Interleukin-1 Interleukin-6 Research Articles

The inhibitory potential of chemical constituents of Ficus carica targeting interleukin-6 (IL-6) mediated inflammation.

Inflammation is an innate reaction of the body of an individual when subjected to the noxious factors repeatedly. Pharmacological approaches focused at disrupting cytokine signaling networks have become significant therapeutic alternatives for the treatment of inflammatory illnesses, cancer and autoimmune disorders. High levels of inflammatory mediators, particularly interleukin IL-1, IL-6, IL-18, IL-12, and tumor necrosis factor alpha leads to a cytokine storm in the body. Among all the released cytokines in a patient suffering from inflammatory disorder, IL-6 mediator has a pivotal role in this inflammatory cascade which progresses to a cytokine storm. Therefore, the blockage of the IL-6 inflammatory mediator could be a promising treatment option for the patients with hyper inflammatory conditions. The phytochemicals could provide the new lead compounds against the IL-6 mediator. Ficus carica has been the ideal plant of research and investigation due to its commercial, economic and medical importance. The anti-inflammatory properties of F. carica were further investigated by in silico and in vivo approaches. The docking scores of Cyanidin-3,5-diglucoside, Kaempferol-7-O-rutinoside, Cyanidin-3-rhamnoglucoside, and Rutin are -9.231, -8.921, -8.840, and -8.335 Kcal/mole respectively. The free energy of binding and stability of the docked complexes of these top four phytochemicals with the IL-6 were further analyzed by Molecular Mechanics-Generalized Born Surface Area and Molecular Dynamic simulations, respectively. The in vivo anti-inflammatory carrageenan-induced rat paw edema model was used for the validation of in silico results. The maximum percentage paw edema inhibition with petroleum ether and ethyl acetate was 70.32% and 45.05%, respectively. The in vivo anti-inflammatory activity confirms the anti-inflammatory potential of F. carica. Therefore, it is predicted that Cyanidin-3,5-diglucoside, Kaempferol-7-O-rutinoside, Cyanidin-3-rhamnoglucoside, and Rutin have the potential to inhibit the IL-6 mediator which will aid in mitigating the cytokine storm in patients with acute inflammations.

Cytokine Levels and Severity of Illness Scoring Systems to Predict Mortality in COVID-19 Infection.

Various scoring systems and cytokines have been cited as predicting disease severity in COVID-19 infection. This study analyzed the link between mortality rate, levels of cytokines, and scoring systems such as the Glasgow Coma Scale (GCS), Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), and Charlson Comorbidity Index in patients infected with COVID-19. Adult patients infected with COVID-19 were followed up in the intensive care unit (ICU) and analyzed prospectively. We measured serum cytokine levels (Interleukin-10 (IL-10), Interleukin-8 (IL-8), Interleukin-6 (IL-6), Interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and High mobility group box 1 (HMGB-1)) and recorded GCS, APACHE II, SOFA, and Charlson comorbidity index scores on admission to the ICU. Receiver operating curve (ROC) analysis was performed to predict mortality from IL-1β, IL-6 IL-10, IL-8, TNF-α, and HMGB-1 values. Study participants were grouped as follows: Group A, survivors, and Group B, deceased, during the 28-day follow-up. The mean age was 65.69 (±13.56) in Group A (n = 36) and 70.85 (±10.06) in Group B (n = 27). The female/male ratio was 23/40. Age, sex, body mass index (BMI), comorbid illnesses, GCS, APACHE II, SOFA, and Charlson scores, duration of hospitalization or ICU admission, therapeutic choices, and lymphocyte, PMNL, NLR, platelet, D-dimer, fibrinogen, GGT, CRP, procalcitonin, and lactate levels were similar between the groups. The frequency of acute kidney injury (AKI) was higher in Group B (p = 0.005). Serum IL-10, IL-8, IL-6, IL-1β, TNF-α, HMGB-1, ferritin, and LDH values were higher, and PaO2/FiO2 was lower in Group B than in Group A. ROC analysis showed that there was an association between serum IL-1β (>1015.7), serum IL-6 (>116.7), serum IL-8 (>258.4), serum IL-10 (>247.5), serum TNF-α (>280.7), and serum HMGB-1 (>23.5) and mortality. AKI gave rise to a greater risk of mortality (odds ratio: 7.081, p = 0.014). Mortality was associated with serum IL-10, IL-8, IL-6, IL-1β, TNF-α, and HMGB-1 but not with GCS, APACHE II, SOFA, or Charlson comorbidity index scores. AKI increased the risk of mortality by seven times. Our findings suggest that cytokine levels (serum IL-10, IL-8, IL-6, IL-1β, TNF-α, and HMGB-1) were predictors of mortality in COVID-19 infection. In addition, our results might give an opinion about the course of COVID-19 infection.

