Higher Concentrations Of IL-6 Research Articles

P132: Inflammation, immune disorders and cell destruction at the local level in patients with choroidal melanoma

Purpose To research the characteristics of the inflammation immune disorders and cell destruction at the local level in the lacrimal and intraocular liquids in patients with choroidal melanoma. Materials and methods Investigation of concentration of the cytokines interleukin (IL) IL-4, IL-6, IL-8, IL-10, autoantibodies to antigens of native DNA (AAB to Ag of nDNA) in the lacrimal and intraocular liquids was performed in 36 patients (72 eyes) aged 34–83 years. The mean age of the study group patients was 60.45 years (15 males and 21 females). As standard indicators, survey results of 20 “healthy” donor lacrimal liquid – volunteers were used. For statistical data processing, descriptive statistics and methods of inter-group comparisons were used. Quantitative characteristics are presented as the median (25, 75 percentile). For comparison of quantitative traits, regression analysis was used. P value of Results A significant positive relation of concentration of IL-4, IL-6, IL-8, IL-10, AAB to Ag of nDNA in lacrimal liquid of eye with choroidal melanoma and paired “healthy” eye was reveled (p Conclusions 1.It was established that in the pathogenesis of choroidal melanoma, local Inflammation plays an important role as evidenced by a significant high concentration of IL-6, IL-8 due to lower levels of IL-4 and expressed immune disorders, cell destruction, as evidenced by significantly high level of AAB to Ag of nDNA, compared with the control group. 2.Use of lacrimal liquid is suitable for the study of the inflammation, immune disorders and cell destruction at the local level in patients with choroidal melanoma. 3.Significant increase in IL-6 level in lacrimal liquid was observed for all stages of choroidal melanoma, however, it was more pronounced in early stages (T1–T2), than in later stages (T3–T4). 4.A significant increase in IL-10 may indicate the severity of the local immunosuppression induced by tumor growth in the mechanisms of choroidal melanoma. A significant positive relationship between the concentrations of IL-4, IL-6, IL-8, IL-10, AAB to Ag of nDNA in the lacrimal liquids of eye and paired “healthy” eye was found in patients with choroidal melanoma.

Suppression of IL-10 production by activated B cells via a cell contact-dependent cyclooxygenase-2 pathway upregulated in IFN-γ-treated mesenchymal stem cells

The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well documented in various models in vitro and in vivo. Furthermore, a population of regulatory B cells (Bregs) that produce relatively high concentrations of IL-10 has been recently described. To study the relationship between MSCs and Bregs, we analyzed the effects of MSCs on IL-10 production by lipopolysaccharide (LPS)-activated mouse B cells. The production of IL-10 by B cells remained preserved in the presence of MSCs and was even significantly enhanced by IFN-γ. However, the production of IL-10 was strongly suppressed in cultures containing MSCs and IFN-γ. Preincubation of MSCs, but not of B cells, with IFN-γ induced the suppression of IL-10 secretion in cultures containing MSCs and B cells. The supernatants from IFN-γ-treated MSCs had no inhibitory effect, and the suppression of IL-10 production was abrogated if the MSCs and B cells were separated in a transwell system. Analysis of the gene expression of IFN-γ- or IFN-γ and LPS-treated MSCs revealed a strong upregulation of genes for indoleamine-2,3-dioxygenase (IDO), cyclooxygenase-2 (Cox-2) and programmed cell death-ligand 1 (PD-L1). While the inhibition of IDO activity or the inclusion of the neutralization monoclonal antibody anti-PD-L1 did not abrogate the suppression, indomethacin, an inhibitor of Cox-2, completely inhibited the MSC-mediated suppression of IL-10 production. Accordingly, the production of IL-10 by B cells was inhibited by exogenous prostaglandin E2. The results thus suggest that IFN-γ-treated MSCs strongly inhibit IL-10 production by activated B cells by a mechanism requiring cell contact and involving the Cox-2 pathway.

