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Objective: To investigate the relationship between interferon-γ (IFN-γ), IFN-γ-producing immunocompetent cells, their related cytokines, and the clinical features in adult-onset Still's disease (AOSD)., Methods: Twenty-five patients with AOSD before initiating treatment (acute AOSD), 9 patients after remission (remission AOSD), and 12 healthy controls (HC) were included. Circulating IFN-γ-producing CD4+ and CD8+ cells, natural killer (NK) cells, and IFN-γ production in NK cells were evaluated by flow cytometry. Serum levels of IFN-γ, interleukin (IL)-6, IL-12, IL-15, and IL-18 were also measured. The obtained results were statistically analyzed with clinical findings., Results: Serum levels of IFN-γ, IL-6, IL-12, IL-18, intracellular expression of IFN-γ in CD4+, CD8+, and NK cells were significantly higher in acute AOSD than in HC. The proportion of NK cells was significantly lower in acute AOSD than in HC. Serum levels of IFN-γ and IFN-γ expression in CD4+ cells were significantly correlated with serum ferritin levels. The proportion of NK cells had a significant inverse correlation with serum IFN-γ levels. A lower proportion of NK cells was significantly noted in patients refractory to initial immunosuppressive treatment. In remission AOSD, serum levels of IL-6, IL-12, and IL-18 were significantly higher than in HC., Conclusion: Increased serum levels of IFN-γ, increased expression of IFN-γ in CD4+ cells, and decreased NK cell proportion correlate with disease activity in AOSD. Moreover, a lower proportion of NK cells may be useful for predicting a refractory clinical course. Meanwhile, increased serum levels of IL-6, IL-12, and IL-18 may persist after clinical remission., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Clinical reports on early immune dysregulation in acute pancreatitis (AP) are scarce. Herein we investigate the initial temporal development of selected biomarkers. Blood samples were taken at 0-24 and 25-48 h after onsets of AP were acquired. Mean values and temporal intermediate difference (delta-values) of IL-1β, IL-6, IL-8, IL-10, IL-12, IFN-γ and TNF-α were calculated. Differences between severity groups, predictive capacity of the biomarkers and association with severe disease were analyzed. Paired comparison of samples (n = 115) taken at 0-24 and 25-48 h after onsets of AP showed a change over time for IL-1β, IL-6, IL-8 and IL-10 ( p < 0.05) and a significant difference between severity groups after 24 h. In ROC-analysis an IL-6 cut-off level of 196.6 pg/mL could differentiate severe AP (sensitivity 81.9, specificity 91.3). The delta-values of IL-1β and IL-6 were significantly associated with severe outcomes (odds ratios 1.085 and 1.002, respectively). Data of this work demonstrate a distinct change in IL-1β, IL-8, IL-10 and IL-6 over the first 48 h after onset of AP. The temporal development of biomarkers can assist in the early stratification of the disease. Herein IL-1β and IL-6 were associated with severe disease, however the prognostic capacity of investigated biomarkers is low.

Background: Inflammatory cytokines participate in immune reactions and the pathogenesis of autoimmunity. Herein, we quantified four groups of inflammatory cytokines, including interferons (IFNs), the tumor necrosis factor (TNF) superfamily (TNFSF), interleukin (IL)-related cytokines, and bone and extracellular matrix remodeling-related cytokines to determine their contributions in women with overt Graves' disease (GD)., Methods: Forty-three women with GD were enrolled in this cross-sectional study. Thirty-seven cytokines, thyroid-stimulating hormone (TSH), free thyroxine, and TSH receptor antibody (TSHRAb) were quantified. GD patients with a low TSH level at the time of sample collection were defined as having active GD., Results: Patients with active GD had higher IFN-α2, IFN-γ, IFN-λ1, and IFN-λ2 levels than those with inactive GD. In addition, certain TNFSF cytokines, including soluble cluster of differentiation 30 (sCD30), TNFSF member 14 (TNFSF14), pentraxin (PTX)-3, soluble TNF receptor 2 (sTNF-R2), and thymic stromal lymphopoietin (TSLP) were higher in active GD than in inactive GD. Moreover, active GD patients had higher IL-2, IL-12(p40), osteocalcin (OCN), and matrix metalloproteinase (MMP)-3 than inactive GD patients. All IFNs except IFN-λ1 were correlated with TSHRAb titers. Moreover, TNFSF cytokines, consisting of B-cell-activating factor, sCD30, TNFSF14, PTX-3, sTNF-R2, and TSLP, were associated with TSHRAb levels., Conclusions: Serum IFNs could be the most remarkable cytokines in modulating the disease severity and TSHRAb titers in women with full-blown GD. Further molecular-based research to clarify the actual role of IFNs in the disease progression of GD is needed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In this study, we examined the differential associations of various proinflammatory and anti-inflammatory cytokines with depression severity from the development of breast cancer to subsequent chemotherapy treatment., Methods: A cross-sectional study was conducted on a sample of 116 women: 29 controls without cancer, 55 patients with breast cancer who were not receiving chemotherapy, and 32 patients with breast cancer who were receiving chemotherapy. Blood samples were assayed to evaluate serum levels of the following cytokines: interferon-γ, interleukin (IL)-12 (p70), IL-1β, IL-2, tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-10, IL-13, IL-6, and IL-17A. Depression severity was assessed using the Patient Health Questionnaire., Results: After adjustment for sociodemographics, consistent patterns of the association between cytokine and depression were noted in the different groups. No significant associations were observed in the controls. Inverse associations were observed between cytokines levels and depression severity in patients with breast cancer who were not receiving chemotherapy, whereas positive associations were noted in patients with breast cancer who were receiving chemotherapy. Specific differential relationships between IL-5 levels and depression severity were found between patients with breast cancer who were receiving and not receiving chemotherapy., Conclusions: Our study revealed differential relationships between cytokine levels and depression severity with the development of cancer. Immunostimulation and immunosuppression in breast cancer and cancer treatment may account for the differential responses with the development of breast cancer.

Objective: Pre-eclampsia (PE) is a common multi-systemic disease, and the effect of cytokines on PE is not clear. The purpose of this meta-analysis was to evaluate the circulating levels of interferon gamma (IFN-γ), interleukin (IL)-1, IL-17 and IL-22 in patients with PE., Study Design: Relevant studies were identified after a preliminary investigation of studies published up to May 2019 using PubMed and Embase. In this study, all 27 included articles underwent quality rating, with a total of 495 patients with PE and 557 controls. Among them, eight papers and 932 subjects contributed to the meta-analysis of IFN-γ, and six papers and 343 subjects contributed to the meta-analysis of IL-17. Based on the inclusion and exclusion criteria, the retrieved papers were screened and evaluated independently. Relevant data for IFN-γ and IL-17 were extracted for meta-analysis and subgroup analysis, and the stability of the results was evaluated by sensitivity analysis. At the same time, a systematic evaluation was carried out for IL-1 and IL-22 with a small number of included papers., Results: Several papers included in the systematic review showed that the circulating levels of IL-22 were higher in patients with severe PE than in controls, while IL-1 levels did not differ significantly between the two groups. The meta-analysis showed that patients with PE had higher circulating levels of IFN-γ than controls [standardized mean difference (SMD) 1.45, 95 % confidence interval (CI) 0.56-2.34]. There was no evidence of a difference in the circulating levels of IL-17 between patients with PE and controls (SMD 0.53, 95 %CI -0.43 to 1.48)., Conclusion: This meta-analysis suggested that changes in circulating levels of IFN-γ might be associated with PE., Competing Interests: Declaration of Competing Interest All the authors declare that they have no potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Probiotics and prebiotics, which are multifunctional agents, have potential benefits in chronic mucosal inflammation, including the prevention of necrotizing enterocolitis. However, the mechanisms and the results of these immunomodulatory effects are not clear. This study aimed to investigate the cytokine response to the combination of Lactobacillus and Bifidobacterium together with fructo- and galacto-oligosaccharides (symbiotic) and lactoferrin in very low birth weight neonates., Population and Methods: Infants ≤ 32 GWs and ≤ 1,500 g were randomly assigned to receive a symbiotic combination or 1 ml distilled water as placebo starting with the first feed until discharge. Blood samples were obtained at postnatal 0 ± 2, 14 ± 2, and 28 ± 2 days, and the serum levels of interferon-y, interleukin (IL)-5, IL-10, and IL-17A were measured., Results: In the study group (n = 25), the IL-10 levels decreased throughout the study period (p = 0.011) but did not change in the control group. The IL-5 levels remained steady in the first 14 days and decreased significantly thereafter (p = 0.042) in the study group, whereas they increased in the first 14 days (p = 0.019), and then decreased in 28 days (p = 0.011) in the control group (n = 25). The levels of the other cytokines did not change throughout the study period., Conclusion: The combined use of probiotics with oligosaccharides and lactoferrin was associated with a decrease in IL-10 levels, but no change was observed in the other cytokines., Competing Interests: The preparation and ELISA kits were supplied from Nobel pharmacy Inc., (Sociedad Argentina de Pediatría.)

