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

Aged ; Humans ; Male ; Middle Aged ; Receptors, Interleukin-2 ; blood ; Silicosis ; blood ; classification ; T-Lymphocyte Subsets ; metabolism

BACKGROUNDCC chemokine receptor 3 (CCR3), expressed on some inflammatory cells, is a member of the chemokine receptor family. Its ligand is eotaxin/CCL11. In this research, we studied the expression and function of CCR3 induced by interleukin-2 (IL-2) and interleukin-4 (IL-4) on human germinal centre (GC) B cells.

METHODSCells isolated from human tonsils were stimulated with IL-2 or/and IL-4 followed by bonding with eotaxin/CCL11. Flow cytometry was used to detect expression of CCR3 on GC B cells and apoptosis of GC B cells. Real time quantitative reverse transcription polymerase chain reaction and Northern blot assays were used to analyse the CCR3 mRNA expressed in the GC B cells. Chemotaxis and adhesion assays were used to determine the effect of eotaxin/CCL11 ligand bonded to CCR3 on GC B cells.

RESULTSThere was no CCR3 expression on human freshly isolated GC B cells. The combination IL-2 and IL-4 could upregulate CCR3 mRNA and protein expression on GC B cells. Eotaxin could not induce GC B cell chemotaxis and adhesion but triggered apoptosis of GC B cells.

CONCLUSIONIL-2 and IL-4 together induced expression of CCR3 on GC B cells, and the receptor acted as a death receptor.

Apoptosis ; B-Lymphocytes ; metabolism ; pathology ; Cell Adhesion ; Chemotaxis, Leukocyte ; Germinal Center ; metabolism ; pathology ; Humans ; Interleukin-2 ; pharmacology ; Interleukin-4 ; pharmacology ; RNA, Messenger ; analysis ; Receptors, CCR3 ; Receptors, Chemokine ; genetics

ObjectiveTo investigate the expressions of substance P (SP) and neurokinin-1 receptor (NK-1R) in the posterior horn of the L5－S2 spinal cord in the rat model of chronic nonbacterial prostatitis (CNP) at different time points of modeling.

METHODSForty adult male SD rats were randomly divided into four groups of equal number, control, 45 d model, 60 d model, and 90 d model, and proteins were obtained from the prostatic tissue of another 30 rats. The CNP model was made by intraperitoneal injection of 0.5 ml DPT vaccineand intradermal injection of mixed solution of 1 ml prostatein extract and complete adjuvant at a 1∶1 ratio, while the control rats were injected with the same volume of normal saline. At 45, 60, and 90 days after modeling, we measured the paw withdrawal threshold (PWT) of the rats, determined the levels of TNF-α, IL-1β, IL-2, and IL-10 in the prostate tissue by ELISA, observed the histomorphological changes in the prostate by transmission electron and light microscopy, and detected the expressions of SP and NK1-R in the L5－S2 spinal cord by immunohistochemistry.

RESULTSThe model rats showed significantly increased sensitivity to pain, with remarkably lowered PWT at 45, 60, and 90 days after modeling. The levels of TNF-α, IL-1β, IL-2, and IL-10 in the prostate tissue were markedly elevated in the CNP models as compared with those in the controls (all P<0.05), most significantly at 90 days (all P<0.05). Immunohistochemistry showed that the expressions of SP and NK-1R were remarkably higher in the CNP model groups than in the control (all P<0.05), the highest at 90 days. Light microscopy revealed no inflammatory cell infiltration in the prostate tissue of the control rats, and obvious edema and increased lymphocytes were observed with the prolonged time of modeling.Transmission electron microscopy showed inflammatory changes in the prostate tissue of the model rats and that peritubular interstitial edema was most obvious at 90 days, with widened intervals between peritubular cells and the epithelial base and increased numbers of fibroblasts and collagen fibrils.

CONCLUSIONSThe synthesis of SP and the level of NK-1R were increased in the posterior horn of the L5－S2 spinal cord in the rat model of CNP.

