-10 gene polymorphisms and susceptibility to periodontitis in an Iranian population. In this case-control study, a total of 64 patients with periodontitis and 128 healthy subjects were recruited. The PCR-RFLP technique was used to detect IL-10 promoter genotypes at the positions of -1082 (G/A), -819 (C/T), and -592 (C/A) in association with the susceptibility to severe chronic periodontitis. Regarding IL-10 -592 (C/A) and IL-10 -819 (C/T) alleles and genotypes, no significant association was observed between the risk of periodontitis and genotype frequencies. However, the frequency of GG genotype in IL-10 -1082 (G/A) polymorphic region was higher in normal subjects and was associated with the decreased risk of periodontitis under recessive model [OR=2.89, 95% CI (0.99-8.43), p=0.039]. Haplotype analysis revealed a significantly higher presence of H7 (AGC; -592/-1082/-819) [OR=97.74, 95% CI (95.52-99.96), p<0.0001]. IL-10 -1082(G/A) polymorphism and AGC (-592/-1082/-819) haplotype could be associated with the susceptibility to chronic periodontitis.

The cAMP Pathway Amplifies Early MyD88-Dependent and Type I Interferon-Independent LPS-Induced Interleukin-10 Expression in Mouse Macrophages

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine, secreted by macrophages and other immune cells to attenuate inflammation. Autocrine type I interferons (IFNs) largely mediate the delayed expression of IL-10 by LPS-stimulated macrophages. We have previously shown that IL-10 is synergistically expressed in macrophages following a costimulus of a TLR agonist and cAMP. We now show that the cAMP pathway directly upregulates IL-10 transcription and plays an important permissive and synergistic role in early, but not late, LPS-stimulated IL-10 mRNA and protein expression in mouse macrophages and in a mouse septic shock model. Our results suggest that the loss of synergism is not due to desensitization of the cAMP inducing signal, and it is not mediated by a positive crosstalk between the cAMP and type I IFN pathways. First, cAMP elevation in LPS-treated cells decreased the secretion of type I IFN. Second, autocrine/paracrine type I IFNs induce IL-10 promoter reporter activity only additively, but not synergistically, with the cAMP pathway. IL-10 promoter reporter activity was synergistically induced by cAMP elevation in macrophages stimulated by an agonist of either TLR4, TLR2/6, or TLR7, receptors which signal via MyD88, but not by an agonist of TLR3 which signals independently of MyD88. Moreover, MyD88 knockout largely reduced the synergistic IL-10 expression, indicating that MyD88 is required for the synergism displayed by LPS with cAMP. This report delineates the temporal regulation of early cAMP-accelerated vs. late type I IFN-dependent IL-10 transcription in LPS-stimulated murine macrophages that can limit inflammation at its onset.

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

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

The mitochondrial chaperone Prohibitin 1 negatively regulates interleukin-8 in human liver cancers

Prohibitin 1 (PHB1) is a mitochondrial chaperone whose expression is dysregulated in cancer. In liver cancer, PHB1 acts as a tumor suppressor, but the mechanisms of tumor suppression are incompletely understood. Here we aimed to determine PHB1 target genes to better understand how PHB1 influences liver tumorigenesis. Using RNA-Seq analysis, we found interleukin-8 (IL-8) to be one of the most highly up-regulated genes following PHB1 silencing in HepG2 cells. Induction of IL-8 expression also occurred in multiple liver and nonliver cancer cell lines. We examined samples from 178 patients with hepatocellular carcinoma (HCC) and found that IL-8 mRNA levels were increased, whereas PHB1 mRNA levels were decreased, in the tumors compared with adjacent nontumorous tissues. Notably, HCC patients with high IL-8 expression have significantly reduced survival. An inverse correlation between PHB1 and IL-8 mRNA levels is found in HCCs with reduced PHB1 expression. To understand the molecular basis for these observations, we altered PHB1 levels in liver cancer cells. Overexpression of PHB1 resulted in lowered IL-8 expression and secretion. Silencing PHB1 increased c-Jun N-terminal kinase (JNK) and NF-κB activity, induced nuclear accumulation of c-JUN and p65, and enhanced their binding to the IL-8 promoter containing AP-1 and NF-κB elements. Conditioned medium from PHB1-silenced HepG2 cells increased migration and invasion of parental HepG2 and SK-hep-1 cells, and this was blocked by co-treatment with neutralizing IL-8 antibody. In summary, our findings show that reduced PHB1 expression induces IL-8 transcription by activating NF-κB and AP-1, resulting in enhanced IL-8 expression and release to promote tumorigenesis.

