OBJECTIVE: Schizophrenia is a disabling disorder of unknown aetiology, lacking definite diagnostic method and cure. A reliable biological marker of schizophrenia is highly demanded, for which traceable immune mediators in blood could be promising candidates. We aimed to gather the best findings of neuroinflammatory markers for first-episode psychosis (FEP). METHODS: We performed an extensive narrative review of online literature on inflammation-related markers found in human FEP patients only. RESULTS: Changes to cytokine levels have been increasingly reported in schizophrenia. The peripheral levels of IL-1 (or its receptor antagonist), soluble IL-2 receptor, IL-4, IL-6, IL-8, and TNF-α have been frequently reported as increased in FEP, in a suggestive continuum from high-risk stages for psychosis. Microglia and astrocytes establish the link between this immune signalling and the synthesis of noxious tryptophan catabolism products, that cause structural damage and directly hamper normal neurotransmission. Amongst these, only 3-hydroxykynurenine has been consistently described in the blood of FEP patients. CONCLUSION: Peripheral molecules stemming from brain inflammation might provide insightful biomarkers of schizophrenia, as early as FEP or even prodromal phases, although more time- and clinically-adjusted studies are essential for their validation.
Astrocytes ; Biomarkers ; Encephalitis ; Humans ; Interleukin-1 ; Interleukin-4 ; Interleukin-6 ; Interleukin-8 ; Metabolism ; Methods ; Microglia ; Polytetrafluoroethylene ; Psychotic Disorders ; Receptors, Interleukin-2 ; Schizophrenia ; Synaptic Transmission ; Tryptophan

OBJECTIVE: IL-17-producing T cells (Th17 cells) have been identified as a distinct lineage of CD4+ T helper cells in mice. Since this discovery, many efforts have been made to investigate the characteristics and the role of human Th17 cells and the factors involved in their differentiation. This study was undertaken to assess the effects of cytokines and stimulatory conditions on the differentiation of human CD4+ T cells into Th17 cells. METHODS: Peripheral blood CD4+ T cells were isolated from healthy humans and then these cells were cultured with using various stimulatory conditions. The Th17 cells and regulatory T (Treg) cells were detected by flow cytometry (FACs). The related gene expressions of cytokines, transcription factors and chemokine receptors were determined by ELISA and RT-PCR. RESULTS: In the presence of inflammatory cytokines, TNFa and IL-1b, the human CD4+ T cells rapidly produced IL-17 in response to anti-CD3/anti-CD28 stimulation, whereas, with anti-CD3/anti-CD28 stimulation alone, the CD4+ T cells expressed low levels of IL-17. TNFa and IL-1b were also important inducers of IL-22 production. IL-6 and IL-23 up-regulated the RORgammat, CCR4 and CCR6 expressions in the human CD4+ T cells. In response to TGF-b and IL-2, the human CD4+ T cells were rapidly induced to express FoxP3, IL-10 and CCR7, as compared with anti-CD3/anti-CD28 stimulation alone. CONCLUSION: The effect of inflammatory cytokines on the differentiation of human Th17 cells may help us to understand their pathogenic role. Moreover, the differential expression of chemokine receptors and transcription factors of the subsets of CD4+ T cells with the different features of Th17 and Treg, may raise new issues concerning the pathogenesis of autoimmune inflammatory diseases.
Animals ; Cytokines ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression ; Humans ; Interleukin-10 ; Interleukin-17 ; Interleukin-2 ; Interleukin-23 ; Interleukin-6 ; Interleukins ; Mice ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Receptors, Chemokine ; T-Lymphocytes ; T-Lymphocytes, Helper-Inducer ; T-Lymphocytes, Regulatory ; Th17 Cells ; Transcription Factors

