Search

Background: The COVID-19 (SARS-CoV-2) epidemic has posed a major challenge to global public health, especially in children. Some children may experience secondary infection with Mycoplasma pneumoniae after SARS-CoV-2 infection, which has attracted widespread attention. Studies have shown that eosinophils play an important role in respiratory tract infections and are involved in regulating immune responses and inflammatory processes. However, there is a lack of systematic research on the specific manifestations and mechanisms of eosinophils in secondary infection with Mycoplasma pneumoniae after SARS-CoV-2 infection., Objective: This study aims to explore the characteristics of immune response in children with SARS-CoV-2 infection and Mycoplasma pneumoniae infection, focusing on the changes in immune indicators such as eosinophils (EOS), immunoglobulin E (IgE), interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin (PCT)., Methods: This study is a retrospective observational study, and a total of pediatric patients who were treated in our hospital from January 2023 to December 2023 were included. The study group included children who were diagnosed with SARS-CoV-2 infection and further infected with Mycoplasma pneumoniae, and the control group included children who were only infected with SARS-CoV-2 and had no other pathogens. The clinical data of the two groups of patients, including absolute eosinophil value, IgE quantification, IL-6, CRP and PCT levels, were collected and analyzed, and statistical comparisons were performed., Results: A total of 134 children were included, including 79 in the study group and 55 in the control group. The absolute eosinophil value [0.17 (0.09, 0.31) vs. 0.09 (0.06, 0.23), P < 0.01] and IgE level [59.28 (37.54, 256.88) vs. 22.00 (11.00, 113.10) P < 0.01] of the children in the study group were significantly higher than those in the control group, while IL-6 [16.81(4.72,31.86) vs. 9.5(3,57.3), P = 0.602], CRP [2.82(1.10,6.13) vs. 1.94(0.50,8.94), P = 0.528] and PCT[0.12(0.08,0.20) vs. 0.12(0.10,0.24), P = 0.329] were no significant difference between the two groups. Binary logistic regression analysis showed that the absolute value of eosinophils and IgE were independent risk factors for secondary infection of Mycoplasma pneumoniae after SARS-CoV-2 infection., Conclusion: This study shows that after SARS-CoV-2 infection, the increase in eosinophils and the increase in related immune indicators IgE may be closely related to secondary infection with Mycoplasma pneumoniae. This study provides an important basis for understanding the immune response of children after SARS-CoV-2 infection and its related clinical management, suggesting that clinicians should closely monitor the eosinophil count and IgE level of children after SARS-CoV-2 infection, especially for children at risk of secondary infection, so as to take timely intervention measures to prevent secondary infection with Mycoplasma pneumoniae and improve the prognosis of children., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Luoyang Maternal and Child Health Hospital (LWOPN 2024020801.0). It was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The need for informed consent to participate was waived by the ethics committee that approved the study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Authors’contributions: Pingping Wang wrote the original draft. Jin Yao and Yaqiong Li revised the manuscript. Zhanjun Zhang supervised the investigation. Ruiling Zhang and Shouting Lu performed the data analysis. Meixia Sun and Xiaorong Huang translated the draft. All authors read and approved the final manuscript. Clinical trial number. Not applicable., (© 2025. The Author(s).)

To evaluate the clinical utility of PCT, CRP, IL-6, NLR, and TyG index in improving the early diagnosis and severity assessment of acute pancreatitis (AP). This retrospective study included 137 AP patients and 30 healthy controls from Hunan Provincial People's Hospital (January 2021-September 2023). Univariate and multivariate logistic regression analyses assessed the associations between biomarkers and severe acute pancreatitis (SAP). Receiver operating characteristic (ROC) curves, DeLong test, and Bonferroni correction were used to evaluate predictive performance. Model robustness was validated via 5-fold cross-validation. PCT, CRP, IL-6, NLR, and TyG index levels were significantly elevated in AP patients compared to controls (P < 0.001) and correlated with disease severity (P < 0.05). CRP and NLR levels differed significantly among mild, moderate, and severe AP (P < 0.01). Alcohol consumption and hyperlipidemia were significantly linked to AP severity (P for trend < 0.0001). Multivariate analysis identified hyperlipidemia (OR = 3.030, P = 0.040), CRP (OR = 1.011, P < 0.001), and NLR (OR = 1.078, P = 0.020) as independent SAP predictors. The combined model of CRP + NLR + TyG achieved the highest AUC (0.882, sensitivity = 77.2%, specificity = 88.5%), though it was not significantly better than CRP + NLR or CRP + TyG models (P > 0.05). 5-fold cross-validation confirmed consistent performance (mean AUC = 0.817 ± 0.118). PCT, CRP, IL-6, NLR, and TyG index are valuable in diagnosing and assessing AP prognosis. Hyperlipidemia, CRP, and NLR are reliable independent predictors of SAP. Combining multiple biomarkers enhances diagnostic precision and provides guidance for personalized treatment strategies in AP., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Informed consent: Not applicable. Ethical approval: Not applicable., (© 2025. The Author(s).)

The male reproductive impairment caused by environmental estrogens (EEs) stands as a pivotal research area in environmental toxicology. Alpha2-macroglobulin (A2M) emerges as a promising molecule capable of counteracting oxidative stress induced by EEs. This study conducted exposure experiments spanning PND1 to PND56 employing ICR mice, aiming to delve into the expression patterns of A2M and its modulated IL-6 in the testicular tissue of mice subsequent to diethylstilbestrol (DES) and benzophenone (BP) exposure, while elucidating the pivotal role of ERs in this intricate process. Our findings revealed that upon DES exposure (10 and 100 nM), there was a pronounced upregulation of A2M (mRNA and in situ protein levels) in mouse testicular tissue. Similarly, exposure to BPs (BP-1, BP-2, and BP-3, each at 10 and 1000 nM) exhibited comparable effects and increasing A2M levels in serum. Notably, BP exposure also caused an elevation in IL-6 levels (which could be directly regulated by A2M) within testicular tissue (mRNA and in situ protein). Remarkably, the specific estrogen receptor antagonist ICI 182780 (0.5 mg/kg/day) was effective in reversing the upregulation of both A2M and IL-6 induced by BP exposure. Significantly, the results of theoretical prediction of the potential ERE site in the A2m gene promoter region and ChIP-qPCR experiment provide essential and strong evidence for the key conclusion that A2m is the target gene of ER. Taken together, our study highlights EEs' ability to regulate A2M expression in the male reproductive system via the ER signaling pathway. This vital insight deepens our understanding of molecular mechanisms protecting against oxidative stress caused by EEs.

Interleukin-6 (IL-6) expression in mesenchymal stem cells (MSCs) has been shown to play a pivotal role in modulating cartilage regeneration and immune responses, particularly in the context of diseases that involve both degenerative processes and inflammation, such as osteoarthritis (OA). However, the precise mechanism through which IL-6 and other immune-regulatory factors influence the therapeutic efficacy of autologous adipose-derived stem cells (ASCs) transplantation in OA treatment remains to be fully elucidated. This study aims to investigate the relationship between IL-6 expression in autologous ASCs isolated from OA patients and their impact on immune modulation, particularly focusing on the regulation of Receptor Activator of Nuclear factor Kappa-Β Ligand (RANKL), a key mediator of immune-driven cartilage degradation in OA. Autologous ASCs were isolated from the stromal vascular fraction (SVF) of adipose tissue obtained from 22 OA patients. The isolated ASCs were cultured and characterized using reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry to the phenotype and immune regulatory factors of MSCs. Based on IL-6 expression levels, ASCs were divided into high and low IL-6 expression groups. These groups were then co-cultured with activated peripheral blood mononuclear cells (PBMCs) to evaluate their immune-modulatory capacity, including the induction of regulatory T cells, inhibition of immune cell proliferation, and regulation of key cytokines, such as interferon-gamma (IFN-γ). Additionally, RANKL expression, a critical factor in osteoclastogenesis and cartilage degradation, was assessed in both ASC groups. High IL-6-expressing ASCs demonstrated a significantly greater capacity to inhibit immune cell proliferation and IFN-γ production compared to their low IL-6-expressing counterparts under co-culture conditions. Moreover, the group of ASCs with high IL-6 expression showed a marked reduction in RANKL expression, suggesting enhanced potential to control osteoclast activity and subsequent cartilage defect in OA. Conclusion: Autologous ASCs with elevated IL-6 expression exhibit enhanced immunomodulatory properties, particularly in regulating over-activated immune response and reducing osteoclastogenesis through RANKL suppression. These findings indicate that selecting ASCs based on IL-6 expression could enhance the therapeutic efficacy of ASC-based treatments for OA by mitigating immune-driven joint inflammation and cartilage degradation, potentially slowing disease progression., Competing Interests: Authors H.-J.L., D.-Y.K., S.Y.L., H.N., and J.A.Y. were employed by the company N- BIOTEK Co., Ltd. Authors S.J.W., Y.S.J., J.H.B., and D.J.R. were employed by Inha University Hospital. The authors declare no conflicts of interest.