Concentrações de IL-6, TNF-α e MCP-1 em crianças com excesso de massa corporal

O objetivo desta revisão sistemática foi verificar a relação das concentrações de IL-6, TNF-α e MCP-1 em crianças com excesso de massa corporal. As bases de dados investigadas PUBMED, SciELO, LILACS e Periódico Capes foram consultadas retrospectivamente para os últimos seis anos (2009 a 2014) utilizando combinações de palavras chaves como inflamação, IL-6, TNF-α, MCP-1 combinadas com crianças e escolares. Foram analisados 21 artigos. Foi encontrado associação entre sobrepeso/obesidade com IL-6, TNF-α e MCP-1 em 73,3% (11/15), 80% (12/15) e 60% (3/5) dos estudos que analisaram tais marcadores, respectivamente. Crianças com excesso de massa corporal possuem concentrações elevadas de IL-6, TNF-α e MCP-1 resultando em inflamação sistêmica crônica e aumentando o risco de desenvolvimento de outras doenças cardiovasculares.

Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study

Existing evidence suggests that proinflammatory cytokines play an intermediary role in postchemotherapy cognitive impairment. This is one of the largest multicentered, cohort studies conducted in Singapore to evaluate the prevalence and proinflammatory biomarkers associated with cognitive impairment in breast cancer patients. Chemotherapy-receiving breast cancer patients (stages I-III) were recruited. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, interferon-γ and tumor necrosis factor-α] were evaluated at 3 time points (before chemotherapy, 6 and 12 weeks after chemotherapy initiation). The FACT-Cog (version 3) was utilized to evaluate patients' self-perceived cognitive disturbances and a computerized neuropsychological assessment (Headminder) was administered to evaluate patients' memory, attention, response speed and processing speed. Changes of cognition throughout chemotherapy treatment were compared against the baseline. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations on self-perceived cognitive disturbances and each objective cognitive domain. Ninety-nine patients were included (age 50.5 ± 8.4 years; 81.8% Chinese; mean duration of education = 10.8 ± 3.3 years). Higher plasma IL-1β was associated with poorer response speed performance (estimate: -0.78; 95% confidence interval (CI) -1.34 to -0.03; P = 0.023), and a higher concentration of IL-4 was associated with better response speed performance (P = 0.022). Higher concentrations of IL-1β and IL-6 were associated with more severe self-perceived cognitive disturbances (P = 0.018 and 0.001, respectively). Patients with higher concentrations of IL-4 also reported less severe cognitive disturbances (P = 0.022). While elevated concentrations of IL-6 and IL-1β were observed in patients with poorer response speed performance and perceived cognitive disturbances, IL-4 may be protective against chemotherapy-associated cognitive impairment. This study is important because cytokines would potentially be mechanistic mediators of chemotherapy-associated cognitive changes.

Chlamydia pneumoniae and Chlamydia Trachomatis Infection Differentially Modulates Human Dendritic Cell Line (MUTZ) Differentiation and Activation.

Chlamydia trachomatis and Chlamydia pneumoniae are important human pathogens that infect the urogenital/anorectal and respiratory tracts, respectively. Whilst the ability of these bacteria to infect epithelia is well defined, there is also considerable evidence of infection of leucocytes, including dendritic cells (DCs). Using a human dendritic cell line (MUTZ), we demonstrate that the infection and replication of chlamydiae inside DCs is species and serovar specific and that live infection with C. pneumoniae is required to upregulate costimulatory markers CD80, CD83 and human leucocyte antigen (HLA)-DR on MUTZ cells, as well as induce secretion of interleukin (IL)-2, IL-6, IL-8, IL-12 (p70), interferon-gamma and tumour necrosis factor-alpha Conversely, C. trachomatis serovar D failed to upregulate DC costimulatory markers, but did induce secretion of high concentrations of IL-8. Interestingly, we also observed that infection of MUTZ cells with C. pneumoniae or C. trachomatis serovar L2, whilst not replicative, remained infectious and upregulated lymph node migratory marker CCR7 mRNA. Taken together, these data confirm the findings of other groups using primary DCs and demonstrate the utility of MUTZ cells for further studies of chlamydial infection.

Pro-inflammatory interleukins in middle ear effusions from atopic and non-atopic children with chronic otitis media with effusion.