Endotoxin Activity Reflects an Increase in Body Temperature in Cirrhotic Patients With Ascites Undergoing Cell-free and Concentrated Ascites Reinfusion Therapy.

Ascites commonly complicates cirrhosis and is refractory to the vasopressin-2 antagonist tolvaptan and fluid restriction in approximately 60% of patients. We aimed to identify risk factors associated with adverse events following cell-free and concentrated ascites reinfusion therapy (CART) in patients with cirrhosis and ascites. We evaluated the efficacy and tolerability to the CART system in 18 patients with decompensated liver cirrhosis and ascites. We determined serum endotoxin activity using endotoxin activity (EA) assays and serum and ascitic fluid concentrations of interleukin 6 (IL6) and tumor necrosis factor-α (TNFα) before and after the CART procedures. Body weight and waist circumference significantly decreased after CART (both p<0.001). Body temperature (BT) increased significantly at an average rate of 1.1°C during CART (p<0.001). The change in BT was correlated with EA and not interleukin IL6 or TNFα. The rise in BT was positively correlated with serum EA levels at baseline. The increase in BT was significantly higher in the group with high EA (≥0.37) than in the low EAA group (<0.37) (p=0.02). TNFα and serum IL6 levels in ascites were significantly increased during CART (both p<0.001). However, no significant differences in the EA, serum TNFα or IL6 levels were found in ascitic fluid before and after the CART procedures. Although this discovery warrants further study, EA assay can indicate an increase in BT during effective CART in patients with cirrhosis and ascites.

Atorvastatin suppresses lipopolysaccharide-induced inflammation in human coronary artery endothelial cells

The present study was designed to examine the effects of atorvastatin on vascular inflammatory responses in human coronary artery endothelial cells(HCAECs), when challenged by lipopolysaccharide (LPS), a Toll-like receptor-4 (TLR4) ligand. HCAECs were pretreated with atorvastatin and induced by LPS. The expression of TLR4, interleukin -6(IL-6), monocyte chemoattractant protein 1(MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecular-1(ICAM-1), nuclear factor-κB (NF-κB) and p38 mitogen activated protein kinase(p38 MAPK) were evaluated using Real-time polymerase chain reaction, cytokine ELISA assay and Western blotting. The results showed that pretreatment with atorvastatin down-regulated the expression of TLR4 in LPS-activated HCAECs. Atorvastatin also attenuated the LPS-induced expression of interleukin IL-6 and MCP-1, at both the transcription and translation level in HCAECs. LPS-induced endothelial cell adhesion molecules, ICAM-1 and VCAM-1 expression were also reduced by pretreatment with atorvastatin. Furthermore, atorvastatin efficiently suppressed LPS-induced phosphorylation of NF-κB and p38 MAPK in HCAECs. These findings show that atorvastatin suppresses endothelial cell inflammation, suggesting that atorvastatin may be suitable for development as a therapeutic agent for inflammatory cardiovascular disease.

Myeloid-derived suppressor cells impede T cell functionality and promote Th17 differentiation in oral squamous cell carcinoma.