Background: Various studies have observed an association between interleukin-6 (IL-6), serum ferritin, d-dimer, and in-hospital mortality in COVID-19 patients. However, multivariate regression analysis was not done in the majority of the studies, Also, the role of interleukin-6 (IL-6), serum ferritin, and d-dimer in hospitalized COVID-19 patients was not adequately studied and reported from our region., Method: It was a retrospective cohort study in which the serum IL-6, serum ferritin, and d-dimer of 305 hospitalized COVID-19 patients were analyzed, and their association with mortality was determined., Results: In COVID-19 patients, the levels of IL-6 (P = 0.007), serum ferritin (P = 0.011), and d-dimer (P = 0.004) were significantly elevated in patients with severe SARS-CoV-2 illness (SpO2 < 90 % at admission). IL-6 levels were significantly elevated (186 pg/ml vs. 215 pg/ml, P = 0.003) in non-survivors compared to survivors. However, d-dimer (mg/ml) (P = 0.129) and serum ferritin (mg/ml) (P = 0.051) levels were similar between the two groups. The ROC curve (receiver operating characteristic curve) analysis showed a significant but poor area under the curve (AUC) between elevated IL-6 (>208 pg/ml) and in-hospital mortality (P < 0.008, AUC = 0.61). Kaplan-Meir survival analysis showed poor survival in patients with elevated IL-6 (>208 pg/ml) (Pby log-rank: 0.010) and elevated d-dimer (>1780 mg/ml) (P by log-rank: 0.036). The multivariate cox-regression analysis did not show any association between IL-6, serum ferritin, d-dimer, and in-hospital mortality (P > 0.05). Also, no association was found between serum levels of IL-6, serum ferritin, d-dimer, and the use of a ventilator (P > 0.05) and the severity of SARS-CoV-2 illness (P > 0.05) on multivariate binary logistic regression analysis., Conclusion: In this study, the serum levels of IL-6, serum ferritin, and d-dimer were not associated with in-hospital mortality in hospitalized COVID-19 patients on multivariate cox-regression analysis, and were the markers of severe SARS-CoV-2 illness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Exogenous assaults interfere with homeostatic processes in the body by inducing stress responses. Corticosteroid-binding globulin (CBG) binds to stress hormone glucocorticoids to transport and dynamically control their availability to target tissues. In our previous study, we confirmed that CBG is locally produced by Leydig cells in the testes. Here, we explored the potential regulators of CBG using a murine Leydig tumor cell line (mLTC-1). Results indicated that luteinizing hormone (LH) and interleukin-6 (IL-6) were important factors stimulating the release of CBG from mLTC-1 cells. In addition, IL-6 stimulated mLTC-1 cells to release alpha-1 antitrypsin (AAT), a serine proteinase inhibitor (serpin) that affects CBG conformation. The results implied that any challenge that altered LH or IL-6 levels also changed the release and binding status of CBG with steroid hormones in the testicular microenvironment and modulated cellular responses to these stress hormones. In addition, secretory proteomic analysis indicated that the extracellular matrix (ECM), cytoskeleton, and proteasomes were essentially produced by the mLTC-1 cells, and LH evoked the secretion of proteins involved in binding and metabolism. These results emphasize that Leydig cells may undertake more functions than just steroidogenesis, and the regulation of Leydig cells by LH is versatile., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Interleukin-6 (IL-6) belongs to the cytokine family and plays a vital role in regulating immune response, bone maintenance, body temperature adjustment, and cell growth. The overexpression of IL-6 can indicate various health complications, such as anastomotic leakage, cancer, and chronic diseases. Therefore, the availability of highly sensitive and specific biosensing platforms for IL-6 detection is critical. In this study, for the first time, epitope-mediated IL-6-specific magnetic molecularly imprinted core-shell structures with fluorescent properties were synthesized using a three-step protocol, namely, magnetic nanoparticle functionalization, polymerization, and template removal following thorough optimization studies. The magnetic molecularly imprinted polymers (MMIPs) were characterized using dynamic and electrophoretic light scattering (DLS and ELS), revealing a hydrodynamic size of 169.9 nm and zeta potential of +17.1 mV, while Fourier transform infrared (FTIR) spectroscopy and fluorescence spectroscopy techniques showed characteristic peaks of the polymer and fluorescent tag, respectively. Scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM) investigations confirmed the successful encapsulation of the magnetic core within the ca. 5-nm-thick polymeric shell. The MMIP-based electrochemical sensing platform achieved a limit of detection of 0.38 pM within a linear detection range of 0.38-380 pM, indicating high affinity (dissociation constant K D  = 1.6 pM) for IL-6 protein in 50% diluted serum samples. Moreover, comparative investigations with the non-imprinted control polymer demonstrated an imprinting factor of 4, confirming high selectivity. With multifunctional features, including fluorescence, magnetic properties, and target responsiveness, the synthesized MMIPs hold significant potential for application in various sensor techniques as well as imaging., (© 2024. The Author(s).)

Background: Periplex ® is a rapid point-of-care test based on the detection of interleukin-6 (IL-6) or matrix metalloproteinase-8 (MMP-8) to diagnose peritonitis in peritoneal dialysis (PD) patients., Methods: This single-centre study was conducted in Singapore General Hospital from 2019 to 2022. The study recruited PD patients suspected of having peritonitis. Periplex was performed at the presentation and recovery of peritonitis. Primary outcomes were sensitivity and specificity of Periplex at presentation. The positive and negative predictive values of tests were also performed., Results: A total of 120 patients were included in the study. The mean age was 60.9 ± 14.9 years, 53% were male, 79% were Chinese and 47.5% had diabetes mellitus. Periplex was positive in all patients with peritonitis ( n = 114); sensitivity of 100%; 95% confidence interval (CI): 100-100%. Periplex was falsely positive in three patients with non-infective eosinophilic peritonitis, resulting in a low specificity of 50%; 95% CI: 41.1-59.0%. Periplex had a positive predictive value of 97.4% and a negative predictive value of 100%. During recovery from peritonitis, Periplex had high specificity (93.6%) and negative predictive value (98.7%) to indicate the resolution of infection. MMP-8 was more sensitive than IL-6 in detecting peritonitis. Periplex was positive in all patients with peritonitis regardless of the types of PD solutions used., Conclusions: Periplex had high sensitivity, and positive and negative predictive values in the diagnosis of peritonitis can be considered as a screening tool for peritonitis. Given its high specificity and negative predictive value, it may also be used to document the resolution of peritonitis., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: HH has received consultancy fees, speaker’s honoraria and travel sponsorships from Baxter Healthcare and consultancy fees and travel sponsorships from AWAK Technologies, speaker’s honoraria from Fresenius Medical Care, grants from Johnson & Johnson Company, grants from SingHealth NIG, outside the submitted work, and MWYF has received grants from National Medical Research Council for the study; consultancy fees and speaker’s honoraria and travel sponsorships from Baxter Healthcare, consultancy fees and travel sponsorships from AWAK Technologies. DWJ has received consultancy fees, research grants, speaker’s honoraria and travel sponsorships from Baxter Healthcare and Fresenius Medical Care, consultancy fees from Astra Zeneca and AWAK, speaker’s honoraria and travel sponsorships from ONO and travel sponsorships from Amgen. The other authors have nothing to disclose.

Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. Maternal obesity during pregnancy is linked to systemic inflammation and elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6). In our previous work, we demonstrated that increased maternal IL-6 during gestation impacts intrauterine development in mice. We hypothesized that IL-6-induced inflammation alters gene expression in the developing fetus. To test this, pregnant mice were administered IL-6 or saline during mid-gestation. Newborn mouse kidneys were analyzed using mRNA-seq, miRNA-seq and whole-genome bisulfite-seq (WGBS). A multi-omics approach was employed to quantify mRNA gene expression, miRNA expression and DNA methylation, using advanced bioinformatics and data integration techniques. Our analysis identified 19 key genes present in multiple omics datasets, regulated by epigenetics and miRNAs. We constructed a regulatory network for these genes, revealing disruptions in pathways such as Mannose type O-glycan biosynthesis, the cell cycle, apoptosis and FoxO signaling. Notably, the Atp7b gene was regulated by DNA methylation and miR-223 targeting, whereas the Man2a1 gene was controlled by DNA methylation affecting energy metabolism. These findings suggest that these genes may play a role in fetal programming, potentially leading to CKD later in life due to gestational inflammation.

Nasopharyngeal carcinoma (NPC) is often diagnosed at a very advanced stage due to its location and non-specific initial symptoms. Moreover, no clinically useful serological marker has been established so far for early detection of NPC. In this study, we have investigated the clinical significance of plasma Epstein-Barr virus DNA load along with interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels to evaluate if these three all together can be useful as a strong serological marker for early detection and prediction of treatment response in patients with NPC. Plasma EBV DNA load, IL-6 level, VEGF expressions were measured in 24 patients with NPC at presentation and various time points during and after treatment. There was a positive correlation between high plasma EBV DNA load with higher IL-6 and VEGF expression, which was closely associated with therapeutic response as well. Persistent or recurrent plasma EBV load with higher IL-6 and VEGF levels can potentially predict disease progression and may be useful to select patients for additional therapy and longer follow-up., (© 2024. The Author(s).)