Chronic otitis media with effusion (OME) is associated with irreversible changes in the middle ear, sometimes leading to hearing loss and abnormal language development in children. While the pathogenesis of OME is not fully understood, inflammatory and allergic factors are thought to be involved. The study aimed to investigate the role of cytokines in the local development of chronic OME, and assess differences in the cytokine profiles between atopic and non-atopic children. 84 atopic and non-atopic children with chronic OME (mean age of 6years 7months) were studied. Age-matched children with hypertrophy of the adenoids and Eustachian tube dysfunction served as the control group. The number of past acute otitis media (AOM) episodes, their age, and the type of effusion were recorded for all children. Pro-inflammatory cytokine concentrations (TNF-α, IL-1β, IL-6 and IL-8) were determined and the presence of pathogenic bacteria in the patients' effusions was examined. High concentrations of TNF-α, IL-1β, IL-6 and IL-8 were found in the effusions in all children with chronic OME, with the highest levels observed in the non-atopic group. The atopic group showed persistently high IL-1β levels, while in the non-atopic children, IL-1β and TNF-α levels positively correlated with the patient's age and the number of past AOM episodes. Pathogenic bacteria were more frequently isolated from effusions in non-atopic children. In both atopic and non-atopic children, pro-inflammatory cytokines are found at high concentrations. This argues in favor of instituting anti-inflammatory management for treating OME, regardless of atopy.

Association between muscular strength and inflammatory markers among elderly persons with cardiac disease: results from the KORA-Age study.

Little is known about the association between muscle strength and inflammation in diseased individuals and particularly in cardiac patients. Thus, our purpose was to examine the association of muscular strength with the inflammatory status in older adults with and without cardiac disease. The cross-sectional analysis was based on 1079 adults aged 65-94years, who participated in the KORA-Age study. Participants underwent an interview and extensive physical examinations including anthropometric measurements, registration of diseases and drug intake, determination of health-related behaviors, collection of blood samples for measurements of interleukin-6 and hs-CRP and muscle strength measurement using hand-grip dynamometry. Cardiac patients (n=323) had higher levels of IL-6 and poorer muscle strength compared with older adults without cardiac disease. Among persons with cardiac diseases, muscle strength in the lower tertile compared to the upper tertile was significantly associated with increased odds of having elevated IL-6 levels (OR 3.53, 95% CI 1.18-10.50, p=0.024) after controlling for age, gender, body fat, alcohol intake, smoking status, diseases, medications and physical activity, whereas the association between muscle strength and hs-CRP remained borderline significant (OR 2.80, 95% CI 0.85-9.24, p=0.092). The same trends, with slightly lower odds ratios, were also observed in older adults without cardiac disease. Lower levels of muscular strength are associated with higher concentrations of IL-6 and hs-CRP in elderly individuals with and without cardiac disease suggesting a significant contribution of the muscular system in reducing low-grade inflammation that accompanies cardiac disease and aging.

Effect of Statins on Development of Early Cognitive Dysfunction After Coronary Artery Bypass Grafting

We studied the effect of rosuvastatin on the development of early postoperative cognitive dysfunction (POCD) in patients after coronary artery bypass grafting (CABG). One hundred nine men aged 45-70 year was divided into two groups. Group 1 comprised 69 patients (mean age 56.8 ± 5.2 years) who were given 20 mg of rosuvastatin for 10-14 days before CABG and until discharge. Patients of group 2 (n=40, mean age 55.9 ± 5.3 years) did not take rosuvastatin. It was shown that patients of group 2 had better neuropsychological parameters after CABG in comparison with the patients of group 2. Patients of group 1 had lower concentrations of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor α, high sensitivity C reactive protein, and higher concentrations of IL-10. Group 2 patients had worse neuropsychological parameters which were associated with higher concentrations of proinflammatory cytokines. These results may indicate that preoperative therapy with rosuvastatin had decreased the severity of systemic inflammatory response and reduced the development of early POCD after CABG.

Mid-trimester amniotic fluid pro-inflammatory biomarkers predict the risk of spontaneous preterm delivery in twins: a retrospective cohort study.