BACKGROUND: The assay of cytokines and their soluble receptors in the synovial fluid of inflammatory arthropathy may be useful in studying pathogenetic and immunoregulatory mechanisms of different arthritis. The aim of this study is to investigate cytokine profiles in rheumatoid arthritis and to find the characteristic pattern of cytokine concentration in rheumatoid arthritis according to the clinical manifestations. METHODS: We measured the concentration of TNF-alpha, IL-1 beta, IL-2, IL-6, IL-8 and IL-10, soluble TNF receptor I, II, IL-1 soluble receptor 2 and IL-6 soluble receptor in synovial fluid from the patients with rheumatoid arthritis using ELISA method. We compared these data with result from osteoarthritis patients. In rheumatoid arthritis, we investigated differences of cytokine profile according to clinical manifestations such as duration of disease, radiographic bone erosions and existence of rheumatoid factor. RESULTS: All of the concentrations of cytokines except IL-2 were significantly elevated in synovial fluid of rheumatoid arthritis than osteoarthritis. When we grouped RA patients according to existence of rheumatoid factor and compared the concentration of cytokines, there were no significant differences between seropositive and seronegative group. We also compared early and late disease, and erosive and non-erosive group but there were no significant differences in cytokine level. CONCLUSION: Our data support the results from other studies that concentration of pro-inflammatory or anti-inflammatory cytokines were elevated in rheumatoid arthritis than osteoarthritis. However, we cannot find the relationship between clinical findings and cytokine profiles in joint fluid.
Arthritis ; Arthritis, Rheumatoid* ; Cytokines ; Enzyme-Linked Immunosorbent Assay ; Humans ; Interleukin-1 ; Interleukin-10 ; Interleukin-1beta ; Interleukin-2 ; Interleukin-6 ; Interleukin-8 ; Joints ; Osteoarthritis ; Receptors, Tumor Necrosis Factor ; Rheumatoid Factor ; Synovial Fluid* ; Tumor Necrosis Factor-alpha

Blood Cell Count ; Bone Marrow Cells ; pathology ; Child ; Cytokines ; analysis ; Fever ; Histiocytosis, Non-Langerhans-Cell ; metabolism ; pathology ; therapy ; Humans ; Interleukin-2 ; analysis ; Interleukin-6 ; analysis ; Receptors, Interleukin-1 ; analysis

To determine whether adiponectin may have synergistic effects in combination with the proinflammatory cytokine interleukin (IL)-1beta regarding the production of proinflammatory mediators during arthritic joint inflammation, synovial cells from rheumatoid arthritis (RA) patients were treated with adiponectin, IL-1beta, and their combination for 24 h. Culture supernatant was collected and analyzed by enzyme-linked immunosorbent assay for levels of IL-6, IL-8, prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs). Adiponectin-mediated intracellular signaling pathways were investigated to elucidate the molecular mechanisms underlying their synergy. The association of proinflammatory mediators with adiponectin was investigated in the synovial fluid of arthritis patients. Adiponectin functioned synergistically with IL-1beta to activate IL-6, IL-8, and PGE2 expression in RA fibroblast-like synoviocytes; Levels of VEGF, MMP-1, and MMP-13 were not synergistically stimulated. Adiponectin and IL-1beta each increased the expression of both adiponectin receptor 1 and IL-1 receptor 1. However, adiponectin and IL-1beta did not synergistically support the degradation of IkappaB-alpha or the nuclear translocation of NF-kappaB. Synergistically increased gene expression was significantly inhibited by MG132, an NF-kappaB inhibitor. Supporting the in vitro results, IL-6 and IL-8 levels were positively associated with adiponectin in synovial joint fluid from patients with RA, but not osteoarthritis (OA). In conclusion, adiponectin and IL-1beta may synergistically stimulate the production of proinflammatory mediators through unknown signaling pathways during arthritic joint inflammation. Adiponectin may be more important to the pathogenesis of RA than previously thought.
Adiponectin/administration & dosage/*metabolism ; *Arthritis, Rheumatoid/metabolism/pathology ; Cells, Cultured ; Cyclooxygenase 2/metabolism ; Gene Expression Regulation/drug effects ; Humans ; *Inflammation/metabolism/pathology ; Interleukin-1beta/administration & dosage/*metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Joints/metabolism/pathology ; Matrix Metalloproteinases ; NF-kappa B/metabolism ; Obesity/metabolism/pathology ; Osteoarthritis ; Receptors, Adiponectin/metabolism ; Receptors, Interleukin-1/metabolism ; *Synovial Fluid/cytology/metabolism