Knee osteoarthritis (KOA) is linked to an enhanced release of interleukin-6 (IL-6). Increased levels of IL-6 are associated with greater pain and insomnia. While total knee arthroplasty (TKA) typically results in the reduction of pain, for a subgroup of patients, pain does not improve. Understanding patients' propensity to upregulate IL-6 may provide insight into variation in the clinical success of TKA for improving pain, and insomnia may play an important modulatory role. We investigated the association between pre- and post-surgical changes in clinical pain and IL-6 reactivity, and whether change in insomnia moderated this association. Patients (n = 39) with KOA came in-person before and 3-months after TKA. At both visits, patients completed validated measures of clinical pain and insomnia, as well as underwent quantitative sensory testing (QST). Blood samples were collected to analyze IL-expression both before and after QST procedures to assess changes in IL-6 in response to QST (IL-6 reactivity). Patients were categorized into two groups based on change in clinical pain from pre- to post-surgery: 1) pain decreased > 2 points (pain improved) and 2) pain did not decrease > 2 points (pain did not improve). Based on this definition, 49 % of patients had improved pain at 3-months. Among patients with improved pain, IL-6 reactivity significantly decreased from pre- to post-surgery, whereas there was no significant change in IL-6 reactivity among those whose pain did not improve. There was also a significant interaction between pain status and change in insomnia, such that among patients whose insomnia decreased over time, improved pain was significantly associated with a reduction in IL-6 reactivity. However, among patients whose insomnia increased over time, pain status and change in IL-6 reactivity were not significantly associated. Our findings suggest that the resolution of clinical pain after TKA may be associated with discernible alterations in pro-inflammatory responses that can be measured under controlled laboratory conditions, and this association may be moderated by perioperative changes in insomnia. Randomized controlled trials which carefully characterize the phenotypic features of patients are needed to understand how and for whom behavioral interventions may be beneficial in modulating inflammation, pain, and insomnia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Interleukin-6 (IL-6) is a versatile cytokine crucial for immune response modulation, inflammation regulation, and various physiological processes in the body. Its wide-ranging functions underscore its importance in maintaining health. Dysregulated IL-6 is closely associated with many diseases, making it a key research and therapeutic target. Elevated IL-6 levels in the central nervous system worsen neuroinflammation in neurodegenerative diseases by activating microglia and astrocytes and releasing pro-inflammatory cytokines and neurotoxic molecules. Moreover, dysregulated IL-6 weakens the blood-brain barrier, exacerbating neuroinflammation and neuronal damage by allowing peripheral immune cells and inflammatory mediators to enter the brain. Mesenchymal stem cells (MSCs) show promise in modulating neuroinflammation by regulating IL-6 levels. They effectively suppress pro-inflammatory cytokines, including IL-6, while promoting anti-inflammatory factors. This therapeutic approach highlights the importance of targeting IL-6 and other inflammatory mediators to alleviate neuroinflammation and its adverse effects on neurological disorders. This review provides a comprehensive overview of IL-6's involvement in neurological disorders, examining endogenous IL-6 and IL-6 derived from MSCs. We explore IL-6's mechanisms affecting neuronal function, survival, and immune modulation in the central nervous system. Additionally, we discuss the potential of MSC-derived IL-6 in neuroregeneration and neuroprotection. By elucidating IL-6's interplay with neurological pathologies, this review offers insights into novel therapeutic strategies targeting IL-6 signaling pathways for neurological disorders., Competing Interests: Author Rodrigo Pinheiro Araldi was employed by BioDecision Analytics Ltda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kerkis, Silva and Araldi.)

Background: Immune-inflammatory response is a key element in the occurrence and development of olfactory dysfunction (OD) in patients with allergic rhinitis (AR). As one of the core factors in immune-inflammatory responses, interleukin (IL)-6 is closely related to the pathogenesis of allergic diseases. It may also play an important role in OD induced by diseases, such as Sjögren's syndrome and coronavirus disease 2019. However, there is no study has reported its role in OD in AR. Thus, this study aimed to investigate the role of IL-6 in AR-related OD, in an attempt to discover a new target for the prevention and treatment of OD in patients with AR., Methods: Differential expression analysis was performed using the public datasets GSE52804 and GSE140454 for AR, and differentially expressed genes (DEGs) were obtained by obtaining the intersection points between these two datasets. IL-6, a common differential factor, was obtained by intersecting the DEGs with the General Olfactory Sensitivity Database (GOSdb) again. A model of AR mice with OD was developed by sensitizing with ovalbumin (OVA) to verify the reliability of IL-6 as a key factor of OD in AR and explore the potential mechanisms. Furthermore, a supernatant and microglia co-culture model of nasal mucosa epithelial cells stimulated by the allergen house dust mite extract Derp1 was established to identify the cellular and molecular mechanisms of IL-6-mediated OD in AR., Results: The level of IL-6 in the nasal mucosa and olfactory bulb of AR mice with OD significantly increased and showed a positive correlation with the expression of olfactory bulb microglia marker Iba-1 and the severity of OD. In-vitro experiments showed that the level of IL-6 significantly increased in the supernatant after the nasal mucosa epithelial cells were stimulated by Derp1, along with significantly decreased barrier function of the nasal mucosa. The expression levels of neuroinflammatory markers IL-1β and INOS increased after a conditioned culture of microglia with the supernatant including IL-6. Then knockdown (KD) of IL-6R by small interfering RNA (siRNA), the expression of IL-1β and INOS significantly diminished., Conclusion: IL-6 plays a key role in the occurrence and development of OD in AR, which may be related to its effect on olfactory bulb microglia-mediated neuroinflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Transcription factor MAFB regulates various homeostatic functions of macrophages. This study explores the role of MAFB in brown adipose tissue (BAT) thermogenesis using macrophage-specific Mafb-deficient (Mafb f/f ::LysM-Cre) mice. We find that Mafb deficiency in macrophages reduces thermogenesis, energy expenditure, and sympathetic neuron (SN) density in BAT under cold conditions. This phenotype features a proinflammatory environment that is characterized by macrophage/granulocyte accumulation, increases in interleukin-6 (IL-6) production, and IL-6 trans-signaling, which lead to decreases in nerve growth factor (NGF) expression and reduction in SN density in BAT. We confirm MAFB regulation of IL-6 expression using luciferase readout driven by IL-6 promoter in RAW-264.7 macrophage cell lines. Immunohistochemistry shows clustered organization of NGF-producing cells in BAT, which are primarily TRPV1 + vascular smooth muscle cells, as additionally shown using single-cell RNA sequencing and RT-qPCR of the stromal vascular fraction. Treating Mafb f/f ::LysM-Cre mice with anti-IL-6 receptor antibody rescues SN density, body temperature, and energy expenditure., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Fetal inflammatory response syndrome (FIRS) is defined by elevated levels of inflammatory cytokines circulating in fetal blood, which may result in preterm morbidities. Serum interleukin-6 (IL-6) level has been reported to be a good indicator of FIRS; however, changes in IL-6 levels after birth remain to be elucidated. Herein, we characterized early changes in serum IL-6 levels in extremely premature newborns (EPNs, < 28 wks gestation), and then determined the cut-off values for detecting fetal inflammation at each postnatal epoch., Methods: In this single-center study, 49 EPNs were retrospectively studied. Serum IL-6 measurements are routinely performed at delivery, 1-3, 6-12, and 24-36 h of life. Receiver operating characteristic (ROC) curve analyses were performed for detecting the presence of funisitis, the histologic counterpart of FIRS., Results: Overall, serum IL-6 levels were significantly elevated at 1-3 (298 [31-4719] pg/mL) and 6-12 (29 [2-12,635] pg/mL) hours of life, then returned to at-delivery levels at 24-36 h of life. When comparing serum IL-6 levels at each postnatal epoch, the levels at delivery, 1-3, and 6-12 h of life were significantly higher in the EPNs with funisitis. Serum IL-6 cut-off values at delivery, 1-3, 6-12, and 24-36 h of life for the presence of funisitis were 20, 572, 290, and 13 pg/mL with area under ROCs of 0.75, 0.71, 0.68, and 0.53, respectively., Conclusions: Serum IL-6 levels in EPNs significantly increase early after birth, then decrease to at-delivery levels by 24-36 h of life. Therefore, postnatal age-dependent cut-off values of serum IL-6 might be considered for detecting fetal inflammation with confirmed funisitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