To evaluate the association between the concentrations of immune-related proteins in mid-trimester amniotic fluid (AF) and the subsequent risk of spontaneous preterm delivery in twins. The study population consisted of consecutive women with a twin pregnancy who underwent clinically indicated genetic amniocentesis at 15 to 20 weeks, and had a subsequent spontaneous delivery in the early preterm period (<32 weeks (cases)) or at term (37 to 42 weeks (controls)). AF was analyzed for cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13 and IL-15, interferon-γ, tumor necrosis factor-α), matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12), and chemokines (complement factor-D/Adipsin, Serpin E1/PAI-1, Adiponectin/Acrp30, C-Reactive Protein, CCL2/MCP-1, Leptin, Resistin) using multiplex immunoassay kits. The association between AF protein levels and subsequent early preterm birth were examined. A total of 96 sets of twins were enrolled, including 17 early preterm birth cases and 79 term controls. AF concentrations of IL-6, IL-8, MMP-3, MMP-8 and MMP-9, and CCL2/MCP-1 were significantly higher in cases than controls. Among these analytes, the combination of AF IL-8 and MMP-9 values had the highest predictive value for early preterm birth. The risk was 8% (10/132) for IL-8<1200 pg ml(-1) and MMP-9<1000 pg ml(-1), 30% (15/50) for IL-8>1200 pg ml(-1) or MMP-9>1000 pg ml(-1), and 90% (9/10) for IL-8>1200 pg ml(-1) and MMP-9>1000 pg ml(-1) (P<0.001). High concentrations of IL-8 and MMP-9 in mid-trimester AF in twins predicted well the risk of early preterm birth.

Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity

Background: Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). Methods: Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. Results: Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. Conclusions: Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity.

T-Regulatory Cells and Inflammatory and Inhibitory Cytokines in Malawian Children Residing in an Area of High and an Area of Low Malaria Transmission During Acute Uncomplicated Malaria and in Convalescence.

BackgroundMalaria still infects many Malawian children, and it is a cause of death in some of them. Regulatory T cells (Tregs) help in negating immune-related pathology, it but can also favor multiplication of malaria parasites. The question remains whether children recovering from uncomplicated malaria (UCM) have higher Tregs and interleukin (IL)-10 levels in convalescence.MethodsWe recruited children between the ages of 6 and 60 months presenting with acute UCM in Blantyre (low transmission area) and Chikwawa (high transmission area). We observed the children after 1 month and 3 months and analyzed their blood samples for parasitemia, lymphocyte subsets, and levels of the cytokines interferon (IFN)-γ, IL-10, and transforming growth factor (TGF)-β. Blood samples from age-matched controls were also analyzed for the same parameters.ResultsCompared with controls, acute UCM was associated with mild lymphopenia, splenomegaly, and high levels of IFN-γ, tumor necrosis factor-α, and IL-10, which normalized in convalescence. In Chikwawa, Treg counts were significantly (P < .0001) higher in convalescence compared with acute disease, whereas in Blantyre, these were as low as in healthy controls both during acute disease and in convalescence. Blantyre had a higher percentage of parasiteamic children (15% versus 12%) in convalescence compared with Chikwawa, but none of these developed symptomatic malaria during the study duration. Concentrations of TGF-β were higher at time points for the study participants and in controls from Blantyre compared with those recruited in Chikwawa.ConclusionsThe high transmission area was associated with high Tregs counts and IL-10 concentrations in convalescence, which could have an effect on parasite clearance. We recommend that children recovering from UCM, especially those from high transmission area, should sleep under insecticide-treated nets, be screened for parasitemia, and a provision of antimalarial prophylaxis should be considered.

High blood levels of IL-6 nicely correlate with animal survival in trained C26 bearing mice

Exercise is a beneficial adjunct therapy to maintain or enhance quality of life in cancer patients. Recently, few studies demonstrated a correlation between high concentrations of IL-6 and a poor survival. This depends on the equilibrium between the concentrations of IL-6 and sIL-6R. Exercise induces a beneficial increase in circulating IL-6 (1). Fresh fragments of solid C26 tumor were inoculated in healthy 3 months-old mice (n=230, M=115 and F=115). The experimental procedure were 12 weeks long. During the first 6 weeks, mice were randomly assigned to one of the experimental conditions: sedentary (SED) or progressive training (TR P ). After the first 6 weeks, all mice were inoculated with a fresh fragment of tumor. All trained adult mice after the tumor inoculation were randomly assigned to a different training program: low intensity training (TR L ), moderate intensity training (TR M ) and high intensity training (TR H ). Mice run 5 days per week on a Rota-Rod following one of the specific training program (TR P ,TR L , TR M and TR H ) (2). After tumor inoculation the mice were daily weighted and tumor size monitored until death. Moreover, 8 mice for each group were sacrificed when cachexia occurred (>9% body weight loss), and blood samples were stored for CBA Enhanced flex set flow-cytometric assays (IL-6 and TNF-alpha). The TR M and TR H training protocol performed by trained adult male mice extend the median survival compared to the sedentary adult mice and trained female mice. Interesting the beneficial effect of exercise seemed to be mediated extending the survival days. Significant high blood levels of IL-6 were recorded among the male trained mice (TR M and TR H ) groups in comparison with sedentary adult mice and trained female mice (TR M and TR H ). The results suggest that endurance exercise as adjuvant therapy is gender and physical training level specific. This effect seems to be mediated by IL-6 blood levels.