Oral tumor microenvironment is characterized by chronic inflammation signified with infiltrating leukocytes and soluble mediators which cause immune suppression. However, how immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) maintain the immunosuppressive tumor microenvironment and influence T cell function in oral squamous cell carcinoma (OSCC) patients remains poorly understood. In the present study, we found that percentages of MDSCs were higher in oral cancer patients compared to healthy individuals and correlated with cancer stage. Monocytic MDSCs (M-MDSCs) were prevalent in the periphery, while granulocytic/polymorphonuclear subset dominated the tumor compartment. M-MDSCs suppressed the lymphocyte proliferation and decreased the CD3-ζ (zeta) chain expression and interferon gamma production. The percentage of M-MDSCs in peripheral blood correlated inversely with CD3-ζ chain expression in T cells of these patients. Interleukin 6 (IL-6)-induced phosphorylated STAT3-regulated programmed cell death ligand 1, CCAAT/enhancer-binding proteins alpha and beta and Interleukin 10 expression in MDSCs. MDSCs inhibited TGF-β-driven generation of induced regulatory T cells in vitro. M-MDSCs secreted interleukins IL-6, IL-1β, IL-23 and PGE2 and facilitated T-helper 17 (Th17) cell differentiation which utilizes nitric oxide synthase and cyclooxygenase 2 enzyme activity. Interestingly, OSCC patients showed increased levels of Th17 cells in peripheral blood and tumor tissue. Thus, increased frequency of MDSCs, Th17 cells and decreased expression of CD3-ζ chain portray T cell tolerance and chronic inflammatory state facilitating tumor growth.

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

BackgroundRecurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Tumour-infiltrating natural killer cells (NK cells) display powerful cytotoxicity to tumour cells and play a pivotal role in tumour therapy. However, the phenotype and functional regulation of NK cells in oesophageal squamous cell carcinoma (ESCC) remains largely unknown.MethodsSingle cell suspensions from blood and tissue samples were isolated by physical dissociation and filtering through a 70 μm cell strainer. Flow cytometry was applied to profile the activity and function of NK cells, and an antibody chip experiment was used to identify and quantitate cytokine levels. We studied IL-6 and IL-8 function in primary oesophageal squamous carcinoma and NK cell co-cultures in vitro and by a xenograft tumour model in vivo. Western blotting was used to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Finally, we performed an IHC array to analyse IL-6/IL-8 (interleukin 6/interleukin 8) expression in 103 pairs of tumours and matched adjacent tissues of patients with ESCC to elucidate the correlation between IL-6 or IL-8 and clinical characteristics.ResultsThe percentages of NK cells in both peripheral blood and tumour tissues from patients with ESCC were significantly increased in comparison with those in the controls and correlated with the clinical characteristics. Furthermore, the decrease in activating receptors and increase in inhibitory receptors on the surface of tumour-infiltrating NK cells was confirmed by flow cytometry. The level of granzyme B, the effector molecule of tumour-infiltrating NK cells, was also decreased. Mechanistically, primary ESCC cells activated the STAT3 signalling pathway on NK cells through IL-6 and IL-8 secretion, leading to the downregulation of activating receptors (NKp30 and NKG2D) on the surface of NK cells. An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function. Moreover, the expression of IL-6 or IL-8 in tumour tissues was validated by immunohistochemistry to be positively correlated with tumour progression and poor survival, respectively.ConclusionsTumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy.

Effect of dexmedetomidine on inflammatory factors level and cognitive function after femoral head replacement in elderly patients