This study aimed to investigate the therapeutic effect of fasudil on treating experimental autoimmune neuritis (EAN). Twenty-four EAN mice were randomly assigned to fasudil treatment (Fasudil group) or saline treatment (EAN model group) for 28 days. Clinical symptom score was evaluated every other day; inflammatory cell infiltration, demyelination, anti-myelin basic protein (MBP), inflammatory cytokines, inducible nitric oxide synthase (iNOS), and arginase-1 were detected in sciatic nerves at day 28. Th1, Th2, Th17, and Tregs proportions in splenocytes were detected at day 28. Clinical symptom score was found to be attenuated in the Fasudil group compared to the EAN model group from day 12 to day 28. Sciatic nerve inflammatory cell counts by HE staining and demyelination by luxol fast blue staining were both reduced, while MBP was increased in the Fasudil group compared to the EAN model group at day 28. Interferon γ (IFN-γ) and interleukin (IL)-17 were reduced, while IL-4 and IL-10 were elevated in the Fasudil group at day 28. Sciatic nerve M1 macrophages marker iNOS was decreased while M2 macrophages marker arginase-1 was increased in the Fasudil group at day 28. CD4+IFN-γ+ (Th1) and CD4+IL-17+ (Th17) cell proportions were both decreased, CD4+IL-4+ (Th2) cell proportion was similar, while CD25+FOXP3+ (Treg) cell proportion in splenocytes was increased in the Fasudil group. In summary, fasudil presented a good therapeutic effect for treating EAN by attenuating Th1/Th17 cells and promoting Tregs activation as well as M2 macrophages polarization.

Following recent attention focused on IL-32 as an important component involved in the inflammatory cytokine network, we speculated that IL-32's action on IFN-γ and IFN-γ secreting T cell subsets may help sustain the immune activation and dysregulation found in patients with HIV-1 achieving viral suppression. To explore this hypothesis, transcript levels of IL-32 and IFN-γ were evaluated in PBMC from 139 virologically suppressed HIV-1-infected patients and from 63 healthy individuals by Real Time RT-PCR assays. IL-32 and IFN-γ mRNA levels were also analyzed in CD4+ T cells, CD14+ monocytes and lamina propria lymphocytes (LPL) of the gut district in a subgroup of HIV-1-infected subjects. IFN-γ secreting CD4+ (Th1) and CD8+ (Tc1) T cell subset frequencies were evaluated in LPL by multiparametric flow cytometry. Gene expression results revealed that IL-32 and IFN-γ levels in PBMC from HIV-1-positive patients were significantly elevated compared to those from healthy donors, correlated with each other and increased with patient age. Both IL-32 and IFN-γ genes were also more strongly expressed in CD4+ T cells than in CD14+ monocytes. By contrast, IL-32 levels in LPL were comparable to those measured in PBMC, while IFN-γ levels were higher in PBMC than those in LPL. Negative correlations were found between IL-32 levels and the frequencies of Th1 and Tc1 subsets in gut mucosa. Collectively, our results provide the first evidence that IL-32 levels remain elevated in treated HIV-1-infected patients and correlate with IFN-γ, Th1 and Tc1 subsets., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Success with calcineurin inhibitors (CNIs) such as cyclosporine A (CSA) and tacrolimus (TAC) in organ transplantation has demonstrated that cytokine suppression is a key factor in patient management. However, the exact effects of recently introduced immunosuppressive agents other than CNI on cytokine expression remain unknown. In this study, the action of the mTOR-inhibitor everolimus (EVR) and that of the antimetabolite mycophenolic acid (MPA) on the transcription of several cytokines was investigated., Methods: Peripheral blood mononuclear cells obtained from healthy volunteers were stimulated with anti-CD3/28 microbeads in the presence of CSA, TAC, EVR, and/or MPA for 8 hours. The mRNA levels of each cytokine were measured using quantitative real-time polymerase chain reaction., Results: MPA had no inhibitory effect on any of the cytokines tested. EVR showed moderate inhibition of IL-2, IL-10, IL-21, and IFNγ levels. These cytokines were further analyzed to investigate the additive effect of EVR in combination with CNI. The beneficial effect of EVR addition was seen at low concentrations of CSA or TAC, while no additive effect was observed at high concentrations., Conclusions: EVR might effectively inhibit the activation of recipient immune cells in combination with a low dose of CNI, maximizing clinical benefit by preventing graft rejection and alleviating CNI-induced adverse effects.

Background: Few studies showed the changes in cytokine profiles after infection by hepatitis B virus (HBV), the most common viral liver disease worldwide. This study examined the relationship between interleukin (IL)-32, IL-1, and interferon (IFN)-γ levels and HBV load., Methods: IL-32, IL-1, and IFN-γ levels in hepatitis B patients serum and HBV-stimulated PBMCs were measured by ELISA. Gene transcripts in PBMCs from hepatitis B patients and HBV-stimulated PBMCs from healthy controls were measured by real-time PCR., Results: IL-32, IL-1, and IFN-γ protein levels in serum from hepatitis B patients were significantly higher than those in healthy volunteers (P<0.05). Hepatitis B patients showed significantly higher expression of IL-32, IL-1, and IFN-γ transcripts than healthy volunteers (P<0.05). IL-32, IL-1, and IFN-γ levels in PBMCs stimulated by different amounts of HBV were significantly higher than those in HBV-unstimulated PBMCs (P<0.05). Real-time PCR results were consistent with the ELISA results., Conclusions: The levels of IL-32, IL-1, and IFN-γ protein and transcripts in serum and PBMCs from hepatitis B patients were higher than those in healthy volunteers. Similarly, both were higher in PBMCs from healthy volunteers stimulated by HBV in vitro. However, the changes in cytokine levels were not proportional to the viral load., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The severity of cardiac disease in chronic Chagas disease patients is associated with different features of T-cell exhaustion. Here, we assessed whether the ability of T cells to secrete IFN-γ in response to T. cruzi was linked to disruption in immune homeostasis and inflammation in patients with chronic Chagas disease., Methodology/principal Findings: PBMCs from chronic Chagas disease patients and uninfected controls were examined for frequencies of T. cruzi-responsive IFN-γ-producing cells by ELISPOT and cellular expression and function of IL-7R using flow cytometry. Serum levels of IL-7, IL-21, IL-27, soluble IL-7R, and inflammatory cytokines were also evaluated by ELISA or CBA techniques. Patients possessing T. cruzi-specific IFN-γ-producing cells (i.e. IFN-γ producers) had higher levels of memory T cells capable of modulating the alpha chain of IL-7R and an efficient response to IL-7 compared to that in patients lacking (i.e. IFN-γ nonproducers) parasite-specific T-cell responses. IFN-γ producers also showed low levels of soluble IL-7R, high basal expression of Bcl-2 in T cells and low basal frequencies of activated CD25+ T cells. Modulation of IL-7R was inversely associated with serum IL-6 levels and positively associated with serum IL-8 levels. Circulating IL-21 and IL-27 levels were not associated with the frequency of IFN-γ producing cells but were reduced in less severe clinical forms of the disease. In vitro stimulation of PBMCs with IL-7 or IL-27 enhanced IFN-γ production in IFN-γ producers but not in IFN-γ nonproducers., Conclusions/significance: Alterations of the IL-7/IL-7R axis and in the levels of inflammatory cytokines were linked to impaired T. cruzi-specific IFN-γ production. These alterations might be responsible of the process of immune exhaustion observed in chronic Chagas disease., Competing Interests: The authors have declared that no competing interests exist.