Immune environment in the knee synovial fluid of patients with spondyloarthritis involves simultaneous high percentages of Treg and Th17 cells and high concentrations of pro-inflammatory cytokines.

Immune environment in the knee synovial fluid of patients with spondyloarthritis involves simultaneous high percentages of Treg and Th17 cells and high concentrations of pro-inflammatory cytokines.

Pyodermatitis-Pyostomatitis Vegetans Associated with Crohn's Disease.

Dear Editor: Pyodermatitis-pyostomatitis vegetans (PD-PSV) is a rare, chronic, inflammatory dermatosis characterized by mucocutaneous vesiculopustular eruptions1. The cutaneous lesions present as papulopustules that coalesce to form large vegetating plaques. The oral lesions manifest friable and yellowish pustules that form a snail-track. A strong correlation of PD-PSV with inflammatory bowel disease (IBD) is well documented. Ulcerative colitis (UC) is more commonly associated with PD-PSV than Crohn's disease2. In this study, we describe a case of PD-PSV associated with Crohn's disease. A 27-year-old male patient presented with a 2-month history of bullous eruption on the whole body. Physical examination revealed annular and polycyclic erythematous vesicopustules on the face, neck, trunk, and extremities (Fig. 1A). The gingiva was involved, exhibiting coalescing pustules with a characteristic snail-track shape (Fig. 1B). The patient also had a 2-year history of Crohn's disease that has been treated with mesalazine and azathioprine. Histology revealed epidermal hyperplasia and intraepidermal neutrophilic microabscess with some eosinophils and acantholytic keratinocytes (Fig. 2). The direct and indirect immunofluorescence tests were negative for immunoglobulin (Ig) G, IgA, and C3, and the routine laboratory findings were normal except for peripheral blood eosinophilia (1,040/µl). Analysis of the serum cytokine level revealed elevated tumor necrosis factor (TNF)-α (18.55 pg/ml), interleukin (IL)-8 (8.31 pg/ml), and IL-10 (100.10 pg/ml). However, the level of interferon (IFN)-γ, IL-17A, IL-4, and IL-6 were within normal limits. A diagnosis of PD-PSV was made, and the patient was treated with prednisolone (20 mg/day), dapsone, and colchicine. The skin and oral lesions were greatly improved within 2 weeks; however, a low dose of prednisolone and dapsone was required to control the disease. Fig. 1 (A) Annular vesiculopustular eruptions on the neck. (B) Coalescing pustules with the characteristic shape of a snail-track on the gingiva. Fig. 2 Histopathology revealed (A) intraepidermal splitting (H&E, ×100), (B) with predominantly neutrophilic and eosinophilic infiltrates, with a few acantholytic cells at the level of splitting (H&E, ×200). PD-PSV is a rare inflammatory dermatosis of unknown cause. The association with IBD occurs in approximately 70% of cases2. Of the 61 cases of PD-PSV, 36 (59%) involved coexistent UC and 7 (11%) were associated with Crohn's disease. This suggests a much stronger association of PD-PSV with UC than with Crohn's disease. In most cases, gastrointestinalsymptoms of IBD precede PD-PSV. However, cutaneous lesions may precede gastrointestinal symptoms in approximately 15% of patients3, indicating the need for the evaluation for IBD even if patients with PD-PSV have no gastrointestinal symptoms. Commonly, the clinical course of PD-PSV is parallel to that of IBD. Treatment of IBD with sulfasalazine or mesalazine or surgical treatment may lead to the resolution of PD-PSV. Also, the severity of coexisting IBD has an effect on the prognosis and treatment of PD-PSV. PD-PSV should be differentiated from other blistering diseases presenting vegetating vesicopustular eruptions such as pemphigus vegetans, IgA pemphigus, subcorneal pustular dermatosis, dermatitis herpetiformis, and herpes simplex. The pustules with characteristic snail-track ulcers and the association with IBD distinguish PD-PSV from other blistering diseases. Moreover, intraepithelial and subepithelial splitting with neutrophilic and eosinophilic microabscess and negative immunofluorescence findings sug gest PD-PSV rather than other immunobullous disorders such as pemphigus. The serum cytokine profile revealed enhanced TNF-α, IL-8, and IL-10. As far as we know, this is the first report of a serum cytokine analysis in PD-PSV. TNF-α is a prominent cytokine that is associated with most inflammatory skin diseases4. The high IL-8 concentrations imply neutrophil chemotaxis, as shown by the histological findings. IL-10 is an anti-inflammatory cytokine produced by Th2 cells and regulatory T cells. Thus, the elevation of IL-10 might be paradoxical; however, IL-10 is also a potent B-cell stimulator, and high serum levels of IL-10 and IL-8 were reported in patients with UC, suggesting the close relation between PD-PSV and UC5.