To examine whether circulating interleukin-6 (IL-6) levels (CirIL6) have a causal effect on blood pressure using Mendelian randomization (MR) methods. We used data from genome-wide association studies (GWAS) of European ancestry to obtain genetic instruments for circulating IL-6 levels and blood pressure measurements. We applied several robust MR methods to estimate the causal effects and to test for heterogeneity and pleiotropy. We found that circulating IL-6 had a significant positive causal effect on systolic blood pressure (SBP) and pulmonary arterial hypertension (PAH), but not on diastolic blood pressure (DBP) or hypertension. We found that as CirIL6 genetically increased, SBP increased using Inverse Variance Weighted (IVW) method (for ukb-b-20175, β = 0.082 with SE = 0.032, P = 0.011; for ukb-a-360, β = 0.075 with SE = 0.031, P = 0.014) and weighted median (WM) method (for ukb-b-20175, β = 0.061 with SE = 0.022, P = 0.006; for ukb-a-360, β = 0.065 with SE = 0.027, P = 0.014). Moreover, CirIL6 may be associated with an increased risk of PAH using WM method (odds ratio (OR) = 15.503, 95% CI, 1.025-234.525, P = 0.048), but not with IVW method. Our study provides novel evidence that circulating IL-6 has a causal role in the development of SBP and PAH, but not DBP or hypertension. These findings suggest that IL-6 may be a potential therapeutic target for preventing or treating cardiovascular diseases and metabolic disorders. However, more studies are needed to confirm the causal effects of IL-6 on blood pressure and to elucidate the underlying mechanisms and pathways., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the effect of the individualized positive end-expiratory pressure (PEEP) lung protection ventilation strategy by combining driving pressure (ΔP) and pulmonary ultrasound (LUS)-based titration on lung function and postoperative cognitive function in patients with chronic obstructive pulmonary disease (COPD) during laparoscopic surgery., Methods: A total of 108 patients with COPD undergoing laparoscopic gastrointestinal surgery under general anesthesia were included in this study. They were randomly divided into three groups (n = 36): traditional volume ventilation group (Group C), fixed PEEP 5 cmH 2 O group (Group P), and ΔP combined with LUS-based PEEP titration in the resuscitation room group (Group T). All three groups were given volume ventilation mode, I:E = 1:2; In group C, VT was 10 mL/kg and PEEP was 0 cmH 2 O; In groups P and T, VT was 6 mL/kg and PEEP was 5 cmH 2 O; After mechanical ventilation for 15 min in Group T, ΔP in combination with LUS was used to titrate PEEP. The oxygenation index (PaO2/FiO2), airway platform pressure (Pplat), dynamic lung compliance (Cdyn), Montreal Cognitive Assessment (MoCA), and venous interleukin-6(IL-6) were recorded at the corresponding time points, and the final PEEP value in Group T was recorded., Results: The final PEEP value of Group T was (6.4 ± 1.2) cmH 2 O; Compared with groups C and P: PaO 2 /FiO 2 and Cdyn in Group T were significantly increased (P < 0.05) and value of IL-6 was significantly decreased (P < 0.05) at the corresponding time points. Compared with group C, the MoCA score on day 7 after surgery in Group T was significantly higher (P < 0.05)., Conclusion: Compared with the traditional ventilation strategy, the individualized ΔP combined with LUS-based PEEP titration in patients with COPD during the perioperative period of laparoscopic surgery can play a better role in lung protection and can improve postoperative cognitive function., (© 2023. The Author(s).)

Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial-mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators-twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPβ. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPβ toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPβ and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression.

Background: The prevalence of obesity, as well as obesity-induced chronic inflammatory diseases, is increasing worldwide. Chronic inflammation is related to the complex process of angiogenesis, and we found that adipose-derived stem cells from obese subjects (obADSCs) had proangiogenic features, including higher expression levels of interleukin-6 (IL-6), Notch ligands and receptors, and proangiogenic cytokines, than those from control subjects. We hypothesized that IL-6 and Notch signaling pathways are essential for regulating the proangiogenic characteristics of obADSCs., Objective: This study aimed to investigate whether the inflammatory cytokine interleukin 6 (IL-6) promotes the proangiogenic capacity of adipose stem cells in obese subjects via the IL-6 signaling pathway., Methods: We compared the phenotype analysis as well as cell doubling time, proliferation, migration, differentiation, and proangiogenic properties of ADSCs in vitro. Moreover, we used small interfering RNAs to inhibit the gene and protein expression of IL-6., Results: We found that ADSCs isolated from control individuals (chADSCs) and obADSCs had similar phenotypes and growth characteristics, and chADSCs had a stronger differentiation ability than obADSCs. However, obADSCs were more potent in promoting EA.hy926 cell migration and tube formation than chADSCs in vitro. We confirmed that IL-6 siRNA significantly reduced the transcriptional level of IL-6 in obADSCs, thereby reducing the expression of vascular endothelial growth factor (VEGF)- A, VEGF receptor 2, transforming growth factor β, and Notch ligands and receptors in obADSCs., Conclusion: The finding suggests that inflammatory cytokine interleukin-6 (IL-6) promotes the proangiogenic ability of obADSCs via the IL-6 signaling pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: The decision to surgically intervene in a hydronephrotic kidney in children is based on many debatable guidelines, some requiring repeated ultrasounds or renal scans. Urinary proteins have the potential to reflect renal disorders and hence can be the alternatives to such scans. Here, we aim to assess the role of urinary Neutrophil Gelatinase-Associated Lipocalin, Monocyte Chemoattractant Protein-1, and Interleukin-6 (IL-6) in such patients., Methods: Seventeen children had obstructive hydronephrosis requiring pyeloplasty (UPJO), while seven were kept on conservative management in view of non-obstructive dilation (NOD). Urine samples were measured for the three urinary proteins at the time of presentation and following pyeloplasty using commercially available ELISA kits., Results: The levels of all three urinary proteins were significantly higher in patients with UPJO children compared to the NOD group. Cut-off values to differentiate obstructive from non-obstructive hydronephrosis were obtained. A significant fall in the post-operative value of urinary IL-6 was also observed., Conclusion: This study highlights the potentiality of urinary proteins as biomarkers in identifying children with hydronephrosis and picking out the ones with obstructive hydronephrosis who will require pyeloplasty. The drop in levels after pyeloplasty can be employed to evaluate the effectiveness of pyeloplasty when sent serially., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production., Competing Interests: Authors MH and IC received funding from Ionis Pharmaceuticals for experiments in an unrelated study using the GFAP-IFN mice. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 West, Viengkhou, Campbell and Hofer.)

We report the development of a distance-based paper analytical device combined with a hydrophilic bridge valve (B-dPAD) as a quantitative immunoassay method to monitor human interleukin-6 (IL-6) in human samples. Our device design features (i) a circular sample inlet zone, (ii) a circular capture zone with immobilized anti-IL-6 (anti-Ab 1 ), and (iii) a detection zone channel coated with methylene blue (MB). Two hydrophilic valves are positioned between these three zones. IL-6 levels were determined quantitatively by measuring the extent of degradation of MB to a colorless product along the length of the detection zone channel. Following method optimization, we obtained a linear range from 0.05 to 25.0 pg/mL ( R 2 = 0.9995) and a detection limit (LOD) of 0.05 pg/mL by the naked-eye readout. This is directly within the clinically relevant range. The system does not require any external instrumentation, and the bridge valves can be easily connected and disconnected by a minimally trained operator. The total analysis time is 35 min, significantly reduced from a typical ELISA assay, which takes around 1 h since the B-dPAD workflow circumvents washing steps. The device was tested for IL-6 quantification in human saliva and urine samples of volunteers, with no significant difference found between our method and the standard clinical laboratory method at 95% confidence levels. Recoveries ranged from 98 to 105% with the highest standard deviation at 3.9%. Our B-dPAD immunodevice is therefore a promising approach for rapid IL-6 monitoring in the context of point-of-care diagnostics and analysis in resource-limited settings.

Elevated levels and enhanced sensing of the pro-inflammatory cytokine interleukin-6 (IL-6) are key features of many autoimmune and inflammatory diseases. To better understand how IL-6 signaling may influence human T cell fate, we investigated the relationships between levels of components of the IL-6R complex, pSTAT responses, and transcriptomic and translational changes in CD4 + and CD8 + T cell subsets from healthy individuals after exposure to IL-6. Our findings highlight the striking heterogeneity in mbIL-6R and gp130 expression and IL-6-driven pSTAT1/3 responses across T cell subsets. Increased mbIL-6R expression correlated with enhanced signaling via pSTAT1 with less impact on pSTAT3, most strikingly in CD4 + naïve T cells. Additionally, IL-6 rapidly induced expression of transcription factors and surface receptors expressed by T follicular helper cells and altered expression of markers of apoptosis. Importantly, many of the features associated with the level of mbIL-6R expression on T cells were recapitulated both in the setting of tocilizumab therapy and when comparing donor CD4 + T cells harboring the genetic variant, IL6R Asp358Ala (rs2228145), known to alter mbIL-6R expression on T cells. Collectively, these findings should be taken into account as we consider the role of IL-6 in disease pathogenesis and translating IL-6 biology into effective therapies for T cell-mediated autoimmune disease., Competing Interests: JB is a Scientific Co-Founder and Scientific Advisory Board member of GentiBio, a consultant for Bristol-Myers Squibb and Hotspot Therapeutics, and has past and current research projects sponsored by Amgen, Bristol-Myers Squib, Janssen, Novo Nordisk, and Pfizer. She is a member of the Type 1 Diabetes TrialNet Study Group, a partner of the Allen Institute for Immunology, and a member of the Scientific Advisory Boards for the La Jolla Institute for Allergy and Immunology and BMS Immunology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lambert, Diggins, Jones, Hundhausen, Maerz, Hocking, Sanda, Greenbaum, Linsley, Cerosaletti and Buckner.)