Foot and mouth disease (FMD) is one of the most contagious diseases of cloven footed animals causing significant economic impediment in livestock production system. The immune response to FMD virus (FMDV) infection is regulated by a complex interplay between various cells, cytokines and other immune components. Based on the well established role of Interferon-gamma (IFN-γ) and Interleukin-21 (IL-21) in viral infections, this study aimed to determine expression level of these cytokines in clinically infected adults and calves; and the results were compared with those in the subclinically infected animals up to 120 days post outbreak (DPO) in a vaccinated cattle herd. The expression level of IFN-γ and IL-21 was assayed on 0, 7, 14, 28, 60, 90, and 120 DPO by enzyme linked immunosorbent assay (ELISA) with simultaneous assessment of FMDV structural protein-antibody titer against serotype 'O' by liquid phase blocking ELISA (LPBE) and nonstructural protein-antibody, a differential marker of infection, using r3AB3 indirect ELISA (r3AB3 I-ELISA). Although, the peak expression of IFN-γ was observed on 14 DPO across all categories of animals, the clinically infected animals registered a significant increase in IFN-γ level as compared to the subclinically infected population possibly due to the difference in the extent of virus replication and inflammation. The IL-21 level increased significantly during 14-28 DPO and highest expression was noticed on 28 DPO. The increase in the expression level of IFN-γ and IL-21 at 28 DPO correlated with the increase in antibody titer as determined by LPBE suggesting the role of these cytokines in augmenting immune response to FMDV infection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A chicken multiplex cytokine assay (Bio-Plex) to detect four different cytokines (IL-2, IL-12, IL-10, and interferon gamma) simultaneously in plasma samples was designed. Most standard curves range between 1 to 5 pg/mL and 5,000 pg/mL, except for IFNγ with the range of 50 to 25,000 pg/mL. Such a chicken multiplex assay proved to be fast and reliable, and comparable in sensitivity, accuracy, and reproducibility to conventional enzyme-linked immunosorbent assays. Comparison of the multiplex assay with the ELISA technique using the same clones of detection and capture antibodies resulted in correlation coefficients for all cytokines ranging from 0.95 to 0.99. Lower limit of detection and limit of quantification values were obtained for all tested cytokines by the Bio-Plex assay compared with ELISA. To reduce the risk of cross-reaction with other proteins, the Bio-Plex system was used, combining the principle of sandwich immunoassay with the Luminex bead-based technology. The cytokine standard recoveries for each cytokine varied between 86 and 118% in dynamic concentration ranges. A chicken multiplex cytokine assay (Bio-Plex) provided a more complete picture of differences between the Th1/Th2 cytokine profiles of the immunized via a new system of antigen delivery into chicken antigen-presenting cells and control groups. This multiplexed fluorescent-bead-based detection assay can be used as a quantitative or comparative tool for the study of the chicken ex vivo cellular immune response.

Background: We aimed in our study to research the role of new cytokines such as IL-35, IL-22, and IL-17 that may form a target for novel treatment approaches., Methods: IL-10, IL-17, TGF- β , IFN- γ , IL-22, and IL-35 serum levels of allergic rhinitis (AR) patients were measured using ELISA method. Allergic sensitization was demonstrated by the skin prick test. Patients only with olive tree sensitivity were evaluated for seasonal AR (SAR). Patients only with mite sensitivity were included in the study for perennial AR (PAR). AR clinic severity was demonstrated by the nasal symptom scores (NSS)., Results: In total, 65 AR patients (patient group), having 31 PAR and 34 SAR patients, and 31 healthy individuals (control group) participated in the study. Cytokine levels between the patient group and the control group were compared; IL-17 ( p = 0.038), IL-22 ( p = 0.001), and TGF- β ( p = 0.031) were detected as high in the patient group, and IFN- γ ( p < 0.001) was detected as low in the patient group. When correlation analysis was made between age, gender, prick test result, NSS, AR duration, and cytokine levels in the patient group, a negative correlation was detected only between IFN- γ ( p = 0.032/ r = -0.266) level and NSS., Conclusions: Accompanied by the literature information, these results made us think that T cell subgroups and cytokines have an important role in AR immunopathogenesis. It is thought that future studies to be conducted relating to this subject will form new targets in treatment.

Objective: To explore the levels of T-lymphocyte subsets and IL-17, IL-35, IFN-γ in peripheral blood of patients with multiple myeloma(MM) and their clinical significance., Methods: A total of 86 MM patients in our hospital from January 2014 to January 2017 were enrolled in MM group and 30 healthy persons were enrolled in control group, the CD4 + /CD8 + T cells ratio, CD4 + CD25 high/+ CD127 low/- Treg level in peripheral blood were detected by flow cytometer. The levels of IL-17, IL-35 and IFN-γ in peripheral serum were detected by ELISA, and the differences of detected indicators between different groups were compared., Results: Compared with control group, the proportion of CD4 + T cells and CD4 + /CD8 + T cells ratio decreased, the proportion of CD8 + T cells and Treg increased in MM group. The differences of T lymphocyte subsets level between group III stage of MM and control group were statistically significant (P<0.05). With enhancing of clinical stages, Treg level showed a increasing trend, especially in III stage (P<0.05), the serum level of IL-17 as followed in turn: III stage>II stage>I stage>control, the serum level of IL-35 and IFN-γ as followed in turn: control>I stage>II stage>III stage (P<0.05). In terms of disease status, the propurtion of Treg cells as fllowed in turn: disease progression stage>stable stage>control (P<0.05), the serum level of IL-17 as followed in turn also: disease progression stage>stable stage (P<0.05), while the serum level of IL-35 and IFN-γ as followed in turn: control>disease table stage>progression stage (P<0.05)., Conclusion: The abnomal level of T-lymphocyte subsets, Treg, IL-17, IL-35 and IFN-γ are related with progression and prognosis of MM patients.

Various inflammation parameters are increased with childhood obesity, but few comparable data are found in lean growing athletes. This study aims to characterize differences in 12 simultaneously measured inflammatory parameters between pubertal rhythmic gymnasts (RG) and untrained controls (UC), and to examine the relationship between body composition and inflammatory markers. Sixty 10-12-year-old girls were divided into RG (n = 30) and UC (n = 30). Fat mass (FM) and fat free mass (FFM) were measured by dual-energy X-ray absorptiometry. Leptin and 12 inflammatory parameters (interleukin [IL]-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor, interferon-gamma [IFN-γ], tumor necrosis factor-alpha, IL-1α, IL-1β, monocyte chemotactic protein-1 and epidermal growth factor) were measured from fasting blood samples. No differences were seen in 12 inflammatory markers between studied groups. As expected, leptin (RG: 2.4 ± 1.1; UC: 7.6 ± 4.2 ng ml -1 ) and FM (RG: 7.3 ± 2.3; UC: 11.8 ± 5.1 kg) were lower (p < .05) in RG compared to UC. In the whole group of lean pubertal girls, 69.0% of the variability in body FM was determined by leptin, and 11.2% of the variability in body FFM was explained by IFN-γ. In conclusion, measured 12 inflammatory biomarkers were not different between RG and UC, despite lower leptin and FM in RG. In lean pubertal girls, IFN-γ was independently associated with FFM, and leptin with FM.