Animals ; Interleukin-10 ; metabolism ; Interleukin-1beta ; metabolism ; Interleukin-2 ; metabolism ; Male ; Pain ; Prostatitis ; metabolism ; physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurokinin-1 ; metabolism ; Spinal Cord ; metabolism ; Substance P ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

This article reviews that as a functionally and phenotypically distict immunoregulatory T cell subpopulation, CD4(+)CD25(+) regulatory T cells can suppress the activation and proliferation of CD4(+)CD25(-) T cells and CD8(+) T cells and the production of IL-2 and IFN-gamma. These regulatory cells play an important role in allograft tolerance, although the mechanisms are not completely understood to date. CD4(+)CD25(+) regulatory T cells can be isolated, activated and expanded in vitro without loss of their immunoregulatory function. The suppressive function of activated CD4(+)CD25(+) cells is antigen non-specific. Ex vivo activated and expanded regulatory T cells have a perspective for practical use.
CD4 Antigens ; blood ; CD8 Antigens ; blood ; Cell Division ; immunology ; Humans ; Interferon-gamma ; blood ; Interleukin-2 ; blood ; Receptors, Interleukin-2 ; blood ; T-Lymphocytes ; cytology ; immunology ; metabolism ; Transplantation Tolerance ; immunology

Inability to synthetize adequate amounts of IL-2 has been suggested to be the basis of defective T-cell function following anesthesia with the operation. The present study was designed to examine the effect of anesthesia and operation on host defence mechenism. serum soluble IL-2R(sIL-2R) levels and hemo-dynamic parameters were measured in 30 patients. Patients were divided into two groups (G: general anesthesia with isoflurane, E:epidural anesthesia with bupivacaine) according to the method of anesthesia. Venous blood samples were taken before anesthesia(T1), 10 mins after induction of anesthesia(T2), 10 mins after injection of bupivacaine in epidural anesthesia(T2), 1 hour after skin incision(T3), 30 mins after completion of operation(T4), and 24 hours after completion of operation(T5). Simultaneously arterial blood pressure and heart rate were measured. Six mililiter of perip-heral blood was obtained for sIL-2R studies in plain tubes. Serum concentration of sIL-2R was measured by human IL-2 receptor ELISA kit(Boehringer Mannheim Biochemica, Mannheim, Germany). Any significant change in IL-2R level was not seen in patients under general anesthesia with isoflurane and operation. Also any significant change in IL-2R level was not seen in patients who had an epidural anesthesia with bupivacaine and operation. The results suggest that suppression of T-lymphocyte function and decrease in lymphocyte counts induced by anesthesia and operation is not due to alteration of intracellular metabolism, but due to extracellular immune depressor. And general anesthesia operation with isoflurane as well as epidural anesthesia with bupivgcaine is safe and can be selected for immunosuppressive patients.
Anesthesia ; Anesthesia, Epidural* ; Anesthesia, General* ; Arterial Pressure ; Bupivacaine* ; Enzyme-Linked Immunosorbent Assay ; Heart Rate ; Humans ; Interleukin-2* ; Isoflurane* ; Lymphocyte Count ; Metabolism ; Receptors, Interleukin-2 ; Skin ; T-Lymphocytes

Regulation of P2X7 receptor expression is of interest because activation of this receptor by extracellular ATP triggers a wide variety of cell functions in leukocytes. However, its expression and modulation in human peripheral blood mononuclear cells (PBMC) and monocytes remain unclear. RT-PCR was used to detect the constitutive level of P2X7 receptor and the levels upon stimulation with bacteria, bacterial product, mitogen and various cytokines in human PBMC and monocytes. P2X7 receptor mRNA was detected in PBMC and monocytes. P2X7 receptor expression in PBMC was up-regulated by interleukin-2, -4, -6 (IL-2, IL-4, IL-6) tumour necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS) and heat-inactivated Staphylococcus aureus Cowan strain I (SAC). However, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and phytohemagglutinin-M (PHA-M) had little effect on the expression of P2X7 receptor. Furthermore, LPS and M-CSF could up-regulate P2X7 receptor expression in monocytes, while IFN-gamma, TNF-alpha and GM-CSF had weak effects, but pretreatment with these inducers could not further enhance LPS-stimulated P2X7 receptor expression in monocytes. The results obtained demonstrate that inflammatory stimuli drive P2X7 expression, thus supporting the hypothesis that P2X7 receptor may play a role in the inflammatory responses against bacteria infection, which need further verification.
Humans ; Interleukin-2 ; physiology ; Interleukin-4 ; physiology ; Leukocytes, Mononuclear ; drug effects ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Receptors, Purinergic P2X7 ; genetics ; metabolism ; Tumor Necrosis Factor-alpha ; physiology

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

OBJECTIVETo investigate the influence of high mobility group box-1 protein (HMGB1) on the immunosuppression function of splenic regulatory T cells (Tregs) and its potential regulatory mechanism underlying the effect on CD4+ CD25- T cells in mice.

