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Several Cytokines (several + cytokine)
Selected AbstractsSignal transducers and activators of transcription 3 signaling pathway.INFLAMMATORY BOWEL DISEASES, Issue 2 2005An Essential Mediator of Inflammatory Bowel Disease, Other Forms of Intestinal Inflammation Abstract Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of chronic inflammatory bowel disease (IBD), are characterized by mucosal immune cell activation that is driven by a cytokine imbalance. Several cytokines involved in IBD act through the activation of the signal transducers and activators of transcription (STAT) family. We investigated the activation of STAT3 in the mucosa of CD and UC patients, and evaluated whether this event is specific for IBD patients. Using immunofluorescence and immunoblotting, total and phosphorylated STAT3 levels were assessed in biopsy specimens, isolated lamina propria mononuclear cells, and peripheral blood mononuclear cells from patients with CD, UC, other forms of intestinal inflammation, and control subjects. Immunoblotting revealed phosphorylated STAT3 in mucosal biopsy specimens from patients with CD, UC, celiac disease, and acute self-limited colitis, but not in the normal mucosa of control subjects. In IBD patients, STAT3 activation was confined to actively inflamed areas. Accordingly, activated STAT3 was detected in isolated lamina propria mononuclear cells from inflamed IBD tissues, but not in peripheral blood mononuclear cells from control subjects or IBD patients. Immunofluorescence demonstrated that the sources of activated STAT3 were macrophages and T lymphocytes, but not neutrophils. STAT3 activation also was detected in T cells infiltrating the duodenal mucosa of celiac disease patients. We conclude that STAT3 signaling occurs in both CD and UC, where it is strictly confined to areas of active inflammation and is limited to infiltrating macrophages and T cells. The occurrence of STAT3 signaling in other acute and chronic intestinal inflammatory conditions suggests that, rather than a specific feature of IBD, it represents a fundamental signaling pathway that is shared by multiple forms of gut inflammation. [source] 3364: Cytokines in enucleated eyesACTA OPHTHALMOLOGICA, Issue 2010MJ JAGER Purpose One of the prognostically bad parameters in uveal melanoma is the presence of an inflammatory phenotype, characterized by an increased expression of HLA antigens and an immunologic infiltrate. We wondered whether the presence of specific chemokines and cytokines in the aqueous humor (AqH) from uveal melanoma-containing eyes is associated with this inflammatory phenotype, with the presence of macrophages, and/or with survival. Methods Directly following enucleation, AqH was obtained from 37 eyes containing uveal melanoma. Samples were stored at -80 °C till use. Using a multiplex bead array, 15 different cytokines were measured. Determination of intratumoral macrophages was performed by immunohistochemistry and immunofluorescence. The presence of specific cytokines was compared to histopathological, genetic and clinical tumor characteristics, as well as patient survival. Results Several cytokines showed a significantly higher expression in the AqH from uveal melanoma-containing eyes compared to the AqH from eyes undergoing cataract surgery. Only MCP-3 was associated with the presence of macrophages and the tumor promoting M2-type macrophage in uveal melanoma patients. Hardly any correlations were found between cytokine levels and known prognostic factors for uveal melanoma. Also, cytokine levels were not of predictive value for survival. Conclusion Although increased levels of inflammation-related cytokines are present in the AqH of uveal melanoma-containing eyes, hardly any associations with the presence of macrophages and their subtypes, with clinical and histopathological parameters, and prognosis were found. [source] Multiple cytokines in human tear specimens in seasonal and chronic allergic eye disease and in conjunctival fibroblast culturesCLINICAL & EXPERIMENTAL ALLERGY, Issue 6 2006A. Leonardi Summary Background Several cytokines are involved in the recruitment and activation of inflammatory cells in ocular allergic diseases. The purpose of the study was to assay multiple cytokines and chemokines in tears, to compare subgroups