Objectives: This study aimed to evaluate serum cytokine concentrations in healthy individuals and laryngeal squamous cell carcinoma patients., Methods: A total of 59 laryngeal squamous cell carcinoma patients and 44 healthy controls were included. Multiplex analysis of interleukins 2, 4, 5, 6, 10, 12, 13 and 17 and interferon-gamma with respect to the presence of laryngeal carcinoma, tumour-node-metastasis T stage, nodal involvement and larynx subsite was performed., Results: Statistical analysis revealed no difference in serum cytokine levels between patients and healthy controls. The serum interleukin-12 concentration was significantly higher in patients with early (T1-2) than in those with late (T3-4) stage disease and without nodal involvement (p < 0.05). Serum interleukin-10 levels were significantly higher in T3-4 stage than in T1-2 stage patients (p < 0.05). Additionally, serum interleukin 10, 12 and 13 concentrations (p < 0.05) and interleukin-6 concentration (p < 0.01) were significantly higher in patients with T1-2 stage supraglottic vs glottic tumours., Conclusion: Serum cytokines level cannot be used as laryngeal squamous cell carcinoma markers. Progression from T1-2 to T3-4 stage is followed by decreased serum interleukin-12 levels and increased interleukin-10 levels. Nodal involvement is associated with lower serum interleukin-12 levels. In patients with early stage tumours, serum interleukin 6, 10, 12 and 13 concentrations are significantly higher in those with supraglottic vs glottic tumours.

A defective chemokine motif in the HIV-1 Tat protein has been hypothesized to alter central nervous system cellular trafficking and inflammation, rendering HIV-1 subtype C less neuropathogenic than B. To evaluate this hypothesis, we compared biomarkers of cellular chemotaxis and inflammation in cerebrospinal fluid (CSF) and serum in individuals infected with HIV-1 subtypes B (n = 27) and C (n = 25) from Curitiba, Brazil. None had opportunistic infections. Chemokines (MCP-1, MIP-1α, MIP-1β, RANTES, IP-10) and cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-10) were measured using the multiplex bead suspension array immunoassays or ELISA HD. CSF and serum biomarker concentrations were compared between subtype B and C groups and HIV-positive and HIV-negative subjects (N = 19) using an independent group t test (unadjusted analysis) and linear regression (adjusted analysis), controlling for nadir CD4 and CSF and plasma HIV RNA suppression. CSF levels of cytokines and chemokines were significantly (p < 0.05) elevated in HIV-positive versus HIV-negative participants for 7/13 biomarkers measured, but levels did not differ for subtypes B and C. Serum levels were significantly elevated for 4/13 markers, with no significant differences between subtypes B and C. Although pleocytosis was much more frequent in HIV-positive than in HIV-negative individuals (27 vs. 0 %), subtypes B and C did not differ (32 and 22 %; p = 0.23). We did not find molecular evidence to support the hypothesis that intrathecal chemotaxis and inflammation is less in HIV-1 subtype C than in subtype B. Biomarker changes in CSF were more robust than in serum, suggesting compartmentalization of the immunological response to HIV., Competing Interests: SERGIO M. DE ALMEIDA , the author declare that have no conflict of interest. YANXIN JIANG , the author declare that have no conflict of interest. INDIANARA ROTTA, the author declare that have no conflict of interest. XIAO LI , the author declare that have no conflict of interest. SONIA M. RABONI , the author declare that have no conflict of interest. CLEA E. RIBEIRO , the author declare that have no conflict of interest. DAVEY SMITH , the author declare that have no conflict of interest. MICHAEL POTTER , the author declare that have no conflict of interest. FLORIN VAIDA , the author declare that have no conflict of interest. SCOTT LETENDRE , the author declare that have no conflict of interest. RONALD J. ELLIS , the author declare that have no conflict of interest.

Objectives: Small-for-gestational-age (SGA) results from abnormalities of the feto-placental-maternal unit. Cytokine profiles during early pregnancy may predict placental changes that lead to SGA, however it is unknown if these altered profiles precede conception. We examined the role of maternal cytokines prior to conception as risk factors for subsequent delivery of an SGA infant., Methods: We included a sample of 80 women and their offspring from a large trial of pre-conceptual multiple micronutrient supplementation. Plasma samples collected before conception were tested with a high sensitivity multiplex assay for IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IFNγ, and TNFα., Results: Pre-conceptual IL-13 and IFNγ were lower in women who gave birth to an SGA child than among control women (0.81 versus 1.14 pg/ml and 7.81 versus 11.01 pg/ml, respectively). Multivariable logistic regression showed that IL-13 (p = 0.029) and IFNγ (p = 0.015) were both inversely associated with SGA., Conclusions: These results suggest maternal immune function prior to conception may indicate an unfavorable immune balance leading to placental abnormalities and high risk of SGA. Preconception assessment of cytokine profiles could potentially contribute to early detection of SGA and to the timely implementation of interventions to prevent it.

Material and Methods: This cross-sectional study included 91 patients with stable CAD who had been under optimized cardiovascular care. Blood levels of IL-1β, IL-6, IL-8, IL-10, IFN-γ, and TNF-α were measured by Luminex technology. A full-mouth periodontal examination was conducted to record probing depth (PD) and clinical attachment (CA) loss. Multiple linear regression models, adjusting for gender, body mass index, oral hypoglycemic drugs, smoking, and occurre:nce of acute myocardial infarction were applied., Results: CAD patients that experienced major events had higher concentrations of IFN-γ (median: 5.05 pg/mL vs. 3.01 pg/mL; p=0.01), IL-10 (median: 2.33 pg/mL vs. 1.01 pg/mL; p=0.03), and TNF-α (median: 9.17 pg/mL vs. 7.47 pg/mL; p=0.02). Higher numbers of teeth with at least 6 mm of CA loss (R2=0.07) and PD (R2=0.06) were significantly associated with higher IFN-γ log concentrations. Mean CA loss (R2=0.05) and PD (R2=0.06) were significantly related to IL-10 concentrations. Elevated concentrations of TNF-α were associated with higher mean CA loss (R2=0.07)., Conclusion: Periodontal disease is associated with increased systemic inflammation in stable cardiovascular patients. These findings provide additional evidence supporting the idea that periodontal disease can be a prognostic factor in cardiovascular patients.

Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-γ, interleukin-2, and TNF-alpha; (2)Th2-mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin-10 and (3)immuno-modulatory cytokines: interleukin-1β, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-γ concentrations at specific time points but also the total IFN-γ amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-γ levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-γ cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-γ concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response.

Background and Objectives: Approximately one-third of hepatitis C virus (HCV) infected patients who complete antiviral therapy with undetectable serum HCV RNA at the end of therapy (ETR), will experience relapse. The reasons for the failure of treatment have not been elucidated. It was showed that HCV RNA can persist and replicate in extra hepatic sites, e.g. in peripheral blood mononuclear cells (PBMCs), but the relevance of its presence with relapse over time is still unknown. Moreover, interferon-gamma (IFN-γ) and IFN-lambdas [IFN-λ1, interleukin-29 (IL-29)], possess potent antiviral activity. We studied if the presence of plus-/minus strand RNA in PBMCs of patients and the serum level of IFN-γ and IL-29, which is the most abundant IFN-lambdas in serum, can be considered as predictive factors in relapse outcomes., Methods: Patients were screened for plus-/minus strand RNA at ETR and after 6 months. Also, we measured the serum level of IFN-γ and IL-29 and compared the result with those who developed a sustained virological response (SVR)., Results: Levels of IL-29 and IFN-? serum were significantly higher in SVR at ETR and 6 months later compared to those of the relapsed patients, but there was no difference between the two groups regarding the presence or absence of plus-/minus HCV strand in PBMCs., Conclusions: Our novel findings showed that the serum level of IL-29 and IFN-γ are predictive of relapse outcomes to HCV treatment, but there was no association between the presence of plus-γminus HCV RNA in PBMCs of patients with an outcome of therapy at ETR and later.