Objectives: Localized scleroderma (LSc) is a disease characterized by the excessive deposition of collagen and thereby thickening of the dermis. In recent years, studies reported that LSc demonstrated compromised skin barrier related to the progression of the disease. However, human studies examining epidermis in scleroderma are still sparse and lack systematic research. This study aims to investigate the structural and functional changes in the LSc epidermis and further explore the underlying mechanisms, providing a new angle to treat LSc in the clinic., Methods: A total of 136 skin sites, including lesion and non-lesion control, from 27 LSc patients were analyzed. Ultrasonic testing, trans-epidermal water loss (TEWL), and epidermal hydration were assessed to investigate the structural and functional alternations; correlations between these parameters were analyzed. To explore the underlying mechanism, skin-fibrosis mouse model and cellular model by bleomycin (BLM) were deployed., Results: The epidermal thickness was markedly increased, with a significant decline of hydration (dryness) in the LSc lesion skin. Epidermal hydration presented a negative correlation with the thickness. TEWL was not altered. The mouse model validated these morphological changes in the epidermis and indicated that interleukin-6 (IL-6) was significantly elevated. Furthermore, cellular study demonstrated that increased phosphorylation of p38 in keratinocyte promoted the secretion of IL-6, stimulating cell proliferation., Conclusion: This study characterized the epidermal alterations in LSc patients, suggesting that keratinocyte-derived abnormal IL-6 secretion can lead to the thickening of the epidermis, promoting dryness. The topical application of moisturizer may largely relieve dryness and related pruritus, thus improve the quality of life in LSc patients. Key Points • Epidermal thickness was increased in LSc lesion skin with declined hydration level. • Skin fibrosis mouse model validated the epidermal alteration in LSc patient. • p38-dependent IL-6 overexpression in keratinocyte result in epidermal thickening., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

(1) Background: To explore the effect of exercise on the formation and recovery of alcoholic liver disease (ALD) and whether the IL-6−p47phox oxidative−stress axis is involved in that process. (2) Methods: Firstly, 23 six-week-old male C57BL/6J mice were randomly divided into the Con group, ALD group, ALD + NOXI group, ALD + Ex group, and ALD + Ex + NOXI group. The Liber−DeCarli alcoholic liquid diet was used for 6 weeks to establish the ALD mice model, and the Con group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet, and exercise intervention was started after the ALD model establishment and lasted for another 6 weeks, with or without administration of the NOX inhibitor apocynin by intraperitoneal injection on every exercise training day. Secondly, 28 mice were randomly divided into the Sed group, Eth group, Eth + Ex group and Eth + Ex + NOXI group. The Sed group was given the TP4030C control diet. The remaining groups were fed with the TP4030B alcoholic diet and exercise intervention was started synchronously combined with or without administration of intraperitoneal apocynin injections on every exercise training day for 5 weeks. After each individual experiment was accomplished, physiological assessment and biochemical analysis of blood and tissue samples were examined. (3) Results: The levels of TG in serum and IL-6 protein content in liver tissue in the ALD group were significantly increased compared to the Con group (p < 0.05); compared with ALD, p47phox expression in muscle was increased significantly in the ALD + NOXI group (p < 0.05), and TG in serum decreased in the ALD + Ex group (p < 0.05). TG in serum, AST/ALT ratio, and IL-6 content in both liver and muscle decreased (p < 0.05) in the ALD + Ex + NOXI group with MDA in muscle significantly increased (p < 0.01). The AST/ALT ratio, TG in serum, SOD in liver, and p47phox in both liver and muscle in the ALD + Ex + NOXI group were significantly decreased compared with the ALD + NOXI group (p < 0.01). Compared with the ALD + Ex group, the liver index and HDL-C levels in serum were decreased (p < 0.05) in the ALD + Ex + NOXI group. The degree of hepatocyte steatosis and inflammatory infiltration were ameliorated after exercise intervention. In the Eth group, the relative epididymal fat content, HDL-C level, and AST/ALT ratio were significantly decreased, and TG and gp91phox in liver were significantly higher than in the Sed group (p < 0.05, p < 0.01). Compared with the Eth group, the AST/ALT ratio, MDA in the liver, and NOX4 and p47phox protein expression in the liver were significantly increased, and body weight decreased significantly in the Eth + Ex group (p < 0.05, p < 0.01), as did TG in the liver and MDA in muscle. In the th + Ex + NOXI group, gp91phox expression in the liver and body weight were significantly decreased (p < 0.05, p < 0.01). In the Eth + Ex + NOXI group, the ratio of AST/ALT and MDA in muscle were increased when compared with the Eth + Ex group, and the protein expression of gp91phox and p47phox were much lower (p < 0.01). (4) Conclusions: 6 weeks of exercise intervention during the recovery phase of ALD ameliorates hepatocyte damage and dyslipidemia through the IL-6−p47phox oxidative−stress axis, and applying a NOX inhibitor in combination could optimize this. However, drinking alcohol during exercise exacerbates dyslipidemia and oxidative stress, with hepatocyte IL-6−p47phox downregulated.

It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers [e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17β (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 "neutralizing" antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered.

Background: Cellular dedifferentiation is a regenerative prerequisite that warrants cell cycle reentry and appropriate mitotic division during de novo formation of cardiomyocytes. In the light of our previous finding that expression of injury-responsive element, Wilms Tumor factor 1 (WT1), in pericardial adipose stromal cells (ADSC) conferred a compelling reparative activity with concomitant IL-6 upregulation, we then aim to unravel the mechanistic network that governs the process of regenerative dedifferentiation after ADSC-based therapy., Methods and Results: WT1-expressing ADSC (eGFP:WT1) were irreversibly labeled in transgenic mice (WT1-iCre/Gt(ROSA)26Sor-eGFP) primed with myocardial infarction. EGFP:WT1 cells were enzymatically isolated from the pericardial adipose tissue and cytometrically purified (ADSC gfp+ ). Bulk RNA-seq revealed upregulation of cardiac-related genes and trophic factors in ADSC gfp+ subset, of which IL-6 was most abundant as compared to non-WT1 ADSC (ADSC gfp- ). Injection of ADSC gfp+ subset into the infarcted hearts yielded striking structural repair and functional improvement in comparison to ADSC gfp- subset. Notably, ADSC gfp+ injection triggered significant quantity of dedifferentiated cardiomyocytes recognized as round-sharp, marginalization of sarcomeric proteins, expression of molecular signature of non-myogenic genes (Vimentin, RunX1), and proliferative markers (Ki-67, Aurora B and pH3). In the cultured neonatal cardiomyocytes, spontaneous dedifferentiation was accelerated by adding tissue extracts from the ADSC-treated hearts, which was neutralized by IL-6 antibody. Genetical lack of IL-6 in ADSC dampened cardiac dedifferentiation and reparative activity., Conclusions: Taken collectively, our results revealed a previous unappreciated effect of IL-6 on cardiac dedifferentiation and regeneration. The finding, therefore, fulfills the promise of stem cell therapy and may represent an innovative strategy in the treatment of ischemic heart disease., (© 2022. The Author(s).)

Interleukin-6 (IL-6) is a multi-tasking cytokine that represents high activity in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and cancer. High concentration of this pleiotropic cytokine accounts for hyperinflammation and cytokine storm, and is related to multi-organ failure in patients with SARS-CoV-2 induced disease. IL-6 promotes lymphopenia and increases C-reactive protein (CRP) in such cases. However, blockade of IL-6 is not a full-proof of complete response. Hypoxia, hypoxemia, aberrant angiogenesis and chronic inflammation are inter-related events occurring as a response to the SARS-CoV-2 stimulatory effect on high IL-6 activity. Taking both pro- and anti-inflammatory activities will make complex targeting IL-6 in patient with SARS-CoV-2 induced disease. The aim of this review was to discuss about interactions occurring within the body of patients with SARS-CoV-2 induced disease who are representing high IL-6 levels, and to determine whether IL-6 inhibition therapy is effective for such patients or not. We also address the interactions and targeted therapies in cancer patients who also have SARS-CoV-2 induced disease., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Gene polymorphisms in interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) may affect the predisposition of Alzheimer's disease (AD), but the results of the so far published studies remain controversial. The authors conducted this meta-analysis to assess relationships between IL-6/IL-8/IL-10 polymorphisms and predisposition of AD by pooling the findings of so far published studies. A comprehensive search of Pubmed, Embase, Web of Science, and CNKI was endorsed by the authors to identify the already published studies. Forty-five studies were found to be eligible for meta-analyses. The pooled meta-analyses results showed that genotypic frequencies of IL-6 - 174 G/C, IL-6 - 572 G/C and IL-10 - 1082 A/G polymorphisms among patients with AD and controls differed significantly. Moreover, genotypic frequencies of IL-6 - 174 G/C, IL-6 - 572 G/C, and IL-8 - 251 A/T polymorphisms among patients with AD and controls in Asians also differed significantly. But no such genotypic frequencies' differences were observed for IL-10 - 819 C/T and 592 C/A polymorphisms. This meta-analysis suggests that IL-6 - 174 G/C, IL-6 - 572 G/C, and IL-10 - 1082 A/G polymorphisms may affect the predisposition of AD in overall population. Moreover, IL-6 - 174 G/C, IL-6 - 572 G/C, and IL-8 - 251 A/T polymorphisms may affect the predisposition of AD in Asians., (© 2020. Belgian Neurological Society.)