Effects of High-Sugar and High-Starch Diets on Postprandial Inflammatory Protein Concentrations in Horses

Mature, nonpregnant, Thoroughbred mares were used to determine the influence of high-starch and high-sugar diets on postprandial inflammation. Plasma samples were obtained hourly from mares (n = 12) consuming one of two treatment diets, either a diet high starch and sugar (STR) or the control (CON) diet that was low in starch and sugar. Plasma was analyzed for concentrations of lipopolysaccharide (LPS) and the inflammatory cytokines interleukin (IL)-1β and IL-6. Hour 0 was included as a covariate in the statistical model, and where interactions between the covariate and other model variables existed, simple effect means were separated at three levels of the covariate: lower 95% confidence limit (CL), mean, and upper 95% CL. For horses with low (P = .016) and average (P = .065) initial LPS concentrations, LPS was greater or tended to be greater in STR compared with CON at hour 2 after feeding. No other differences were detected for LPS concentrations. For horses with low (P = .037), average (P = .006), and high (P = .001) initial IL-1β concentrations, plasma IL-1β was greater in STR than CON at hour 2 after feeding. For horses with high initial IL-1β concentrations, IL-1β also tended to be greater at hour 3 (P = .077). For horses with low (P = .022) or average (P = .063) initial IL-6 concentrations, IL-6 was greater or tended to be greater at hour 1 than 0. No effect of diet was detected for horses that started with high initial IL-6 concentrations. High-starch and high-sugar diets increase postprandial IL-1β concentrations, and it is likely that this effect is independent of LPS.

IL10 and IL10:IL6 Ratio in CSF Is Useful at Diagnosis but Also in the Assessment of Therapeutic Response in Patients with Primary Central Nervous System Lymphoma (PCNSL)

Reliable biomarkers of primary central nervous system lymphoma (PCNSL) are needed to support the magnetic resonance imaging (MRI) findings especially when the cerebral biopsy cannot be performed for pathologic examination. Biomarkers are also needed to optimize the assessment of therapeutic response, which so far relies only on gadolinium uptake on MRI, although large discrepancies of outcomes are observed in patients in complete remission assessed by MRI criteria.The aim of the present study was to evaluate the diagnostic and prognostic values of the cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and IL-6 and of the IL-10:IL-6 ratio in patients with diffuse large B-cell type (DLBCL) PCNSL, at time of diagnosis and after treatment.IL-10 and IL-6 levels were measured in 120 patients with DLBCL-PCNSL and 36 control patients with other brain tumor or inflammatory neurologic diseases, using the quantitative Cytometric Bead Array® technique (human IL-10 CBA kit and human IL-6 CBA kit; BD BiosciencesTM) on a FACSCanto II cytometer (BD BiosciencesTM) according to the manufacturer’s recommendations. Serial measures of cytokines were performed in 57 patients. The IL-10:IL-6 ratio distinguishes PCNSL from other neurological diseases. Using a cutoff level of 1.0, the sensitivity and specificity are 94% and 80% respectively. Meningeal dissemination defined by cytological examination and/or flow cytometry analysis, is significantly associated with a higher IL-10 concentration (417 pg/ml vs 22 pg/ml; p = 0.0024) and a higher IL-10:IL-6 ratio (32 vs 6 ; p = 0.0011). Previous treatment with corticosteroids significantly reduces the IL-10:IL-6 ratio (ratio=7.6 with corticosteroids vs 21.9 without corticosteroids; p= 0.02). With a median follow-up of 25 months, the pre-therapeutic concentration of IL-10 has no prognostic value on overall and progression free survivals. After treatment, the median concentration of IL-10 is significantly decreased in patients entering complete (CR) or partial response (PR) compared to non-responder patients (median = 35.9 pg/ml and 235.5 pg/ml respectively, p = 0.01). We demonstrate for the first time that among patients in CR or PR (as per MRI criteria), a persistent detectable IL-10 level in CSF (> 2,5 pg/ml) has an impact on the progression free survival (1 year PFS: 21.2 % vs 53.6%; p= 0,004) (figure 1).Our study shows that IL-10:IL-6 ratio can be used as a diagnostic biomarker for PCNSL of DLBCL type . Analysis will be done to determine the cut off values of IL10 and IL-10:IL-6 ratio in a predictive model of meningeal dissemination. We also provide evidence that IL-10 concentration may be useful to complete the assessment of therapeutic response in PCNSL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Increased Intake of Carbohydrates from Sources with a Higher Glycemic Index and Lower Consumption of Whole Grains during Puberty Are Prospectively Associated with Higher IL-6 Concentrations in Younger Adulthood among Healthy Individuals