Early life alcohol exposure primes hypothalamic microglia to later-life hypersensitivity to immune stress: possible epigenetic mechanism.

Growing evidence has shown that developmental alcohol exposure induces central nervous system inflammation and microglia activation, which may contribute to long-term health conditions, such as fetal alcohol spectrum disorders. These studies sought to investigate whether neonatal alcohol exposure during postnatal days (PND) 2-6 in rats (third trimester human equivalent) leads to long-term disruption of the neuroimmune response by microglia. Exposure to neonatal alcohol resulted in acute increases in activation and inflammatory gene expression in hypothalamic microglia including tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Adults with neonatal alcohol pre-exposure (alcohol fed; AF) animals showed an exaggerated peripheral stress hormonal response to an immune challenge (lipopolysaccharides; LPS). In addition, there were significantly more microglia present in the hypothalamus of adult AF animals, and their hypothalamic microglia showed more cluster of differentiation molecule 11b (Cd11b) activation, TNF-α expression, and IL-6 expression in response to LPS. Interestingly, blocking microglia activation with minocycline treatment during PND 2-6 alcohol exposure ameliorated the hormonal and microglial hypersensitivity to LPS in AF adult animals. Investigation of possible epigenetic programming mechanisms by alcohol revealed neonatal alcohol decreased several repressive regulators of transcription in hypothalamic microglia, while concomitantly increasing histone H3 acetyl lysine 9 (H3K9ac) enrichment at TNF-α and IL-6 promoter regions. Importantly, adult hypothalamic microglia from AF animals showed enduring increases in H3K9ac enrichment of TNF-α and IL-6 promoters both at baseline and after LPS exposure, suggesting a possible epigenetic mechanism for the long-term immune disruption due to hypothalamic microglial priming.

KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis

KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A–D) constitute an important class of epigenetic modulators in the transcriptional activation of cellular processes and genome stability. Interleukin-8 (IL-8) is overexpressed in gastric cancer, but the mechanisms and particularly the role of the epigenetic regulation of IL-8, are unclear. Here, we report that KDM4B, but not KDM4A/4C, upregulated IL-8 production in the absence or presence of Helicobacter pylori. Moreover, KDM4B physically interacts with c-Jun on IL-8, MMP1, and ITGAV promoters via its demethylation activity. The depletion of KDM4B leads to the decreased expression of integrin αV, which is exploited by H. pylori carrying the type IV secretion system, reducing IL-8 production and cell migration. Elevated KDM4B expression is significantly associated with the abundance of p-c-Jun in gastric cancer and is linked to a poor clinical outcome. Together, our results suggest that KDM4B is a key regulator of JNK/c-Jun-induced processes and is a valuable therapeutic target.

Leucocytic DNA Methylation of Interleukin-6 Promoter Reduction in Pre-Hypertensive Young Adults.