To analyze the effect of dexmedetomidine on the inflammatory factors level and cognitive function after femoral head replacement in elderly patients. From January 2016 to December 2017, 60 elderly patients(more than 60 years old, and Grade I to II of ASA) treated with femoral head replacement were divided into three groups, and 20 in each group. All patients received midazolam, fentanyl, etomidate, cisatracurium anesthesia induction and sevoflurane inhalation anesthesia maintenance. The patients in group B and group C were first given 1.0 μg·kg⁻¹ of dexmedetomidine 10 minutes during the operation. The maintenance volume was 0.3 μg·kg⁻¹·h⁻¹ of dexmedetomidine(in group B) and 0.6 μg·kg⁻¹·h⁻¹ of dexmedetomidine(in group C) by pumping. The same amount of saline was given to the patients in group A in the same way. The time of extubation, wakefulness and recovery, the simple intelligent mental state score (MMSE), the incidence of postoperative cognitive dysfunction (POCD) and the levels of interleukin-6 (IL-6), interleukin-10 (IL-10) and S100β protein expression in the 3 groups were compared. There were significant differences in the time of spontaneous breathing recovery, eye opening tome and the time of extubation, as well as the dosage of propofol among the three groups(P<0.05). On the 1st, 3rd and 7th day after operation, there was a significant difference in MMSE score of group B and group C compared with that of group A(P<0.05), and MMSE score in group C was significantly higher than that of group B(P<0.05). The incidence of POCD was 0.0% (0/20) and the incidence of adverse reactions was 30%(6/20) in group C, but those were 25% (5/20) and 0.0% (0/20) in group A and 5% (1/20) and 10% (2/20) respectively in group B. The difference was statistically significant (P<0.05). Before induction of anesthesia, there was no significant difference in the levels of IL-6, IL-10 and S100β protein among the three groups(P>0.05); but one hour after the operation, the levels of IL-6 IL-10 and S100β protein in group B and group C was statistically different from those in group A(P<0.05). The IL-6 and S100β protein in group C were significantly lower than those in group B (P<0.05), and IL-10 was significantly higher than that in group B (P<0.05). For elderly patients operated for femoral head replacement, dexmedetomidine can reduce the level of inflammatory factors level and propofol consumption, and the incidence of postoperative POCD is low, indicating a dose dependence of dexmedetomidine. But it is necessary to choose the right dose according to the patient's condition.

Nox1/4 dual inhibitor GKT137831 attenuates hypertensive cardiac remodelling associating with the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways in the rats with abdominal artery constriction

NADPH oxidases (Noxs) 1/4 dual inhibitor GKT137831 prevents hypertensive cardiac remodelling in angiotensin II-infused transgenic mice with cardiomyocyte-specific human Nox4 (c-hNo x 4 Tg); however, further research is still required to determine the beneficial role of GKT137831 in hypertensive cardiac remodelling in other types of hypertensive models because this hypertensive model is insufficient to mimic the complicated pathological mechanisms of hypertension. A disintegrin and metalloprotease 17 (ADAM17) promotes the shedding of tumour necrosis factor α (TNF-α), TNF-α receptor, interleukin 1 receptor-II and interleukin 6 (IL-6) receptor from cells, thereby mediating the signalling pathways induced by corresponding proinflammatory cytokines. This study aimed to determine whether GKT137831 prevents hypertensive cardiac remodelling and its mechanisms of action in the rats with abdominal artery coarctation (AAC). The rats subjected to AAC were orally given GKT137831 for a consecutive period of 28 days. Echocardiography and histological analysis were performed to evaluate cardiac remodelling; and immunohistochemistry and real-time PCR were used to detect the expression of proinflammatory cytokines. GKT137831 significantly suppressed hypertensive cardiac remodelling in AAC-induced hypertensive rats. Concurrently, Nox1/4 dual inhibitor GKT137831 reduced the protein and mRNA levels of proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and TNF-α in the left ventricle of AAC-induced hypertensive rats. Moreover, the treatment with GKT137831 markedly diminished the protein and mRNA levels of ADAM17 in the left ventricle of AAC-induced hypertensive rats. In summary, Nox1/4 dual inhibitor GKT137831 protects against hypertensive cardiac remodelling in AAC-induced hypertensive rats, and the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways are related to its beneficial effect on hypertensive cardiac remodelling.

A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamicpituitary- adrenal axis

The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1β, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.