Rationale: Current immunodiagnostic tests for tuberculosis (TB), including the tuberculin skin test and IFN-γ release assay (IGRA), have significant limitations, which include their inability to distinguish between latent TB infection (LTBI) and active TB, a distinction critical for clinical management., Objectives: To identify mycobacteria-specific cytokine biomarkers that characterize TB infection, determine their diagnostic performance characteristics, and establish whether these biomarkers can distinguish between LTBI and active TB., Methods: A total of 149 children investigated for TB infection were recruited; all participants underwent a tuberculin skin test and QuantiFERON-TB Gold assay. In parallel, whole-blood assays using early secretory antigenic target-6, culture filtrate protein-10, and PPD as stimulatory antigens were undertaken, and cytokine responses were determined by xMAP multiplex assays., Measurements and Main Results: IFN-γ, interferon-inducible protein-10 (IP-10), tumor necrosis factor (TNF)-α, IL-1ra, IL-2, IL-13, and MIP-1β (macrophage inflammatory protein-1β) responses were significantly higher in LTBI and active TB cases than in TB-uninfected individuals, irrespective of the stimulant. Receiver operating characteristic analyses showed that IP-10, TNF-α, and IL-2 responses achieved high sensitivity and specificity for the distinction between TB-uninfected and TB-infected individuals. TNF-α, IL-1ra, and IL-10 responses had the greatest ability to distinguish between LTBI and active TB cases; the combinations of TNF-α/IL-1ra and TNF-α/IL-10 achieved correct classification of 95.5% and 100% of cases, respectively., Conclusions: We identified several mycobacteria-specific cytokine biomarkers with the potential to be exploited for immunodiagnosis. Incorporation of these biomarkers into future immunodiagnostic assays for TB could result in substantial gains in sensitivity and allow the distinction between LTBI and active TB based on a blood test alone.

Imbalance of T-helper-cell (TH) subsets (TH1/TH2/TH17) and regulatory T cells (Tregs) is suggested to contribute to the pathogenesis of osteoporosis. Broken TH17/Treg balance has been reported contributing to several inflammatory diseases. Although bisphosphonates are well-recognized inhibitors of osteoclastic activity, there is no serious examination of their effect on T cell subset (TH1/TH2/TH17/Treg) balances. Patients were categorized into 20 osteopenic and 20 osteoporotic patients treated with bisphosphonates for 1 year. We studied plasma levels of interleukins 4 (IL-4), IL-6, IL-10, IL-12, IL-17, IL-23, and interferon-gamma (IFN-γ), and transforming growth factor-beta (TGF-β) and their interrelations and correlation with osteoporosis treatment were evaluated. Treated osteoporotic patients have a significant reduction of plasma IL-6 (p < 0.05), IL-17 (p < 0.05), IL-23 (p < 0.05), and IFN-γ (p < 0.05), a significant increase in IL-4 (p < 0.05), IL-10 (p < 0.05), and TGF-β (p < 0.001), and comparable IL-12 levels as compared to controls. In conclusion, the significant reduction of Th17 cell cytokine cascade (IL-6, IL-17, and IL-23) and elevation of Treg cytokine cascade (IL-10 and TGF-β) might be considered as a very important observation about the effect of bisphosphonates on TH17/Treg imbalance in osteoporosis.

Cryptococcal meningitis (CM) remains as common life-threatening AIDS-defining illness mainly in resource-limited settings. Previous reports suggested that baseline cytokine profiles can be associated to fungal burden and clinical outcome. This study aimed to evaluate the baseline cytokine profiles in AIDS patients with CM and its relation with the outcome at weeks 2 and 10. Thirty AIDS patients with CM diagnosed by cerebrospinal fluid (CSF) Cryptococcus neoformans positive culture, India ink stain and cryptococcal antigen test were prospectively evaluated. As controls, 56 HIV-infected patients without CM and 48 non-HIV individuals were included. Baseline CSF and sera levels of IL-2, IL-4, IL-8, IL-10, IL-12p40, IL-17A, INF-γ and TNF-α were measured by ELISA. Of 30 CM patients, 24 (80%) were male, median age of 38.1. The baseline CSF high fungal burden and positive blood culture were associated with a positive CSF culture at week 2 (p = 0.043 and 0.029). Most CSF and sera cytokines presented higher levels in CM patients than control subjects (p < 0.05). CSF levels of IL-8, IL-12p40, IL-17A, TNF-α, INF-γ and sera TNF-α were significantly higher among survivors at weeks 2 and 10 (p < 0.05). Patients with increased intracranial pression exhibited CSF IL-10 high levels and poor outcome at week 10 (p = 0.032). Otherwise, baseline CSF log10 IFN-γ and IL-17A were negatively correlated with fungal burden (r = -0.47 and -0.50; p = 0.0175 and 0.0094, respectively). The mortality rate was 33% (10/30) at week 2 and 57% (17/30) at week 10. The severity of CM and the advanced immunodeficiency at admission were related to a poor outcome in these patients. Otherwise, the predominant Th1 cytokines profile among survivors confirms its pivotal role to infection control and would be a prognostic marker in cryptococcal meningitis.

Purpose: To evaluate the Th1/Th2/Th17 cytokine levels in plasma and gingival crevicular fluid (GCF) from chronic periodontitis patients and healthy controls., Methods: The concentration of interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-17, TNF, and IFN-γ were determined using a flow cytometric multiplex immunoassay (CBA), and was compared between the periodontitis group and the healthy group. Spearman rho coefficient was used to correlate cytokines in GCF in the periodontitis group and the healthy group, respectively., Results: Comparisons of two groups of Th1/Th2/Th17 cytokine levels in plasma and GCF showed no statistically significant differences (P > 0.05), except Th17 (IL-17) level in plasma that was higher in the periodontitis group than the healthy group (P < 0.05). A stronger correlation between IL-17/IL-4 and IL-17/IL-10 was observed in periodontitis patients than in healthy controls.

Background: Interferon (IFN)-λ1 is a newly described cytokine, member of type III interferons family, which is known for its antiviral, anti-proliferative and antitumor activity. Recent studies indicated that this cytokine has also immune-regulatory function, but its role in the pathogenesis of autoimmune diseases is not established yet. We evaluated serum levels of IFN-λ1 in systemic sclerosis (SSc) patients and healthy controls and its association with IFN-γ and clinical manifestations., Methods: IFN-λ1 and IFN-γ serum levels were measured by ELISA from 52 patients with SSc and 53 healthy controls. Association of cytokines serum levels was sought with clinical parameters., Results: IFN-λ1 and IFN-γ levels in SSc patients were significantly higher than those in healthy individuals (24.82 ± 8.78 and 11.04 ± 3.04 pg/ml, p < 0.0001; 34.11 ± 8.11 and 10.73 ± 2.77 pg/ml, p < 0.0001, respectively). We found a positive correlation between IFN-λ1 and IFN-γ levels in SSc patients (p = 0.0103, r = 0.3526). IFN-γ levels were associated with muscle involvement (p = 0.0483)., Conclusion: We first showed raised IFN-λ1 levels in SSc patients. Furthermore, we found a correlation between IFN-λ1 and IFN-γ levels and an association between IFN-γ and myositis. Additional in vitro and in vivo studies are needed to understand IFN-λ1 role in SSc.

Objective: To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue., Methods: Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34) and fatigued (CIS20r fatigue ≥35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs., Results: Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age., Conclusion: The pro-inflammatory cytokine interleukin-6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS., Trial Registrations: ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.

The primary goal of HCV therapy is to achieve a sustained virological response (SVR). Many host and viral factors influence the treatment response. Cytokines play an important role in the defense against viral infections, where successful treatment of hepatitis C depends on a complex balance between pro- and anti-inflammatory responses. In the present study, we investigated the relationship between the presence and percentage of some cytokines (IL-28, IFN-γ, and TNF-α) regarding different clinicopathological parameters including response to therapy in chronic HCV patients using immunohistochemical technique. This study was carried out on 64 chronic HCV patients (34 responders and 30 non-responders). Of cases, 54% showed IL-28 expression, which was associated with low AST (p = 0.002) and low HAI score (p = 0.006). Of cases, 67 and 45% showed IFN-γ and TNF-α expression, respectively, where the median percentage of TNF-α expression was higher in grade II spotty necrosis compared to grade I. Some inflammatory cytokines expressed by intrahepatic inflammatory cells in chronic HCV patients promote inflammation and injury (pro-inflammatory) such as TNF-α. Other cytokines aid in resolving inflammation and injury (anti-inflammatory) such as IL-28. The balance between these cytokines will determine the degree of inflammatory state. None of the investigated cytokines proved its clear cut role in affecting response to therapy, however, their levels varied between responders and non-responders for further investigations to clarify., (© 2014 APMIS. Published by John Wiley & Sons Ltd.)