METHODSCD4+ CD25+ Tregs isolated from the spleens of male BALB/c mice by magnetic beads were seeded on 96-well (1 x 10(5) cells/well) cell culture plates coated with 1 microg/ml anti-CD3 and soluble CD28. After being stimulated with HMGB1 for different time and concentrations, the secretions of IL-2 and IL-10 were analyzed by ELISA. Tregs stimulated for 72 hours were cultured with CD4+ CD25- T cells together. The suppressive activity of CD4+ CD25+ Treg to CD4+ CD25- T cells was analyzed by MTT test. IL-2, IL-10, IL-4, and interferon (IFN)-gamma in the cell suspensions were determined by ELISA.

RESULTSAfter stimulation with HMGB1, the suppressive activity of splenic Tregs in mice were significantly down-regulated at 72 hours, when the proportion of Tregs to CD4+ CD25- T cells was 1 : 1. The secretion of IL-2 of Tregs stimulated by HMGB1 was not markedly changed (P > 0.05), while a dose-dependent decrease between IL-10 induction and HMGB1 concentration was obviously (P < 0.05). When CD4+ CD25- T cells were cultured with stimulated Tregs, comparing with unstimulated-Treg group, levels of IL-2 and IFN-gamma were elevated following the increased concentration of HMGB1 (P < 0.05 or P < 0.01). Meanwhile the secretion of IL-4 and IL-10 significantly decreased when cultured with stimulated Tregs (P < 0.05).

CONCLUSIONSThese data suggested that HMGB1 stimulation can result in significant down-regulation of immunosuppression of splenic Tregs in mice. HMGB1 might be a potential immunoregulatory signal that influences the proliferation of effector T cells, secretion of IL-2 and cells-polarization by inhibiting CD4+ CD25+ Tregs activity.

Animals ; Cell Communication ; drug effects ; Cells, Cultured ; HMGB1 Protein ; pharmacology ; Interleukin-10 ; metabolism ; Interleukin-2 ; metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Receptors, Interleukin-2 ; Spleen ; cytology ; T-Lymphocytes, Regulatory ; drug effects ; immunology ; metabolism

OBJECTIVETo screen and characterize the short peptides which bind specifically to interleukin-2 (IL-2) receptor alpha chain (IL-2Ralpha) for acquisition of small antagonists for blocking the binding of IL-2 with IL-2Ralpha.

METHODS12-mer phage displayed peptide library was screened with the target cells of MT-2 cells which expressed IL-2Ralpha at high levels. The binding phage clones were eluted by anti-IL-2Ralpha monoclonal antibody. After 3 rounds of screening, the positive phage clones were identified by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, and the amino acid sequences of the positive clones were deduced from the DNA sequences.

RESULTSSeven positive clones were screened out of the 17 phage clones bound to MT-2 cells. The positive clone M15 could bind specifically to MT-2 cell and PHA-activated peripheral blood monouclear cells. Amino acid sequence analysis identified 6 sequences, all of which contained hydrophilic residues, and 5 of these 6 sequences included Tyr, Phe and Leu conservative residues.

CONCLUSIONThe peptide sequences containing Tyr, Phe conservative residues identified in this study can bind to cell surface IL-2Ralpha.

Amino Acid Sequence ; Cell Line, Transformed ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunohistochemistry ; Interleukin-2 ; metabolism ; Interleukin-2 Receptor alpha Subunit ; metabolism ; Peptide Library ; Peptides ; genetics ; metabolism ; Protein Binding ; Receptors, Cell Surface ; metabolism ; T-Lymphocytes ; cytology ; metabolism