Levels of interleukin IL-6 in gingival fluid during orthodontic tooth movement: Children vs. adult

During orthodontic tooth movement comes to remodeling of periodontal ligament and alveolar bone in response to mechanical loading. Mechanical loading, which comes from the orthodontic force causes aseptic inflammatory reaction within the periodontal tissue, which, in turn, initiates the biological processes associated with bone remodeling. As one of the controllers of the process of bone remodeling, during orthodontic treatment, it is mentioned to be interleukin-6 (IL-6). IL-6 stimulates the production of osteoclasts, ie. induces bone resorption to the osteoclastogenesis. The aim of this study was to investigate the influence of patient age on the production of interleukin-6 (IL-6) during the early stages of orthodontic tooth movement Participants were 10 children (mean age 13 years) and 10 adults (mean age 20 years) in which the orthodontic separator placed between the second premolar and first molar on one side and the opposite side served as controls. Samples were taken from treated and control teeth and before 24, 72, and 168 hours of placing the separator. Level of cytokines was determined by means of enzyme-linked whales. The content of IL-6 in gingival fluid of children and adults are remarkably different, when it comes to control, and when it comes to orthodontic treated teeth. IL-6 in gingival fluid control teeth of children was significantly lower than the content of cytokines in gingival fluid control adults. However, during orthodontic treatment, the content of IL-6 in gingival fluid is remarkably increased in children than in adults, in the comparative periods, where the trend changes in the content of this cytokine was the same in children and adults. The degree of increase is higher in children than adults which shows that the immune system of children reacts more quickly to local changes and the metabolic activity of periodontal ligament higher than in adult patients.

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

Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman’s Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology.

Mimecan: A Newly Identified Adipokine and Regulator of Appetite

Originally adipose tissue was considered a site of energy storage, providing mechanical as well as heat insulation and playing a role in the regulation of thermogenesis. However, since the discovery of Leptin in 1994 adipose tissue is now also recognised as an endocrine organ that produces a multitude of substances referred to as “adipokines”. These include adipolin, adiponectin, interleukin-6 (IL-6), leptin, omentin, tumour necrosis factor alpha (TNFα) and visfatin which play important roles in the regulation of food intake and metabolism (Smitka and Maresova, 2015). Adipose tissue is currently considered the largest endocrine organ secreting a multitude of hormones and cytokines known to affect processes both within the peripheral and central nervous system. With respect to leptin and food regulation the adipose tissue acts as a ‘safety valve’ controlling the long term regulation of food intake. Leptin is released in proportion to the degree of adiposity and reduces food intake when energy reserves are sufficient. Unfortunately, in chronic high fat diet induced obesity the ‘safety valve’ malfunctions, with the occurrence of leptin resistance in the hypothalamus exacerbating the problem of obesity (Munzberg et al., 2004). Therefore, as a central target for the treatment of obesity, leptin and leptin analogues have proved disappointing as possible pharmacotherapies. The study by Cao et al. (2015) revealed that mimecan, first identified in the organic matrix of bovine bone, is also expressed in adipose tissue and is a potential target for the treatment of obesity. Cao et al. (2015) described mimecan as a satiety hormone with both intraperitoneal and intracerebroventricular injections suppressing food intake. Information on whether this is due to changes in meal size or meal frequency is unavailable but the cumulative effects of mimecan on food intake appear to be considerable. Cao et al. (2015) demonstrated that the anorexic effects of mimecan are independent from leptin and melanocortin signalling with data showing a reduction in food intake still observed in obese leptin receptor knockout mice (db/db mice) and Agouti mice (AY/a mice) respectively. Cao et al. (2015) suggest mimecan-induced anorexia, within the central nervous system, is probably mediated via interleukin 1β (IL-1 β) and IL-6. It is known that IL-6 production occurs selectively in microglia rather than astrocytes and primary hypothalamic neuronal cells and therefore the study by Cao et al. (2015) supports the emerging evidence for microglia mediated anorexic effects (Le Foll et al., 2015). Microglia and astrocytes may prove to be critical in appetite regulation within the central nervous system with the potential to be new novel targets for the treatment of obesity. There are still many questions to be answered before the importance of mimecan in food intake and appetite regulation can be determined. These include translation of findings in the mouse to the human and establishment of the effectiveness of mimecan on food intake in high fat diet induced obesity. For instance, leptin is effective at reducing food intake in leptin knockout mice (ob/ob mice) (Halaas et al., 1995) and also obese humans with defective leptin production (Paz-Filho et al., 2011). It is only in diet-induced obese conditions that leptin resistance is observed. It is therefore essential to establish the effectiveness of mimecan at reducing food intake in high fat diet induced obese mice. In addition, although the effect of mimecan on food intake is promising there appears to be desensitisation to mimecan over treatment days raising some doubts on the usefulness of mimecan as a pharmacotherapy for obesity. Cao et al. (2015) reason that, as lower concentrations of mimecan were required to elicit an anorexic effect via intracerebroventricular compared to intraperitoneal injections, mimecan is acting centrally. They discount any possible peripheral effect. It would be useful to know the circulating levels of mimecan after intraperitoneal injections in addition to the clearance rates. It is known that numerous adipokines are expressed in other peripheral regions associated with satiety signalling, such as the gastrointestinal tract. For example, leptin is not only expressed in adipose tissue but also the stomach where it modulates vagal afferent satiety signals (Kentish et al., 2013). Cao et al. (2015) demonstrated that mimecan is expressed in other organs and tissue such as the lungs but did not look at expression in the gastrointestinal tract where the short term regulation of food intake and meal size is initiated. It would be interesting to see if specific regions within the gastrointestinal tract express mimecan. In conclusion, mimecan is an adipokine hormone that induces anorexia centrally by increasing IL-1β and IL-6 in the hypothalamus. The role mimecan plays in the regulation of food intake in high fat diet induced obesity and the therapeutic potential of mimecan or analogues of mimecan in the treatment of obesity remains to be determined. The author declares no conflict of interest.