Background: Accumulating evidence shows that physical exercise has a positive effect on the release of neurotrophic factors and myokines. However, evidence regarding the optimal type of physical exercise for these release is still lacking. The aim of this study was to assess the acute and chronic effects of open-skill exercise (OSE) compared to closed-skill exercise (CSE) on serum and plasma levels of brain derived neurotrophic factor (BDNF S , BDNF P ), and serum levels of insulin like growth factor 1 (IGF-1), and interleukin 6 (IL-6) in healthy older adults., Methods: To investigate acute effects, thirty-eight participants were randomly assigned to either an intervention (badminton (aOSE) and bicycling (aCSE), n  = 24, 65.83 ± 5.98 years) or control group (reading (CG), n  = 14, 67.07 ± 2.37 years). Blood samples were taken immediately before and 5 min after each condition. During each condition, heart rate was monitored. The mean heart rate of aOSE and aCSE were equivalent (65 ± 5% of heart rate reserve). In a subsequent 12-week training-intervention, twenty-two participants were randomly assigned to either a sport-games (cOSE, n  = 6, 64.50 ± 6.32) or a strength-endurance training (cCSE, n  = 9, 64.89 ± 3.51) group to assess for chronic effects. Training intensity for both groups was adjusted to a subjective perceived exertion using the CR-10 scale (value 7). Blood samples were taken within one day after the training-intervention., Results: BDNF S , BDNF P , IGF-1, and IL-6 levels increased after a single exercise session of 30 min. After 12 weeks of training BDNF S and IL-6 levels were elevated, whereas IGF-1 levels were reduced in both groups. However, only in the cOSE group these changes were significant. We could not find any significant differences between the exercise types., Conclusion: Our results indicate that both exercise types are efficient to acutely increase BDNF S , BDNF P , IGF-1 and IL-6 serum levels in healthy older adults. Additionally, our results tend to support that OSE is more effective for improving basal BDNF S levels after 12 weeks of training., (© 2021. The Author(s).)

IL-6 was found to be overexpressed in the adipose tissue of obese individuals, which may cause insulin resistance. However, the regulation of IL-6 in adipocytes in obesity setting remains to be explored. Since IL-1β and TNFα are increased in obese adipose tissue and promote inflammation, we investigated whether cooperation between IL-1β and TNFα influences the production of IL-6. Our data show that IL-1β and TNFα cooperatively enhance IL-6 expression in 3T3L-1 adipocytes. Similar results were seen in human adipocytes isolated from subcutaneous and visceral fat. Although adipocytes isolated from lean and obese adipose tissues showed similar responses for production of IL-6 when incubated with IL-1β/TNFα, secretion of IL-6 was higher in adipocytes from obese tissue. TNFα treatment enhanced CREB binding at CRE locus, which was further enhanced with IL-1β, and was associated with elevated histone acetylation at CRE locus. On the other hand, IL-1β treatments mediated C/EBPβ binding to NF-IL-6 consensus, but not sufficiently to mediate significant histone acetylation. Interestingly, treatment with both stimulatory factors amplifies CREB binding and H3K14 acetylation. Furthermore, histone acetylation inhibition by anacardic acid or curcumin reduces IL-6 production. Notably, inhibition of histone deacetylase (HDAC) activity by trichostatin A (TSA) resulted in the further elevation of IL-6 expression in response to combined treatment of adipocytes with IL-1β and TNFα. In conclusion, our results show that there is an additive interaction between IL-1β and TNFα that depends on CREB binding and H3K14 acetylation, and leads to the elevation of IL-6 expression in adipocytes, providing interesting pathophysiological connection among IL-1β, TNFα, and IL-6 in settings such as obesity.

Interleukin-6 (IL-6) can reportedly centrally affect the thermogenesis of brown fat. However, whether the peripheral IL-6 signaling regulates beiging of white fat remains largely unknown. In vitro experiments indicated IL-6-KO-derived white adipocytes exhibited lower thermogenic gene expression compared to the WT, associating with reduced phosphorylation of STAT3 at Tyr705. Mechanistically, exogenous IL-6 application increased the p-STAT3 Tyr705 level, thus the phosphorylated STAT3 bound to the promoter regions, and enhanced the transcription of Pparγ and Ucp1. The protein interaction of PGC-1α with PPARγ was increased by IL-6, which also contributed to stimulate Ucp1 expression. In vivo experiments demonstrated that IL-6 KO decreased the beiging potential of white fat with suppressed STAT3 Tyr705 phosphorylation. Accordingly, IL-6-KO mature mice were associated with disrupted glucose homeostasis and accelerated hepatic steatosis. Collectively, we identified a novel function of peripheral IL-6/STAT3 signaling which is essential for beiging of white fat, such ensuring fat and glucose homeostasis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Biomarkers to prognosticate the outcomes and guide the treatment of patients with severe coronavirus disease 2019 (COVID-19) are currently required. We aimed to investigate whether the dynamic variation of cytokines was associated with the survival of patients admitted to the intensive care unit (ICU)., Methods: A retrospective study was performed on 40 patients with COVID-19 admitted to the ICU in Wuhan, China. Demographic, clinical, and laboratory variables were collected, and serum cytokines were kinetically assessed. A multivariable-adjusted generalized linear regression model was used to analyze the differences in serum cytokine levels between survivors and non-survivors., Results: Among the 40 patients included, we found a positive correlation between multiple cytokines. Serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNFα) in non-survivors were consistently elevated compared to those in the survivors. Kinetic variations in IL-6, IL-8, and IL-10 were associated with a fatal outcome in patients with severe COVID-19, independent of sex, age, absolute lymphocyte count, direct bilirubin, hypertension, chronic obstructive pulmonary disease, and cancer as well as the use of glucocorticoids and tocilizumab., Conclusions: Dynamic changes in serum IL-6, IL-8, and IL-10 levels were associated with survival in patients in the ICU, and could serve as a predictive biomarker to determine the therapeutic options for patients with severe COVID-19.

Background: Severe cutaneous adverse reactions (SCARs) are associated with high morbidity and mortality in patients with cancer. Early identification and treatment of SCARs may improve outcomes., Objective: To identify biomarkers to predict outcomes in hospitalized patients with cancer who developed SCARs., Methods: Retrospective review of 144 hospitalized patients with cancer with a morbilliform rash, recorded testing for serum cytokines (interleukin [IL]-6, IL-10, and tumor necrosis factor [TNF]-α) or elafin, and a dermatology consultation. Rashes were categorized as simple morbilliform rash without systemic involvement or complex morbilliform rash with systemic involvement., Results: Fifty-four of 144 (37.5%) patients died during follow-up. Elevated levels of IL-6, IL-10, and TNF-α were associated with decreased survival. Overall survivals in patients with elevated levels of IL-6, IL-10, and TNF-α were 53.7%, 56.6%, 53.6%, respectively, compared with 85.7%, 82.5% and 83.6%, respectively, in those with lower levels. Patients with increased levels of both IL-6 and TNF-α had a nearly 6-fold increase in mortality (hazard ratio, 5.82) compared with patients with lower levels., Limitations: Retrospective design, limited sample size, and high-risk population., Conclusions: Hospitalized patients with cancer with rash and elevated IL-6 and TNF-α were nearly 6 times more likely to die over the course of follow-up. These biomarkers may serve as prognostic biomarkers and therapeutic targets for this high-risk population., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Gene polymorphisms of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6) may influence the risk of Graves' disease, but the results of so far published studies remain inconclusive. Therefore, the authors conducted this meta-analysis to assess relationships between TNF-α/IL-1/IL-6 polymorphisms and the risk of Graves' disease by pooling the findings of all relevant studies., Methods: A comprehensive literature searching of Pubmed, Embase, Web of Science and CNKI was conducted by the authors, and twenty-eight studies were found to be eligible for pooled analyses., Results: The pooled meta-analyses results showed that genotypic frequencies of TNF-α rs1800629, IL-1A rs1800587, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms among patients with Graves' disease and control subjects differed significantly. Moreover, we found that genotypic frequencies of TNF-α rs1800629 and IL-6 rs1800795 polymorphisms among patients with Graves' disease and control subjects in Caucasians differed significantly, and genotypic frequencies of IL-1A rs1800587, IL-1B rs16944, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms among patients with Graves' disease and control subjects in Asians also differed significantly. Nevertheless, we did not detect such genotypic frequencies differences for TNF-α rs361525 and IL-1B rs1143627 polymorphisms., Conclusions: This meta-analysis suggests that TNF-α rs1800629, IL-1A rs1800587, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms may influence the risk of Graves' disease in overall population. Moreover, TNF-α rs1800629 and IL-6 rs1800795 polymorphisms may influence the risk of Graves' disease in Caucasians, while IL-1A rs1800587, IL-1B rs16944, IL-6 rs1800795 and IL-6 rs1800796 polymorphisms may influence the risk of Graves' disease in Asians.