Chronic low-grade inflammation represents a likely intermediary in the relation between carbohydrate nutrition and both type 2 diabetes and cardiovascular disease. This study assessed the prospective association between carbohydrate quantity and quality [dietary glycemic index (GI), glycemic load (GL), and added sugar, fiber, and whole-grain intake] during puberty, a potentially critical period for later disease, and low-grade inflammation in younger adulthood. The analysis was based on 205 participants (113 girls and 92 boys) from the DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) study with at least 2 3-d weighed dietary records during puberty (girls: 9–14 y, boys: 10–15 y) and blood samples in younger adulthood (18–36 y). Multivariable linear regression models were used to analyze the associations between carbohydrate nutrition and circulating concentrations of pro- and anti-inflammatory immune mediators [high-sensitivity C-reactive protein (hs-CRP), interleukin (IL) 6, IL-18, and adiponectin]. A higher intake of carbohydrates during puberty (P-trend = 0.005), particularly from higher-GI food sources (P-trend = 0.01), was prospectively related to higher concentrations of IL-6 in younger adulthood, independently of baseline BMI and early life, socioeconomic, and other nutritional factors. Furthermore, a higher dietary GL (P-trend = 0.002) and a lower intake of whole grains (P-trend = 0.01) were independently associated with higher IL-6 concentrations in adults. Dietary GI and added sugar and fiber intakes were not independently associated with IL-6 (P-trend ≥ 0.09). Carbohydrate nutrition during puberty was not independently related to hs-CRP, IL-18, and adiponectin concentrations (all P-trend > 0.1). During puberty, a higher intake of carbohydrates from higher-GI food sources and lower whole-grain consumption prospectively predict greater IL-6 concentrations in young adulthood. These data support the hypothesis that diet during puberty influences later inflammation and metabolic dysfunction.

Potent anti-inflammatory activity of betulinic acid treatment in a model of lethal endotoxemia.

Betulinic acid (BA) is a lupane-type triterpene with a number of biological activities already reported. While potent anti-HIV and antitumoral activities were attributed to BA, it is considered to have a moderate anti-inflammatory activity. Here we evaluated the effects of BA in a mouse model of endotoxic shock. Endotoxemia was induced through intraperitoneally LPS administration, nitric oxide (NO) and cytokines were assessed by Griess method and ELISA, respectively. Treatment of BALB/c mice with BA at 67 mg/kg caused a 100% survival against a lethal dose of lipopolysaccharide (LPS). BA treatment caused a reduction in TNF-α production induced by LPS but did not alter IL-6 production. Moreover, BA treatment increased significantly the serum levels of IL-10 compared to vehicle-treated, LPS-challenged mice. To investigate the role of IL-10 in BA-induced protection, wild-type and IL-10(-/-) mice were studied. In contrast to the observations in IL-10(+/+) mice, BA did not protect IL-10(-/-) mice against a lethal LPS challenge. Addition of BA inhibited the production of pro-inflammatory mediators by macrophages stimulated with LPS, while promoting a significant increase in IL-10 production. BA-treated peritoneal exudate macrophages produced lower concentrations of TNF-α and NO and higher concentrations of IL-10 upon LPS stimulation. Similarly, macrophages obtained from BA-treated mice produced less pro-inflammatory mediators and increased IL-10 when compared to non-stimulated macrophages obtained from vehicle-treated mice. In conclusion, we have shown that BA has a potent anti-inflammatory activity in vivo, protecting mice against LPS by modulating TNF-α production by macrophages in vivo through a mechanism dependent on IL-10.