Purpose: IL-1 is a multifunctional proinflammatory cytokine. As the proliferative effects of IL-6 and IL-6 receptor expressions on prostatic cancer cells in response to IL-1 have not been determined, the effects of IL-1 on prostatic cancer cell lines were investigated. Materials and Methods: PC-3 and DU-145 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Cell cultures were supplemented with various concentrations of IL-1 (0, 1, 10, 20 and 40ng/ml), and the MMT growth assay performed. PC-3 and DU-145 cells were treated for 2, 4, 8, 12 and 24 h both with and without IL-1. IL-6 and IL-6 receptor (IL-6R) mRNA expressions were investigated using RT-PCR, and the IL-6 levels in cultured supernatant measured by ELISA. Results: The viability of both PC-3 and DU-145 cells decreased after IL-1 treatment (10, 20 and 40ng/mul). With 40ng/ml the IL-1, IL-6 and IL-6RmRNA expressions were lower in PC-3 cells, but unchanged in DU-145 cells, whereas the IL-6 protein production was higher in both PC-3 and DU-145 cells. Conclusions: IL-1 inhibited the proliferation of both PC-3 and DU145 cells. In the PC-3 cells, IL-1 decreased the expressions of IL-6 and IL-6R mRNA, but paradoxically increased the IL-6 production. In the DU-145 cells, IL-1 treatment did not affect the IL-6 or IL-6R mRNA expressions, but the IL-6 production was increased. This discrepancy between IL-1-induced IL-6 mRNA and protein production may be mediated by modification to the protein synthesis or an increased cellular excretion.
Cell Culture Techniques ; Cell Line ; Enzyme-Linked Immunosorbent Assay ; Interleukin-1 ; Interleukin-1beta* ; Interleukin-6* ; Interleukins* ; Prostatic Neoplasms* ; Receptors, Interleukin* ; Receptors, Interleukin-6 ; RNA, Messenger

OBJECTIVETo assess the value of rheumatoid factors IgM-RF, IgA-RF, IgG-RF, interleukin-1 receptor type I (IL-1RI) and cyclin-dependent kinase 2 (CDK2) in the diagnosis of rheumatoid arthritis (RA).

METHODSIgM-RF, IgA-RF, IgG-RF, IL-1RI and CDK2 were detected in 47 patients with active RA, 47 with inactive RA, 20 with active systemic lupus erythematosus (SLE), 20 with inactive SLE, 20 with acute upper respiratory tract infection (AURTI), and 20 healthy controls using enzyme-linked immunosorbent assay (IgM-RF, IgA-RF, IgG-RF, IL-1RI) and time-resolved fluoroimmunoassay (CDK2).

RESULTSPatients with active and inactive RA showed significant differences in peripheral serum CDK2 and IgA-RF levels (P<0.05). Between active and inactive RA patients, RA patients and SLE patients, RA patients and AURTI patients, and RA patients and the control subjects, the area under curve (AUC) of the receiver operating characteristic curve (ROC) was 0.561, 0.814, 0.799, and 0.888 for IgM-RF, 0.596, 0.678, 0.729, and 0.850 for IgA-RF, 0.614, 0.718, 0.692, and 0.791 for IgG-RF, 0.646, 0.691, 0.762, and 0.835 for IL-1RI, 0.803, 0.753, 0.741, and 0.840 for CDK2, respectively.

CONCLUSIONSIgM-RF may have high value in the diagnosis and differential diagnosis of RA, and CDK2 can be useful for differential diagnosis between active and inactive RA.

Adult ; Area Under Curve ; Arthritis, Rheumatoid ; blood ; diagnosis ; Cyclin-Dependent Kinase 2 ; blood ; Female ; Humans ; Immunoglobulin A ; blood ; Immunoglobulin G ; blood ; Immunoglobulin M ; blood ; Male ; Middle Aged ; ROC Curve ; Receptors, Interleukin-1 Type I ; blood ; Rheumatoid Factor ; blood

OBJECTIVESTo explore serum cytokines levels (including IL-1beta, sIL-2R, IL-6, TNF-alpha, and IFN-upsilon) and their significance in patients with acute coronary syndrome (ACS) and the subsequent follow-ups, with attempt to estimate the role of various serum inflammatory markers in the diagnosis and assessment of ACS.

METHODSThe study population include 40 patients with acute myocardial infarction (AMI), 40 patients with unstable angina pectoris (UAP), and 40 controls. Among the 80 patients, 60 patients attended a follow up 4 months later. Serum inflammatory markers including IL-1beta, slL-2R, IL-6, TNF-alpha, and IFN-upsilon were measured by enzyme linked immunosorbent assay.

RESULTSSerum IL-1beta, sIL-2R, IL-6, TNF-alpha were significantly higher in AMI group or UAP group compared to the control group and became significantly lower 4 months later in the follow-up patients. Serum levels of IFN-upsilon shows no significant difference between AMI group or UAP group and controls, also showing no significant change when measured in follow up patients. There was no correlation between serum creatine kinase-MB isoenzyme levels and serum inflammatory markers either in UAP or AMI group. Furthermore, when divided into two subgroups using Wagner's QRS scoring system in the AMI group, there is no difference of each serum inflammatory marker between < or = 6 scores group and > 6 scores group.