Vascular calcification is the ectopic deposition of calcium hydroxyapatite minerals in arterial wall, which involves the transdifferentiation of vascular smooth muscle cells (VSMCs) toward an osteogenic phenotype. However, the underlying molecular mechanisms regulating the VSMC osteogenic switch remain incompletely understood. In this study, we examined the roles of microRNAs (miRNAs) in vascular calcification. miRNA-seq transcriptome analysis identified miR-223-3p as a candidate miRNA in calcified mouse aortas. MiR-223-3p knockout aggravated calcification in both medial and atherosclerotic vascular calcification models. Further, RNA-seq transcriptome analysis verified JAK-STAT and PPAR signaling pathways were upregulated in both medial and atherosclerotic calcified aortas. Overlapping genes in these signaling pathways with predicted target genes of miR-223-3p derived from miRNA databases, we identified signal transducer and activator of transcription 3 (STAT3) as a potential target gene of miR-223-3p in vascular calcification. In vitro experiments showed that miR-223-3p blocked interleukin-6 (IL-6)/STAT3 signaling, thereby preventing the osteogenic switch and calcification of VSMCs. In contrast, overexpression of STAT3 diminished the effect of miR-223-3p. Taken together, the results indicate a protective role of miR-223-3p that inhibits both medial and atherosclerotic vascular calcification by regulating IL-6/STAT3 signaling-mediated VSMC transdifferentiation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of immature myeloid blasts in the bone marrow (BM). Cytokine provide signals for leukemia cells to improve their survival in the BM microenvironment. Previously, we identified interleukin-33 (IL-33) as a promoter of cell survival in a human AML cell line and primary mouse leukemia cells. In this study, we report that the cell surface expression of IL-33-specific receptor, Interleukin 1 Receptor Like 1 (IL1RL1), is elevated in BM cells from AML patients at diagnosis, and the serum level of IL-33 in AML patients is higher than that of healthy donor controls. Moreover, IL-33 levels are found to be positively associated with IL-6 levels in pediatric patients with AML. In vitro , IL-33 treatment increased IL-6 mRNA expression and protein level in BM and peripheral blood (PB) cells from AML patients. Evidence was also provided that IL-33 inhibits cell apoptosis by activating p38 mitogen-activated protein kinase (MAPK) pathway using human AML cell line and AML patient samples. Finally, we confirmed that IL-33 activated IL-6 expression in a manner that required p38 MAPK pathway using clinical AML samples. Taken together, we identified a potential mechanism of IL-33-mediated survival involving p38 MAPK in pediatric AML patients that would facilitate future drug development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Wang, Su, Yan, Zhang, Tang, Li, Gu and Gong.)

Oxidative damage in retinal pigment epithelial cells (RPE) is considered to be a crucial pathogenesis of age-related macular degeneration (AMD). Although dysregulation of the DNA repair system has been found in RPE cells of AMD patients, the detailed molecular mechanisms of this dysregulation and their relationship with the intraocular microenvironment of AMD patients remain unclear. Here, we established an RPE model of H 2 O 2 -induced oxidative stress and found that Sirtuin 1 (Sirt1)-mediated deacetylation of E2F transcription factor 1 (E2F1) was required for oxidation resistance in RPE cells. Moreover, E2F1 induced the expression of the chromatin-binding protein, high mobility group AT-Hook 1 (HMGA1), which promoted the transcription of glucose 6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, to increase NADPH level for antioxidant defense. Interrupting the E2F1/HMGA1/G6PD regulatory axis increased reactive oxygen species (ROS) levels, DNA damage, and apoptosis in RPE cells under oxidative stress. Notably, interleukin 6 (IL-6), an inflammatory cytokine that is known to be upregulated in the intraocular fluid of AMD patients, induced phosphorylation (S47) of Sirt1 by activating PI3K/AKT/mTOR signaling, thereby inhibiting Sirt1 activity and increasing the acetylation of E2F1. Specific inhibitors of PI3K/AKT/mTOR signaling decreased DNA damage and ROS while increasing NADPH in RPE cells. Collectively, our findings demonstrate that IL-6-induced acetylation of E2F1 impairs the antioxidant capacity of RPE cells by disturbing the pentose phosphate pathway, which elucidates a relationship between the intraocular microenvironment and RPE oxidative damage in AMD and provides a possible therapeutic target for AMD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The rapid recovery of smell and taste functions in COVID-19 patients could be attributed to a decrease in interleukin-6 levels rather than central nervous system ischemic injury or viral damage to neuronal cells. To correlate interleukin-6 levels in COVID-19 patients with olfactory or gustatory dysfunctions and to investigate the role of IL-6 in the onset of these disorders, this observational study investigated 67 COVID-19 patients with taste or smell disorders or both, who did not require intensive care admission, admitted at COVID Hospital of Policlinico of Bari from March to May 2020. Interleukin-6 was assayed in COVID-19 patients with taste or smell disturbances at the time of admission and at the time of swab negativization. At the same time, patients have been given a specific survey to evaluate the severity of taste and smell disturbances. Of 125 patients with smell or taste dysfunctions at onset of disease, 67 fulfilled the inclusion criteria, while 58 were excluded because 35 of them required intensive care admission, 5 were unable to answer, 5 died, 7 had finished chemotherapy recently, and 5 refused to participate. The evaluation of taste and smell disorders was carried out using a survey performed at the time of admission and at the time of swab negativization. Sinonasal outcome test 22 (SNOT-22) was used as a reference for olfactory function assessment, and Taste and Smell Questionnaire Section of the US NHANES 2011-2014 protocol (CDC 2013b) was used as reference for gustatory function assessment. A venous blood sample was taken for each patient to measure IL-6 levels upon entry and at swab negativization. Interleukin-6 levels in COVID-19 patients in relation to olfactory or gustatory disorders were correlated from the time of their admission to the time of swab negativization. Statistically significant correlations were obtained between the decrease of interleukin-6 levels and the improvement of smell ( p value < 0.05) and taste ( p = 0.047) functions at swab negativization. The acquired results demonstrate the key role of interleukin-6 in the pathogenesis of chemosensitive disorders in COVID-19 patients.

Repetitive traumatic brain injuries (TBIs) among military personnel have been linked to chronic behavioral and neurological symptoms, and poor health outcomes. Repetitive TBIs may impact inflammation, which may offer some explanation of the biological basis of these long-term risks, and may improve the care that is provided to these individuals. This study examines the concentrations of TNFα, IL-6 and IL-10 and associations with behavioral symptoms, including post-traumatic stress disorder symptoms and depression in a cohort of 106 military personnel and Veterans with a history of TBI. Group comparisons conducted for those with repetitive TBIs (> 3; n = 44), to participants with less than three TBIs (n = 29), and controls with no TBIs (n = 33). The primary outcomes were serum levels of inflammatory related proteins TNF-α, IL-6 and IL-10, TBI history, and PTSD symptoms. IL-6 mean concentration was significantly higher in the repetitive TBI group compared to those with 1-2 TBI or no TBI history (p = 0.050). Additionally, for participants with a history of TBI, PTSD symptom severity, specifically, intrusion (p = .006 and p = .007) and avoidance (p = .034 and .009), were significant predictors of higher IL-6 and IL-10 concentrations respectively. These findings suggest that repetitive TBIs concurrent with high PTSD symptoms in military personnel and Veterans are associated with chronic inflammation, and specifically elevated concentrations of IL-6. Examining the changes in inflammatory processes may identify potential therapeutic targets for early intervention after TBI in order to prevent the development of neurological deficits and disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Atherosclerosis is an important underlying cause of cardiovascular diseases; vascular endothelial cells play a vital role in inflammatory responses in the initial steps of atherosclerosis. High levels of the pro-inflammatory cytokine interleukin-6 (IL-6) long have been considered a risk factor in the development and complications of atherosclerotic disease. However, it is still controversial whether IL-6 is atherogenic or atheroprotective. Recently, miR-126-3p, an endothelial cell-specific microRNA, has been proposed as an atheroprotective molecule. Therefore, we investigated whether IL-6 accelerates endothelial cell responses through the suppression of miR-126-3p expression in human endothelial cell line EA.hy926. IL-6 yielded concentration-dependent decreases in miRNA-126-3p accumulation in EA.hy926 cells, leading in turn to increased expression of genes targeted by miRNA-126-3p. In addition, adhesion of the human monocyte cell line THP-1 was enhanced by the exposure of EA.hy926 cells to IL-6, with associated increases in the levels of the adhesion molecule intercellular adhesion molecule-1 (ICAM-1). Suppression of miR-126-3p expression resulted in upregulation of miRNA-126-3p-regulated genes, enhanced adhesion of THP-1 cells, and increased ICAM-1 accumulation in EA.hy926 cells. In contrast, miR-126-3p overproduction had the opposite effects. The regulation of miRNA-126-3p by IL-6 may have important implications for the development of novel protective therapies targeting atherosclerosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Interleukin-6 (IL-6) is a pleiotropic cytokine with crucial immunoregulatory functions in both innate and adaptive immune responses. However, the IL-6 sequence and function remain unknown in sturgeon, one chondrostean fish. In the present study, we identified an interleukin-6 homolog from Siberian sturgeon (Acipenser baeri), named AbIL-6. Its open reading frame (ORF) was 657 nucleotides in length, encoding a polypeptide of 218 amino acids, which contains a signal peptide and the IL-6 family domain. Phylogenetic analysis showed that sturgeon IL-6 had close relationship with both teleost and chondrichthyes IL-6s. Abil-6 mRNA was highly expressed in spleen, brain and liver tissues of healthy sturgeon, and significantly up-regulated in the spleen, head kidney and liver by A.hydrophila (A.h) challenge. Heat-killed A.h and LPS effectively stimulated Abil-6 transcripts in primary spleen cells in vitro. In order to understand the bioactivity and influence of AbIL-6 on immune responses, recombinant AbIL-6 (rAbIL-6) was synthesized by prokaryotes and demonstrated to promote the proliferation of spleen cells and head kidney cells in vitro. Additionally, intraperitoneal injection of rAbIL-6 induced significantly higher expression of four immuno-related genes including il-1β, cxcl10, mhcIIβ and igm. rAbIL-6 improved the survival rate and reduced the tissue bacterial load after A.h infection. Taken together, these results suggest that AbIL-6 plays an important role in inflammatory responses and immune defense against bacterial infection of sturgeon., Competing Interests: Declaration of competing interest No conflict of interest was existed., (Copyright © 2020. Published by Elsevier Ltd.)