Serum cytokine profiles were analyzed before and after infection in children with hemopathy in the bone marrow inhibition phase to explore the utility of cytokine variations for detecting infections. Serum Th1/Th2 cytokine levels, including tumor necrosis factor, interleukin (IL)-2, IL-4, IL-6, IL-10, and interferon, were quantitatively determined by cytometric bead array technology in 480 cases (230 children) of children with hemopathy in the bone marrow inhibition phase with signs of infection, such as fever, and without, to establish baseline and affected levels for comparison with healthy control children. We used the cytokine profile of infected, blood culture-positive children to establish a bacterial infection-related cytokine profile (BIRCP) for predicting infections by pathogens in blood culture-negative children. Overall, 82.9% of children with Gram-negative bacterial infections were accompanied by marked increases of IL-6 and IL-10 levels [>10 times (means ± SD)], whereas only a mild increase of IL-6 levels occurred in Gram-positive bacteria-infected children [>2 times (means ± SD)] and only a mild increase of IFN-γ levels occurred in fungal culture-positive children [>2 times (means ± SD)]. Gram-positive bacterial and fungal infections did not cause a marked increase in IL-6 or IL- 10 levels. The effective rate (86.05%, N = 43) of infectious cases predicted by BIRCP was significantly higher than that obtained using traditional methods for selecting antibiotics based on clinical indications (65.45%, N = 55, P < 0.05). In summary, BIRCP can be used to predict the infections by pathogens in children with hemopathy and to select appropriate antibiotics.

Aim: To compare inflammatory response accompanying acute coronary syndrome (ACS) with that following coronary plaque rupture caused by coronary angioplasty (PCI)., Methods: Twenty-seven consecutive subjects with either ACS or treated with PCI in the subacute phase of ACS underwent serial evaluation of circulating interleukin (IL)-2, IL-8, IL-10, interferon (IFN)-γ and tumor-necrosis-factor (TNF)-α levels. Blood samples were drawn immediately before angioplasty (T0) in the PCI group or at admission in the ACS group, 12 h (T1) and 24 h later (T2)., Results: Differences between cytokine levels were substantially not statistically significant when comparing PCI, non-ST-elevation-ACS, and ST-elevation-ACS groups, especially 24 h after plaque rupture (T2, Type-II error 85-94%)., Conclusions: Inflammatory activation during the first 24 h of ACS or after PCI is comparable, regardless of myocardial damage in terms of troponin levels. Coronary plaque rupture may be presumed as being the main responsible for increased circulating cytokine levels in this early phase., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Interleukin-21 (IL-21) has been reported to be involved in many Th1-associated diseases. However, the alteration and immune regulation of IL-21 in emphysema remains unknown. In this study, we tested the levels of IFN-γ and IL-21 and the frequencies of Th1 and Tc1 in peripheral blood from cigarette smoke (CS)-exposed mice and air-exposed mice and explored the effect of IL-21 on generation of Th1 and Tc1 cells in vitro. It was found that the levels of IFN-γ and IL-21 and the frequencies of Th1, Tc1, CD4(+) IL-21(+), CD4(+) IL-21R(+), and CD8(+) IL-21R(+) T cells were much higher in CS-exposed mice. Moreover, the levels of IL-21 were correlated positively with Th1 cells and with Tc1 cells. Finally, the in vitro experiments showed that IL-21 could promote Th1/Tc1 cell generation in CS-exposed mice. These results indirectly provide evidence that IL-21 produced by CD4(+) T cells could promote Th1/Tc1 response, leading to systemic inflammation in emphysema.

We investigated the plasma cytokine profiles of children with febrile seizures or severe acute encephalitis using multiplex cytometry to evaluate the role of cytokines in these diseases. Interleukin-6, -10, -12p70, -17A, -2, -4, -5, -9, -13, -22, and -1β, interferon-γ, and tumor necrosis factor-α were measured in the plasma from children with febrile seizures (n = 9) or severe acute encephalitis (n = 21). In multivariate analysis, interleukin-6 was significantly increased in the plasma of the febrile seizure patients compared to those with severe acute encephalitis, suggesting that interleukin-6 is activated during the acute stage of a febrile seizure. A lower plasma interleukin-6 concentration was significantly associated with severe acute encephalitis. The cytokine network may be deregulated in severe acute encephalitis via the persistence of an uncontrolled inflammatory state in the brain.

We compared cytokine profile of rat serum and brain structures after immune status modulation by LPS (30 μg/kg intraperitoneally). The content of inflammatory (IL-1α, IL-1β, IL-2, IL-6, IFN-γ, and TNF-α) and anti-inflammatory (IL-4 and IL-10) cytokines in biological samples of animals was measured on days 1 and 7 after antigenic stimulation. LPS administration reduced the levels of both inflammatory and anti-inflammatory cytokines in the peripheral blood of the rats, especially on the 1st day. LPS administration was also accompanied by specific changes in cytokine content in the dorsal hippocampus and anterior cingulate cortex. Antigenic stimulation increased the level of anti-inflammatory cytokines IL-4 and IL-10 in the examined brain tissues, the changes were most pronounced on day 1 after LPS injection. No significant changes in the levels of proinflammatory cytokines in the brain tissue of animals were found at the above terms after LPS injection. Thus, peripheral LPS administration to rats shifts the balance between the inflammatory and anti-inflammatory cytokines in the CNS structures towards the latter.

Objective: To explore the relationship between serum IL-4, IFN-gamma, IL-10 levels and the aetiology of juvenile-onset recurrent respiratory papillomatosis., Method: Serum IL-4, IFN-gamma, IL-32 levels of 15 JORRP children were detected by use of enzyme-linked immunosorbent assay (ELISA) and compared with those of healthy control group., Result: Serum IL-4 levels were significantly higher in the JORRP children (P<0.01): (524.65 +/- 147.77)pg/ml in the JORRP children and (213.27 +/- 87.48) pg/ml in the healthy control group. Serum IFN-gamma levels were significantly lower in the JORRP children (P<0.01): (2.87 +/- 0.84) pg/ml in the JORRP children and (10.63 +/- 5.09) pg/ml in the healthy control group. Serum IL-32 levels were significantly lower in the JORRP children (P< 0.01): (2.47 +/- 1.60) pg/ml in the JORRP children and (9.08 +/- 2.66) pg/ml in the healthy control group., Conclusion: 1) While the concentration of Th2 like cytokine IL-4 in children with JORRP was higher than that in control group, the concentration of Th1 like cytokine IFN-gamma in children with JORRP was lower than that in controls, indicating that the polarization of Th1 /Th2 T cell in children with JORRP; 2) The polarization of Th1/Th2 T cell may cause the reduction of the serum IL-32 as a proinflammatory role in host immunity system that could not eradicate HPVs because of lacking enough inflammatory stimulation.

Different studies have shown the regulatory effects of vitamin D(3) on the immune system and bone metabolism. Regarding the effects of vitamin D on immune cells and the importance of cytokines on bone metabolism, we assessed the association between serum levels of interleukin (IL)-6, IL-10, IL-12, IL-17 and IFN-γ cytokines and bone metabolism markers (Ca, P, PTH, ALP) in female students with vitamin D deficiency compared with control group. A total of 100 subjects with 25-hydroxy vitamin D(3) (25-(OH) D(3)) deficiency were selected as case and 100 subjects with sufficient 25-hydroxy vitamin D(3) (25-(OH) D(3)) were selected as the control group. The serum levels of IL-6, IL-10, IL-12, IL-17 and IFN-γ were measured by ELISA method. Ionized Ca, PTH, P, ALP levels were also determined in all participants. The results showed a statistically significant positive correlation between the levels of ALP with IFN-γ, PTH with IL-17 and a significant negative correlation between P with IL-10 in vitamin D deficient group. The results suggest that IL-17, IFN-γ and IL-10 are important mediators of bone metabolism and vitamin D affect bone metabolism, at least in part, through immune system. In addition, not only vitamin D affect bone metabolism but also modulates immune responses.