각질형성세포에서 LPS로 유도된 염증반응에 대한 마가목, 쐐기풀, 죽여 및 오배자 혼합추출물의 항염 효과

Lipopolysaccharide (LPS)-induced inflammatory responses in the HaCaT keratinocyte cell line produce proinflammatory cytokines, such as interleukin-1(IL-1), tumor neurosis factor- (TNF-), interleukin-6 (IL-6), and interleukin- 8 (IL-8) and also increase the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and prostaglandins E2 (PGE2). In this study, we developed new natural ingredients for cosmetics that inhibit the pro-inflammatory responses induced by LPS in HaCaT cells. The mixture of Sorbus commixta (SC), Urtica dioica (UD), Phyllostachys nigra (PN), and Rhus semialata gall (RS) extracts blocked the increase of TNF- IL-1 IL-6, and IL-8. The increase of COX-2, iNOS, and PGE2 were also blocked by it. Finally, the mixture inhibited skin irritation induced by sodium lauryl sulfate (SLS), when applied on skin through IQ chamber. In conclusion, these results show that the mixture of SC, UD, PN, and RS can be used as a primary ingredient to alleviate skin irritation when cosmeceutical products are developed for sensitive skin.

Association of Vascular Access Type with Inflammatory Marker Levels in Maintenance Hemodialysis Patients

Aggressive NIH is a common histopathological lesion found at the sites of venous stenosis in arteriovenous fistula (AVF) and arteriovenous grafts (AVG). Inflammatory mediators have been proposed to play a pathogenic role in NIH, but there is paucity of data evaluating this hypothesis in clinical studies or in animal models. Serum levels of inflammatory mediators can potentially identify patients at high risk of AVF and AVG dysfunction. In a cross-sectional cohort study of 754 HD patients who were part of the NIED study cohort, we examined the associations between inflammatory markers including serum interleukin (IL) 1β, IL-6, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and type of vascular access. Unadjusted and multivariate-adjusted linear regression models were used. In addition, time-dependent regression model was used to assess the association between inflammatory markers and mortality. We observed that in the multivariate-adjusted model, inflammatory mediators interleukin-6 (IL-6), interleukin-1L-ß (IL-1ß), and C-reactive protein (CRP), the predicted value in hemodialysis patients, are lowest in patients with AVF and highest in central venous catheter (CVC) and AVG even in case-mix and malnutrition-inflammation complex syndrome (MICS)-adjusted models. IL-6 and CRP levels fall consistently in the same patients when AVG or CVC is changed to AVF and increase if the same patient changes access from AVF to AVG or CVC. Obesity is a risk factor for fistula failure and fistulas are associated with the lowest mortality compared with CVC and AVG. We did not find any statistically significant association between tumor necrosis factor-α (TNF- α) and vascular access outcomes. Higher levels of inflammatory mediators seen in CVC and AVG compared with AVF could potentially explain the higher mortality seen in patients with CVC and AVG compared with AVF.