CONCLUSIONSerum levels of certain inflammatory markers may have some diagnostic value for ACS, and can be a useful marker reflecting disease stability.

Aged ; Angina, Unstable ; blood ; diagnosis ; Biomarkers ; blood ; Creatine Kinase ; blood ; Creatine Kinase, MB Form ; Cytokines ; blood ; Female ; Follow-Up Studies ; Humans ; Interferon-gamma ; blood ; Interleukin-1 ; blood ; Interleukin-6 ; blood ; Isoenzymes ; blood ; Male ; Middle Aged ; Myocardial Infarction ; blood ; diagnosis ; Receptors, Interleukin-2 ; blood ; Tumor Necrosis Factor-alpha ; metabolism

BACKGROUND: Interleukin-5 (IL-5) is responsible for eosinophilia in allergic diseases. In allergic bronchial asthma, there is a correlation between the extent of eosinophil infiltration in bronchial mucosa and IL-5 concentrations. In addition, IL-2 concentration is elevated in the airways and associated with eosinophilia in symptomatic patients with bronchial asthma. In animal studies, IL-2 can induce eosinophilia by increasing the synthesis of IL-5, however, it is still unknown how IL-2 can induce eosinophila in human being. The aim of this study is to evaluation the effect and mechanism of IL-2 on prolongation of eosinophil survival. METHODS: After purifiing the eosinophils from the venous blood of allergic patients with eosinophilia, we measured the survival rates of eosinophils using trypan blue dye exclusion test, and the number of eosinophils with Randolp's solution. We compared the survival rates of eosinophils in the presence of IL-2 or IL-5. Neutralizing antibody for IL-5 was added in IL-2 treated eosinophils to reveal whether IL-2 induced prolongation of eosinophil survival was mediated by IL-5. We checked IL-5 m-RNA expression of lymphocytes in the presence of IL-2 by using Reverse transcription-Polymerase chain reaction (RT-PCR) method to revealed the effect of IL-2 on IL-5 m-RNA expression on lymphocyte. alpha and beta IL-2 receptors were measured on eosinophils and lymphocytes with flow-cytometer after stimulated with IL-2. RESULTS: 1) Eosinophil survival rates increased dose dependently on IL-5 and IL-2. 2) The eosinophil survival rates increased by IL-2 were not inhibited by the pretreatment with neutralizing antibody for IL-5. 3) IL-5 m-RNA was not expressed on lymphocytes by the treatment with IL-2 up to 96 hours. 4) IL-2 upregulate the expression of IL-2Ralpha on eosinophils, instead of no effect on the expression of IL-2Rbeta. CONCLUSION: Interleukin-2 had the enhancing effect on the survival rates of eosinophils. The mechanism behind IL-2 induced eosinophilia might be the increment of IL-2 receptors on eosinophils rather than IL-5 synthesis by lymphocytes.
Animals ; Antibodies, Neutralizing ; Asthma ; Eosinophilia ; Eosinophils* ; Humans ; Interleukin-2 ; Interleukin-2 Receptor alpha Subunit ; Interleukin-5 ; Lymphocytes ; Mucous Membrane ; Receptors, Interleukin-2 ; Survival Rate ; Trypan Blue

PURPOSE: Interleukin-1 (IL-1) plays a key role in inflammation and immunity and its decoy receptor, IL-1R2, has been implicated in transcriptomic and genetic studies of asthma. METHODS: Two large asthma family collections, the French-Canadian Saguenay-Lac-St-Jean (SLSJ) study and the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA), were used to investigate the association of SNPs in 10 genes that modulate IL-1R2 activities with asthma, allergic asthma, and atopy. Gene-gene interactions were also tested. RESULTS: One SNP in BACE2 was associated with allergic asthma in the SLSJ study and replicated in the EGEA study before statistical correction for multiple testing. Additionally, two SNPs in the MMP2 gene were replicated in both studies prior to statistical correction and reached significance in the combined analysis. Moreover, three gene-gene interactions also survived statistical correction in the combined analyses (BACE1-IL1RAP in asthma and allergic asthma and IL1R1-IL1RAP in atopy). CONCLUSIONS: Our results highlight the relevance of genes involved in the IL-1R2 activity in the context of asthma and asthma-related traits.
Asthma ; Epidemiologic Studies ; Genetics ; Humans ; Inflammation ; Interleukin-1* ; Phenotype* ; Polymorphism, Single Nucleotide ; Receptors, Interleukin-1 Type II*