We investigated whether healthy young (age ≤ 40) and elderly (age ≥ 65) people infected with cytomegalovirus (CMV) had similar levels of CD8(+) T cell cytokine production and proliferation in response to an immunodominant CMV pp65 peptide pool given the role of CD8(+) T cells in controlling viral infection and the association of CMV with immunosenescence. Plus, we determined the effects of aging and CMV-infectious status on plasma levels of IL-27, an innate immune cytokine with pro- and anti-inflammatory properties, as well as on its relationship to IFN-γ in that IL-27 can promote the production of IFN-γ. The results of our study show that young and elderly people had similar levels of CD8(+) T cell proliferation, and IFN-γ and TNF-α production in response to CMV pp65 peptides. Plasma levels of IL-27 were similar between the two groups although CMV-infected young and elderly people had a trend toward increased levels of IL-27. Regardless of aging and CMV-infectious status, plasma levels of IL-27 correlated highly with plasma levels of IFN-γ. These findings suggest the maintenance of CMV pp65-specific CD8(+) T cell proliferation and cytokine production with aging as well as the sustaining of circulatory IL-27 levels and its biological link to IFN-γ in young and elderly people irrespective of CMV infection., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To measure the levels of interleukin (IL)-27, interferon (IFN)-γ, and IL-17 in serum and supernatants of stimulated peripheral blood mononuclear cells (PBMCs) of patients with Behçet's disease (BD) compared with healthy subjects, and to evaluate the effect of recombinant human IL-27 (rhIL-27) on IFN-γ and IL-17 production by PBMCs., Methods: Forty-three patients with BD and 40 healthy controls were included in this study. The serum levels of IL-27, IFN-γ, and IL-17 and their production by PBMCs were measured by enzyme-linked immunosorbent assay (ELISA), together with the effects of levels of rhIL-27 on IFN-γ and IL-17 production by PBMCs., Results: There were significantly higher levels of IL-27, IFN-γ, and IL-17 in sera of patients with BD compared with the controls. Levels of IL-27, IFN-γ, and IL-17 in BD patients with active uveitis were significantly higher than in those without. Moreover, IL-27, IFN-γ, and IL-17 production by stimulated PBMCs was increased in BD patients compared to controls. In the presence of rhIL-27, stimulation of PBMCs from BD patients resulted in decreased production of IL-17 but increased production of IFN-γ., Conclusions: These findings suggest that IL-27, IFN-γ, and IL-17 play a role in the pathogenesis of BD.

It is not well established whether cytokine production differs in response to different clinical forms of visceral leishmaniasis (VL). In this work, we performed a cross-sectional study to investigate the plasma levels of cytokines [interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-10 and IL-12] involved in the pathogenesis of VL in 80 subjects from VL endemic areas, including subjects with active VL, subjects with asymptomatic infection, subjects with cured VL and uninfected controls. The patients were recruited by sampling from a referral hospital and by random selection from a population-based cohort study. The results showed significant differences in the plasma concentration of all cytokines between the groups (p < 0.05). Patients with the active disease had higher plasma levels of IL-10, IL-4, INF-γ and TNF-α relative to the other groups and they produced more IL-12 than asymptomatic and cured subjects. Only the IL-2 concentration was higher in the asymptomatic and cured subjects relative to the patients with active disease (p < 0.05). Our results suggest that these cytokines can be used as markers in epidemiological studies conducted in endemic areas to distinguish between different clinical forms of VL. However, their usefulness should be confirmed in investigations conducted in other endemic areas.

Unlabelled: In alcoholics, the activation of Kupffer cells by gram negative bacteriae leads to an inflammatory response and cytokine secretion, which in turn activate T-lymphocytes. Possibly, Th-1 lymphocytes are activated first, followed by a Th-2 response. Th-2 cytokines, especially interleukin (IL)-13 (scarcely studied in alcoholics), may be involved in the progression to chronic stages., Aims: The aim of the study was to analyze the relationship of Th-1 and Th-2 cytokines with liver function, alcohol consumption, nutritional status and survival., Methods: Serum Th-1 [interferon-γ (IFN-γ)] and Th-2 cytokines (IL-4, IL-13), IL-10, IL-6 and tumor necrosis factor (TNF-α), were determined for 18 controls and 47 stable alcoholics with variable liver function impairment, who were followed-up during a median time of 90 months, a period during which 14 patients died., Results: IL-4 was lower among patients; no differences were observed regarding IL-6, but the remaining ILs were higher among alcoholics. IL-10 and IL-13 were even higher in cirrhotics (Z = 2.88, P = 0.004, and Z = 2.09, P = 0.037, respectively). A significant, direct, correlation was observed between IL-13 and IL-10 (ρ = 0.49, P = 0.001), and non-significant, inverse ones were observed between IFN-γ and IL-13 (ρ = -0.23), IL-4 (ρ = -0.14) and IL-10 (ρ = -0.09). IL-13 and IL-10 were inversely related with liver function and, directly with immunoglobulin A levels, but not with survival., Conclusion: Serum IFN-γ values were increased in alcoholics, who also showed raised IL-13 and IL-10, but lower IL-4 levels. Given the immunomodulatory roles of IL-10 and IL-13, this increase may be interpreted as a compensatory rise of anti-inflammatory cytokines. We failed to find any relation with mortality.

In this study, we investigated the role and expression of T helper type 17 (Th17) cells and Th17 cytokines in human tuberculosis. We show that the basal proportion of interferon (IFN)-γ-, interleukin (IL)-17- and IL-22-expressing CD4(+) T cells and IL-22-expressing granulocytes in peripheral blood were significantly lower in latently infected healthy individuals and active tuberculosis patients compared to healthy controls. In contrast, CD4(+) T cells expressing IL-17, IL-22 and IFN-γ were increased significantly following mycobacterial antigens stimulation in both latent and actively infected patients. Interestingly, proinflammatory IFN-γ and tumour necrosis factor (TNF)-α were increased following antigen stimulation in latent infection. Similarly, IL-1β, IL-4, IL-8, IL-22 and TNF-α were increased in the serum of latently infected individuals, whereas IL-6 and TNF-α were increased significantly in actively infected patients. Overall, we observed differential induction of IL-17-, IL-22- and IFN-γ-expressing CD4(+) T cells, IL-22-expressing granulocytes and proinflammatory cytokines in circulation and following antigenic stimulation in latent and active tuberculosis., (© 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.)

Carbamazepine is a widely used anticonvulsive agent. Its metabolic pathway leads not only to the major active metabolite, carbamazepine-10,11-epoxide, but also to minor terminal metabolites such as iminostilbene and acridine. Carbamazepine is usually well-tolerated, but it may lead to rare, but serious, hypersensitive reactions associated with hypereosinophilia. The mechanisms of hypersensitivity reactions to carbamazepine are still largely unknown, and the implications of the cell-mediated immune response (Th1 pathway) or the humoral immune response (Th2 pathway) are still not understood in these reactions. It is also unclear whether the parent drug or its subsequent metabolites are the primary trigger agent. In our study, we performed ex vivo experiments to evaluate the stimulation of cytokine secretion by carbamazepine, carbamazepine-10,11-epoxide, iminostilbene and acridine. IL-5, IL-6 and IL-10 were quantified as markers of the Th2 pathway, and IL-2 and IFN-γ were used as markers of the Th1 pathway. Blood samples (n=24) were obtained from epileptic patients routinely treated with carbamazepine alone or co-treated with lamotrigine or valproate. The concentrations of cytokines in the plasma were determined before and after 3 h stimulation with drugs. We found a significantly positive effect of co-treatment with valproate on the basal level of IL-5 (p<0.01) and IL-10 (p<0.05). IL-5 production increased only in blood stimulated with a high level of acridine (33 μM), whereas IL-6 production was less specifically stimulated (p<0.05). Because IL-5 is the most potent stimulating factor of the eosinophils, we suggest that the potential helper effect of valproate and acridine can lead to hypersensitive reactions to carbamazepine in the context of the humoral immune response.