Effects of carbohydrate restriction and dietary cholesterol provided by eggs on clinical risk factors in metabolic syndrome

There are a limited number of clinical interventions evaluating the effects of dietary cholesterol in individuals at elevated risk for type 2 diabetes and cardiovascular disease. To investigate the effects of whole egg intake in adults with metabolic syndrome (MetS). Men (n = 12) and women (n = 25) with MetS were instructed to follow a moderate carbohydrate-restricted diet (<30% energy) and randomly assigned to consume either three whole eggs (EGG, n = 20) or egg substitute (SUB, n = 17)/d for 12 weeks. Dietary intake, MetS parameters, and body composition were assessed at baseline and post-intervention. Total carbohydrate (P < .001) intake decreased in all participants over time. The EGG group consumed more dietary cholesterol (P < .001) and choline (P < .001) than the SUB group. MetS was reduced in both groups, with improvements noted in dyslipidemia and decreases in waist circumference (P < .01), weight (P < .001), and percent body fat (P < .001). Reductions in plasma tumor necrosis factor-α (P < .001) and serum amyloid A (P < .05) were seen in the EGG group only. Notably, increases in dietary cholesterol were associated with reductions in plasma tumor necrosis factor-α (r = -0.340, P = .04). Plasma C-reactive protein, adiponectin, interleukin-6 interleukin-10, and cell adhesion molecules were unaffected by the intervention. These results demonstrate that on a moderate carbohydrate background diet, accompanied by weight loss, the inclusion of whole eggs improves inflammation to a greater extent than yolk-free egg substitute in those with MetS.

P164 Evaluation of pro-inflammatory cytokines, and cell growth inhibition in primary human cells culture from oral tissue treated with uretandimethacrylate (UDMA)

Introduction Dental endodontic sealers are in intimate contact with tissues around the root apex for extended periods. New endodontic sealers have been developed in the past decade, but the biological responses to many new products are not well documented.After exposure to endodontic sealer based on Uretandimethacrylate (UDMA) in ex vivo expanded human dental pulp mesenchymal stem cells (DP-MSCs), human periodontal ligament mesenchymal stem cells (PDL-MSCs), human osteoblasts (HOSTs) and human gingival fibroblasts (HGF) were evaluated: morphological features and cells growth. Moreover, the secretion of pro-inflammatory cytokines as: interleukin-1 Beta (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), tumor necrosis factor-Alpha (TNF-α) at 24 h of UDMA treatment was assessed. Methods DP-MSCs and PDL-MSCs were derived from the dental pulps and the periodontal ligament of 10 young donors. HGF was derived from gingival biopsy. HOSTs were derived from maxilla periosteum. After in vitro isolation, DP-MSCs, PDL-MSCs, HGF and HOSTs were treated with UDMA, and after 24, 48 and 72 h and 1 week of incubation, their morphological features were analysed by light and confocal microscopy. To evaluate the, cell growth an MTT assay was performed. The release of IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-alpha was analysed by ELISA test. Differences in the cell growth and in the interleukin secretion were analysed for statistical significance with two-way anova tests and the Holm-Sidak method for multiple comparisons. Results The UDMA treatment induces a cells growth inhibition in all the different analysed cells line. At microscopic level the cells don’t showed morphological changes, in fact the fibroblastoid features with cytoplasmic processes was observable. An up-regulation of IL-6 IL-8 and TNF-α was present in DP-MSCs, PDL-MSCs, HOSTs and HGF at 24 h of treatment. On the contrary IL-12 was over-expressed only in the PDL-MSCs, while the IL-1β in the DP-MSCs. Conclusion This work shows endodontic sealers may alter the cell growth, and in treated samples to induce an up-regulation of soluble mediators of inflammation such as IL-6, IL-8 and TNF-α cytokines. The direct application of UDMA potentially induces an inflammation process that could be the starting point for toxic response and cell damage in DP-MSCs, PDL-MSCs, HGF and HOSTs.