Sequential determination of serum viral titers, virus-specific IgG antibodies, and TNF-α, IL-6, IL-10, and IFN-γ levels in patients with Crimean-Congo hemorrhagic fever.

BackgroundAlthough there have been a number of studies on the pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) recently, knowledge on this topic is still insufficient. This study aims to reveal the kinetics of serum CCHF virus (CCHFV) titers, serum levels of anti-CCHFV immunoglobulin (Ig)G, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and interferon (IFN)-γ in CCHF patients.MethodsIn total, 31 CCHF cases (11 fatal) were studied. Serum samples were obtained daily from all patients from the time of admission and continued for a 7-day hospitalization period for serologic (ELISA), virologic (real-time PCR), and cytokine (ELISA) analysis.ResultsThe mean serum CCHFV titer at admission was 5.5E + 09 copies/mL in fatal cases and 5.7E + 08 copies/mL in survivors (p < 0.001). Compared to survivors, both the mean serum levels of IL-6 and TNF-α at admission were found to be significantly increased in fatal cases. The serum levels of IL-6, TNF-α and serum CCHFV titer at admission were significantly and positively correlated with disseminated intravascular coagulation (DIC) scores (r = 0.626, p = 0.0002; r = 0.461, p = 0.009; and r = 0.625, p = 0.003, respectively). When the data obtained from the sequential determination of CCHFV titer and levels of anti-CCHFV IgG, IL-6, TNF-α, IL-10 and IFN-γ were grouped according to the days of illness, the initial serum CCHFV titer of a fatal patient was 5.5E + 09 (copies/mL) and it was 6.1E + 09 (copies/mL) in a survivor on the 2 day of illness. While significant alterations were observed in all cytokines during the monitoring period, IL-6 levels remained consistently higher in fatal cases and TNF-α levels increased in both in fatal and non-fatal CCHF cases.ConclusionsThe increased CCHFV load and higher concentrations of IL-6 and TNF-α, the presence of DIC, and the absence of CCHFV specific immunity are strongly associated with death in CCHF.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-416) contains supplementary material, which is available to authorized users.

Limited efficacy of intratumoral IL-2 applied to large melanoma metastases.

We recommended increased doses of 6 MIU per individual lesions larger than 2 cm [3, 4]. IL-2 has different known dose dependent, in part opposite effects, like expansion of regulatory T cells and induction of their suppressive characteristics or on the other hand activation of cellular antitumor immunity [5]. Therefore, we assume that a high concentration of IL-2 at a tumor tissue is crucial for efficacy. These high concentrations can only insufficiently be reached through systemic therapy, with its dose-limiting toxicity [6] or by low doses of IL-2 injected in large metastases. Therefore and in contrast to our initial recommendations, we currently restrict intratumoral therapy with free IL-2 to lesions up to 1 cm in longest diameter and increase the dose per lesion as tolerated up to a maximum of 18 MIU units IL-2 per day. Recurrences developing during therapy should be included in subsequent treatments as soon as these become evident. In contrast, the applied dose in the patient presented by Moreno-Ramirez et al. with 6–10 MIU IL-2 applied on two bulky lesions, each with ~5 cm diameter, seems low. Recently, the use of an antibody-based targeted version of IL-2 has exhibited promising anticancer effects in patients with stage IIIC melanoma. The use of the L19–IL2 fusion protein has allowed us to reduce the number of injections and is accompanied by favorable time-to-stage IV profiles [2]. Using this dataset, we now analyzed the rate of complete responses according to longest diameter of the lesion (Table 1). Promising complete responses were likewise observed in lesions larger than 1 cm, but due to the low number of large lesions in this trial, it is not clear whether the targeted form of IL-2 offers an advantage over free IL-2 for treatment of larger lesions. If patients present several metastases of different diameters at baseline, a combined strategy, including initial Dear Editors,