Background: Buruli Ulcer (BU) is a severe cutaneous and subcutaneous disease due to Mycobacterium ulcerans infection, mainly distributed in sub-Saharan Africa and tropical areas. The role of T helper (TH) cytokines in the development and clinical course of the disease has been previously studied by investigating the in vitro immune response of lymphocytes from affected patients and immunohistochemical analyses of bioptic samples., Methods: TH cytokine levels (IFNγ, TNF-α, IL-2, IL-10, IL-4, IL-5, IL-17) were evaluated in serum of 34 Beninese subjects by cytofluorimetric and immunoenzymatic assays: 16 patients affected with active BU, 4 patients who had healed after specific therapy, and 14 matched controls., Results: Levels of IFNγ were higher in patients with late BU (>2 months from onset) and healed patients than in controls, and in ulcerative than in pre-ulcerative patients. Analysis of 4 patients with "late" disease evaluated both at the beginning of antibiotic therapy and 6 months later showed that IFNγ levels were always lower in the second evaluation. By contrast, no differences were found in levels of the other cytokines., Conclusions: IFNγ production is low in early BU, and increases in late BU and healing, suggesting a role of this cytokine in infection clearance. Moreover, evaluation of IFNγ serum levels may be a useful tool to monitor the immune response during the BU course., (© 2010 The International Society of Dermatology.)

Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard pre-programmed responses. To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-γ, lymphotoxin-α (LT-α) and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group. These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components. These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LT-α stimulus. These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key sub-networks such as IL-2:IFN-γ:TNF-α that might be targeted in restoring normal immune function., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Interleukin-21 (IL-21) is critical in the development of autoimmune diseases. The role of IL-21 in the pathogenesis of immune thrombocytopenia (ITP) remains unknown., Materials and Methods: We examined the expression of IL-21, IL-17, and interferon (IFN)-gamma in ITP patients and controls by enzyme-linked immunosorbent assay and flow cytometry. Detection of specific anti-platelet GPIIb/IIIa and/or GPIb/IX autoantibodies was measured by modified monoclonal antibody specific immobilization of platelet antigens., Results: IL-21 was expressed on both CD3(+)CD8(-) T cells and CD3(+)CD8(+) T cells by flow cytometry. Plasma IL-21 level and the percentage of CD3(+)CD8(-)IL-21(+) T cells and CD3(+)CD8(+)IL-21(+) T cells were significantly elevated in ITP patients compared to controls. The percentage of CD3(+)CD8(-)IL-17(+) T (Th17), CD3(+)CD8(-)IFN-gamma(+) T (Th1), and CD3(+)CD8(+)IFN-gamma(+) T (Tc1) cells also significantly increased in ITP patients. Moreover, we found a significant positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th17 cells. In addition, a positive correlation between CD3(+)CD8(-)IL-21(+) T cells and Th1 cells was also found., Conclusion: Together, our results indicated a possible role of IL-21 in ITP patients correlated to Th17 and Th1 cells, and blockade of IL-21 may be a reasonable therapeutic strategy for ITP especially those with active disease.

Objective: To observe changes in T cell subsets and TH1/TH2 secreted cytokines in the plasma of patients with hemorrhagic fever with renal syndrome (HFRS)., Methods: Totally 22 patients with HFRS (9 mild cases and 13 moderate cases) were enrolled. Blood samples were taken 1, 4, and 12 weeks after presentation. T cell subsets were tested by flow cytometry (FCM), and the expression of cytokines in plasma were analysed with enzyme-linked immunosorbent assay (ELISA). Another 16 healthy blood donors were enrolled as the control group., Results: CD3 + CD8 + T lymphocytes increased at week 1 and 4 (P < 0.01), which was more significant in mild cases than in moderate cases (P < 0.05). The change of CD3 + CD4 + T lymphocytes during the disease course were not significantly different from that in control group (P > 0.05). One week after presentation, TH1 [interleukin (IL)-2 and interferon-gamma (IFN-gamma)] and TH2 (IL-6, IL-10) cytokine productions were significantly higher in HFRS patients than in the control group (P < 0.01); IL-2 and IL-10 remained high levels during the whole observation period, and were still significantly higher than in the control group (P < 0.01). At week 4, the plasma IL-5 level was significantly higher in HFRS patients than in the control group (P < 0.01), and were still significantly higher than in the control group at week 12 (P < 0.01). At week 1 and 4, the plasma INF-gamma levels were significantly higher in moderate patients than in mild patients (P < 0.05); at week 12, the plasma IL-10 level was significantly higher in moderate patients than in mild patients(P < 0.05)., Conclusions: CD3 + CD4 + T lymphocytes remarkably increases at the early stage of disease in patients with mild HFRS. The early cell mediated immune response is helpful for disease control. The cytokines INF-gamma and IL-10 increase more obviously in moderate patients, indicating that cytokines also are key pathogenic factors of HRFS.

The human immune response to Plasmodium falciparum infection involves the release of cytokines that may contribute to the control of the parasites' replication. These cytokines are also involved in the pathogenesis of the malaria caused by the infection, leading to the appearance of symptoms of varying severity. In a cross-sectional study, the expression of the genes that code for pro-inflammatory cytokines (tumour necrosis factor, interferon-gamma, interleukin-6 and interleukin-12) and anti-inflammatory cytokines (interleukin-10 and interleukin-4) among 80 children infected with P. falciparum (from a malaria-endemic area of Sudan) and five healthy controls (from a non-endemic area) was explored. The infected children were either non-sicklers, with severe malaria (18 children), mild malaria (30) or no symptoms of malaria (18), or asymptomatic sicklers (14). Interleukin-12 was found to be weakly expressed by all the groups of children. In general, compared with the other groups, the asymptomatic non-sicklers had lower expression of all the cytokines studied. The asymptomatic sicklers had significantly lower expression of tumour necrosis factor than the non-sicklers with severe malaria, but these two groups showed similar expression of interferon-gamma, interleukin-4 and interleukin-6. Gene expression of the regulatory cytokine, interleukin-10, by the asymptomatic sicklers was significantly lower than that by the non-sicklers with severe malaria but higher than that recorded in the non-sicklers with mild malaria. Their regulation of cytokine release appears to protect sicklers from clinical malaria.

Objective: To investigate the level of cytokines and immune cells in the peripheral blood (PB) and peritoneal fluid (PF) of different stages of endometriosis., Methods: A prospective study was conducted to include 97 women with (n 60) and without (n 37) histopathologically confirmed endometriosis. Based on rASRM classification, stage I/II and stage III/IV were categorized as early-and late-staged endometriosis. Prior to surgery, 10 ml of blood was withdrawn from antecubital vein and serum was obtained. Aliquots were made and stored at -70 degrees C until assayed for cytokines. PF was aspirated from the pouch of Douglas. Peripheral and PF samples were analyzed by ELISA in terms of IL-2, IL-4, IL-10 and IFN-gamma. Determinations of T helper, T suppressor, NK, and B cells were assessed by using cluster determinant-3 (CD-3), CD4, CD8, CD25, CD28, CD45, CD16, CD23 and antibodies against early T cell activation antigens such as CD45RA/CD45RO, CD-69 and late activation antigens such as HLA-DR. A multiparameter flow cytometry was applied to detect the cell activation antigen expression., Results: In terms of cytokine levels in PB and PF's of control group and early- and late-staged endometriosis cases, no significant difference was depicted in the cytokine levels (p > 0.05). Levels of immune cells did not differ between three groups (p > 0.05)., Conclusions: The result of this study did not show any significant difference in PB and PF cytokine and lymphocyte subgroups between normal and early- and late-staged endometriosis.