The interleukins IL-6 and IL-1Ra: a mediating role in the associations between BMI and birth weight?

The biological mechanisms in the association between maternal body mass index (BMI) and birth weight are not well understood, but are likely to involve maternal plasma glucose levels and nutrient transport across the placenta, both important modulators of fetal growth. Adipose tissue contributes to circulating levels of interleukins that may affect glucose metabolism and possibly also placental transport of nutrients. We investigated possible mediating roles of Interleukin 6 (IL-6) and Interleukin 1 Receptor antagonist (IL-1Ra) in 208 pregnant women. Known and hypothesized dependencies between BMI in early pregnancy and fasting glucose, IL-1Ra and IL-6 at gestational weeks 30-32, and birth weight were specified in a path diagram. Standardized regression coefficients, expressing direct, indirect and total effects, were estimated by Bayesian path analysis. Mean (s.d.) BMI was 24.9 kg/m2 (4.2) and mean (s.d.) birth weight 3748 g (454). The total effect of BMI on birth weight was 0.24 (95% credibility interval (CrI) [0.12, 0.36]). The direct effect of IL-1Ra on birth weight was not statistically significant, but significant effects of BMI on IL-1Ra (0.61, 95% CrI [0.51, 0.72]), of IL-1Ra on fasting glucose (0.17, 95% CrI [0.01, 0.34]) and of fasting glucose on birth weight (0.14, 95% CrI [0.01, 0.27]) implied an indirect pathway from BMI via IL-1Ra on birth weight. Approximately 20% of the effect of BMI on birth weight was mediated through IL-1Ra. For IL-6, no such effects were found. Our results indicate that IL-1Ra may be a mediator in the association between BMI and birth weight.

Plasma Interleukin-6 Level is Associated with NT-proBNP Level and Predicts Short- and Long Term Mortality in Patients with Acute Heart Failure

Interleukin 6 plays an important role in chronic heart failure (HF), but little is known about its involvement in acute decompensated heart failure (ADHF). The aim of our study is to evaluate the prognostic role of interleukin 6 (IL-6) in the patients with ADHF. Plasma levels of interleukin IL-6, N-terminal pro brain natriuretic peptide levels, and clinical covariates were measured in 92 patients with ADHF. Survival was followed up to 12 months, and prognostic factors were evaluated. Elevated plasma IL-6 levels were increased in nonsurvivors and were associated with 1-year mortality (p < 0.01). Plasma IL-6 levels were associated with plasma NT-proBNP levels. In multivariate analysis, increased plasma IL-6 and NT-proBNP levels remained strong independent predictors of 1-year mortality. Plasma IL-6 levels provide important prognostic information in the patients with ADHF. Measurement combining plasma IL-6 and NT-proBNP should serve as a powerful prognostic tool of multimarker strategy in patients with acute decompensated heart failure.

Effects of IL-6/IL-2 fusion gene transfection on tumour cell biological characteristicsin vitro andin vivo

In order to examine the feasibility of cytokine fusion gene transfer into tumor cells, a retroviral vector(pLXSN) for human interleukin 6/interleukin 2(IL6/IL2) fusion gene was constructed by using PCR and ligating the two genes with a synthesized oligonucleotides linker. The IL6/IL2 fused gene was introduced into B16 melanoma cell line mediated by retrovirus and the changes of adhesive and metastatic ability of fused gene-modified cells were detected. The B16-IL6/IL2 cells showed efficient expression of both cytokines and decreased binding affinity with extracellular matrix (laminin and Matrigel), accompanying with decreased metastases potentials. These data suggest that the mechanism involving the decreased metastases may relate with the changes of biological characteristics and immune stimulating activity of gene-modified cells.