BackgroundPre-hypertension is associated with increased risk of cardiovascular disease. Chronic inflammation plays an important role in the pathophysiology of essential hypertension, with epigenetic dysregulation involvement. Nevertheless, the role of DNA methylation in prehypertensive state is unknown. The aim of this study was to investigate the association between DNA methylation level of interleukin-6 (IL-6) promoter in pre-hypertensive (PreHT) and normotensive (NT) young adults.MethodsA total of 80 NT and 80 PreHT healthy subjects aged between 18–45 years were recruited in Kuantan, Pahang, Malaysia using an observational cross-sectional study approach. DNA methylation level of IL-6 promoter in peripheral leukocytes were measured using bisulphite conversion and MethyLight assay.ResultsThere was no significant difference in age between NT and PreHT (P = 0.655). The mean blood pressure was 110(8)/73(5) mmHg in NT and 125(7)/82(5) mmHg in PreHT subjects. The IL-6 promoter methylation level was significantly lower in PreHT compared to NT subjects (P < 0.001).ConclusionThe current study demonstrates that hypomethylation of IL-6 promoter was associated with pre-hypertension in young adults. Thus, IL-6 methylation could be used as an early indicator for predicting hypertension and related risk of cardiovascular diseases in prehypertensive subjects. Gene expression and longitudinal studies are warranted to examine the methylation effect on IL-6 expression over time.

Association between IL-10 polymorphisms rs1800896 and rs1800871 and risk of acute pancreatitis in Chinese Han population: An update systemic review and meta-analysis.

The association between interleukin-10 (IL-10) promoter region (1082 A/G (rs1800896), 819 C/T (rs1800871)) polymorphisms, and acute pancreatitis (AP) is inconclusive in Chinese Han population. In this study, six eligible studies extracted from the databases of PubMed, Web of Science, and Cochrane Library were evaluated. The results revealed a significant association between 1082 A/G (rs1800896) polymorphism and AP risk in all these five models (AG/AA: OR = 1.19, 95% Cl = 1.02-1.40, P = 0.03; GG/AA: OR = 1.80, 95% Cl = 1.38-2.23, P = 0.01; AG+GG/AA: OR = 1.29, 95% Cl = 1.11-1.50, P = 0.01; GG/AG+AA: OR = 1.62, 95% Cl = 1.27-2.08, P = 0.01; G/A: OR = 1.29, 95% Cl = 1.15-1.45, P = 0.01). In contrast, no statistically significant association was found in all these five models for 819 C/T (rs1800871) polymorphism. In summary, IL-10 polymorphism 1082 A/G (rs1800896) could increase the risk of AP in Chinese Han population.

Influence of Interleukin-6 (IL-6) Promoter Gene Polymorphisms (-174G>C, -572G>C, and -597G>A) on IL-6 Plasma Levels and Their Impact in the Development of Acute Ischemic Stroke in Young Indians.

This study aimed to determine whether there is an influence of interleukin 6 (IL-6) gene promoter polymorphisms on IL-6 plasma levels and its role in the development of ischemic stroke in young Indians. One hundred young patients with ischemic stroke (age ≥ 45 years) and equal number of age- and sex-matched controls were genotyped for 174G>C, −572G>C, and −597G>A promoter polymorphisms by polymerase chain reaction–restriction fragment length polymorphism. Plasma IL-6 levels were measured by enzyme-linked immunosorbent assay. Plasma IL-6 levels were significantly higher in patients as compared to controls (patients: 28.61 ± 8.61 pg/mL, controls: 7.60 ± 4.10 pg/mL, P = .001). Both −174G>C (allelic χ2/P value: 4.79/.028, genotypic χ2/P value: 5.3/.021) and −572G>C (allelic χ2/P value: 9.63/.00113 Genotypic χ2/P value: 74/.0002) polymorphisms exhibited genotypic as well as allelic significant association with the disease phenotype. Comparison was made between patients and controls for all 3 polymorphisms using a recessive model with respect to plasma IL-6 levels; no polymorphism showed any significant correlative association with the increased IL-6 levels (P = .31, .51, .32). Interleukin 6 is an inflammatory marker that is considerably influenced by nongenetic factors and is not a good candidate gene for studying genetic components associated with ischemic stroke. It seems that the variability in IL-6 levels is an integrated effect of nongenetic influences and the inflammatory events that follow ischemic stroke instead of being its cause. It is suggested that there is no direct association between −174G>C, −572G>C, and −597G>A polymorphisms and elevated IL-6 levels in the development of ischemic stroke.