Ovarian carcinoma is the key cause of cancer death from gynecological malignancy of women. Chemotherapy-resistance, metastasis and relapse contribute to the high mortality in ovarian cancer patients. Cancer stem cells (CSCs) stand for the root of kinds of cancer types such as ovarian cancer, are the key driver of tumor initiation, cancer metastasis, and resistance to conventional chemotherapy as well as genomic targeted therapy. Thus, the approach to eliminate CSCs and uncovering the mechanism will have substantial impact on cancer therapy. However, targeting CSC remains unfeasible in clinical practice in ovarian cancer therapy. In this study, we first found that Low-intensity ultrasound (LIUS) was capable of reducing the CSC populations in the xenograft model with ovarian cancer, with blocking survival, anti-apoptosis, self-renewal, and downregulating the cancer stemness genes in ovarian CSCs. Moreover, LIUS ameliorated IL-6/STAT3 inflammatory pathway via inhibiting IL-6-induced STAT3 phosphorylation, DNA binding activity and, the expressions of its downstream effectors in ovarian CSCs while no explicit effect was found in the corresponding bulk cancer cells. Additional approaches in molecular studies showed that LIUS disrupts CSC features via inhibiting IL-6/STAT3 inflammatory pathway. Collectively, our data for the first time elucidate IL-6/STAT3 inflammatory loop as the key CSC or cancer stemness pathway in ovarian cancer by LIUS treatment, providing a novel and potential therapy and a promising target in ovarian cancer., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The results of studies on the relationship between cytokine polymorphisms and polycystic ovary syndrome (PCOS) have been controversial. This meta-analysis was thus designed to more precisely assess the relationship between TNF-α/IL-1/IL-6/IL-10 polymorphisms and PCOS by pooling the results of published studies. A search of PubMed, Embase, Web of Science, and CNKI databases turned up 23 studies that were pooled and analyzed in this meta-analysis. The overall results showed that the distributions of TNF-α -238 G/A, TNF-α -857 C/T, and IL-1B -51 C/T polymorphisms among patients and controls differed significantly. Additionally, the distributions of TNF-α -308 G/A and IL-1B -51 C/T polymorphisms among patients and controls from Asian populations differed significantly, whereas the distributions of IL-6 -174 G/C and IL-1A -889 C/T polymorphisms among patients and controls from Caucasian populations also differed significantly. In conclusion, our meta-analysis demonstrated that TNF-α -238 G/A, TNF-α -857 C/T, and IL-1B -51 C/T polymorphisms might influence susceptibility to PCOS in the overall pooled population. Moreover, TNF-α -308 G/A and IL-1B -51 C/T polymorphisms might influence susceptibility to PCOS in Asians, whereas IL-6 -174 G/C and IL-1A -889 C/T polymorphisms might influence susceptibility to PCOS in Caucasians.

Background: Associations between polymorphisms in interleukin-6 (IL-6)/interleukin-18 (IL-18) and tuberculosis (TB) were already reported by many publications. The aim of this meta-analysis was to better clarify associations between polymorphisms in IL-6/IL-18 and TB by combing the results of all relevant publications., Methods: Eligible publications were searched from Pubmed, Embase, WOS and CNKI. We used Review Manager to combine the results of individual studies., Results: Twenty-five studies were included in this study. IL-6 rs1800795 (dominant comparison: OR 1.43, 95% CI 1.23-1.67; recessive comparison: OR 0.48, 95% CI 0.35-0.65; allele comparison: OR 1.43, 95% CI 1.27-1.62), IL-18 rs1946518 (dominant comparison: OR 1.19, 95% CI 1.04-1.35; recessive comparison: OR 0.82, 95% CI 0.71-0.96; allele comparison: OR 1.14, 95% CI 1.05-1.24) and IL-18 rs187238 (dominant comparison: OR 1.35, 95% CI 1.15-1.58; allele comparison: OR 1.31, 95% CI 1.14-1.50) polymorphisms were all significantly associated with TB in the total population. Subgroup analyses showed that positive findings for rs1946518, rs187238 and rs1800795 polymorphisms were mainly driven by the Asians., Conclusions: Collectively, this meta-analysis proved that IL-6 rs1800795, IL-18 rs1946518 and IL-18 rs187238 polymorphisms may confer susceptibility to TB, especially for Asians., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Associations of polymorphisms in interleukin-6 (IL-6), IL-8 and IL-10 with tuberculosis (TB) susceptibility were already reported by many publications. The aim of this meta-analysis was to more precisely clarify associations between polymorphisms in IL-6/IL-8/IL-10 and TB by combing the results of all relevant publications., Methods: Eligible publications were searched from PubMed, Embase, Web of Science and CNKI. We used Review Manager to combine the results of individual studies., Results: A total of 47 publications were included in this study. IL-6 rs1800795 (1750 cases and 2335 controls, dominant, recessive and allele comparisons), IL-8 rs4073 (1125 cases and 1188 controls, dominant, recessive and allele comparisons), IL-10 rs1800871 (5528 cases and 7671 controls, dominant, recessive and allele comparisons), IL-10 rs1800872 (5269 cases and 7013 controls, dominant and allele comparisons) and IL-10 rs1800896 (7564 cases and 8952 controls, recessive comparison) polymorphisms were all significantly associated with TB in overall combined analyses. In subgroup analyses, we found that the positive results were mainly driven by the pulmonary tuberculosis and Asian subgroups., Conclusions: Collectively, this meta-analysis proved that IL-6 rs1800795, IL-8 rs4073, IL-10 rs1800871, IL-10 rs1800872 and IL-10 rs1800896 may confer susceptibility to TB., (© FEMS 2019.)

Background: Some previous studies already explored associations of interleukin-6 (IL-6) and interleukin-10 (IL-10) polymorphisms with ischemic stroke (IS). However, the results were conflicting. In this meta-analysis, we aimed to better analyze the relationship between IL-6/IL-10 polymorphisms and IS in a larger pooled population., Methods: We performed a systematic search of PubMed, Web of Science, Embase and CNKI. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) to estimate associations between IL-6/IL-10 polymorphisms and IS., Results: Totally 37 studies were included for analyses. A significant association with IS was observed for IL-10 rs1800896 polymorphism in AA versus GG + GA (recessive model, p = .001, OR = 1.42, 95%CI 1.15-1.75) in overall population. Further subgroup analyses showed that IL-6 rs1800795 was significantly associated with IS in Asians in GG versus GC + CC (dominant model, p = .0005, OR = 0.74, 95%CI 0.62-0.88), CC versus GG + GC (recessive model, p = .003, OR = 1.61, 95%CI 1.17-2.21) and G versus C (allele model, p = .01, OR = 0.74, 95%CI 0.58-0.93), whereas IL-10 rs1800896 polymorphism was significantly associated with cerebral infarction (CI) in GG versus GA + AA (dominant model, p = .02, OR = 2.04, 95%CI 1.14-3.64), GA versus GG + AA (overdominant model, p = .03, OR = 0.50, 95%CI 0.27-0.93) and G versus A (allele model, p = .01, OR = 1.92, 95%CI 1.16-3.17)., Conclusions: Our findings indicated that IL-6 rs1800795 polymorphism was significantly associated with individual susceptibility to IS in Asians, but not in Caucasians. In addition, IL-10 rs1800896 polymorphism was also significantly associated with individual susceptibility to IS, especially for CI., (Copyright © 2019. Published by Elsevier B.V.)

An 83-year-old man with stable chronic kidney disease (CKD) exhibited a sudden increase in urinary N-acetyl-β-D-glucosaminidase and protein excretion, suggesting aggravated kidney damage. Simultaneously, he lost diabetic control, requiring up to 54 units of insulin daily. A detailed examination revealed the presence of renal cell carcinoma, which was surgically resected and confirmed to be interleukin-6-positive by immunohistochemistry. Postoperatively, his uni-nephrectomy necessitated hemodialysis, but the patient's insulin resistance was ameliorated; no medication was required to control diabetes, suggesting that the tumor had caused the insulin resistance. This report describes a case of a tumor secreting interleukin-6, which affects both the control of diabetes and CKD progression.

Acute liver injury can result from a number of different diseases. Inflammatory cytokines are known to be involved in the development of this condition; however, their precise roles and effects on liver function remain unclear. The goal of this study was to determine the relationship between serum cytokine levels and both the severity of liver damage and recovery in acute liver injury. We enrolled 100 patients with acute liver injury caused by drug application who were hospitalized from September 2012 to September 2017 and measured serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the cytokines, interleukin (IL)-2 and IL-6, before and after clinical therapy. Our results indicate that IL-2 and IL-6 levels are altered significantly following clinical therapy. However, with the exception of an association between IL-2 and ALT, we found no correlation between the differences in cytokine levels pre- and post-therapy and recovery of liver function. In contrast, we observed that pre- vs post-treatment difference in the IL-2/IL-6 ratio negatively correlates with the pre- vs post-treatment difference in ALT and AST values, and positively correlates with ALT and AST at 1-month post-discharge. Thus, our data suggest that IL-2/IL-6 ratio may represent a novel predictor for the prognosis of liver injury., (© 2019 APMIS. Published by John Wiley & Sons Ltd.)