of allergic conjunctivitis (AC) with controls, and in culture supernatants to determine whether conjunctival fibroblasts produce some of these cytokines. Methods Fifty to one hundred microlitre tears were obtained from patients with active seasonal allergic conjunctivitis (SAC; n=12), vernal keratoconjunctivitis (VKC; n=18), atopic keratoconjunctivitis (AKC; n=6) and non-atopic controls (n=14). Primary conjunctival fibroblasts grown in vitro were stimulated with IL-4, IL-13 or TNF-, for 24 h. Cell-free tear and culture supernatants were assayed for IL-1,, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IFN-,, TNF-,, eotaxin, MCP-1 and RANTES using multiplex bead analysis. Induction of chemokine gene expression was determined by PCR. Results IL-1,, IL-2, IL-5, IL-6, IL-12, IL-13, MCP-1 were increased in all tears groups compared with controls, with highly significant correlations between many of these molecules. In addition IL-4, IFN-,, and IL-10 were elevated in SAC and VKC, while eotaxin and TNF-, were only increased in VKC. IL-6, IL-8, MCP-1, RANTES and eotaxin were detected from fibroblasts cultures, and were all up-regulated by TNF-,. By PCR, fibroblasts expressed MCP-1 transcripts constitutively, whereas IP-10 and Mig were up-regulated by TNF-,. Conclusions Differential cytokine levels support tears as a useful indicator of immune mechanisms occurring during AC. The striking similarities in chemokine profiles between tears and fibroblasts suggest these cells as likely sources of chemokines in tears. [source] IL-33 promotes DC development in BM culture by triggering GM-CSF productionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2009Nobuyasu Mayuzumi Abstract Short-term DC cultures generated with GM-CSF and other cytokines have markedly improved our ability to study the immunobiology of DC. Here, we tested 65 cytokines individually for their potential to promote the generation of CD11c+ cells in a murine BM culture system. In addition to several cytokines known to promote DC survival and/or growth, IL-33 was found to augment DC development time- and dose-dependently. Although the resulting CD11c+ cells generated in the presence of IL-33 exhibited a typical dendritic morphology, they expressed MHC class II molecules only at modest levels, showed negligible responses to TLR ligands, produced no detectable IL-12 p70, displayed PD-L1 and PD-L2 on the surface, and failed to activate immunologically naïve T cells efficiently. IL-33-induced expansion of CD11c+ cells was completely blocked by anti-GM-CSF mAb, and GM-CSF mRNA and protein expression in BM culture was markedly elevated by added IL-33, indicating that IL-33 promotes in vitro DC generation indirectly by a GM-CSF-dependent manner. With regard to the cellular source, IL-33-dependent GM-CSF production was observed exclusively within the CD45+/Fc,RI+ BM population. Not only do our results reinforce the notion that GM-CSF serves as a primary DC growth factor, but they also reveal a previously unrecognized mechanism supporting DC development. [source] Cytokine therapy in dermatologyEXPERIMENTAL DERMATOLOGY, Issue 2 2002K. Asadullah Abstract: Cytokines have been in the focus of scientific interest for some years now. Analysing their expression permitted a better understanding of the pathogenesis of various diseases, including in dermatology. Moreover, they are now far beyond the stage when they were of interest only to the pathophysiological research sector: some cytokine therapies are already being employed as part of the clinical practice. In fact, several cytokines are used for the treatment of malignant, inflammatory and infectious skin diseases. Their stage of development ranges from advanced, already approved and well established therapies (e.g. IFN-, and IL-2 for melanoma) to early explorative trials (e.g. IL-4 and IL-10 for psoriasis). Some of the new approaches currently under investigation will actually lead to registration of new drugs for dermatological treatment and to supplement existing therapeutic options. Beside this, the results of clinical trials with cytokines are significantly contributing to our understanding of the pathophysiology of diseases. They will give a better insight into which mechanisms play a greater or lesser part in their development and may generate momentum for still better targeted pharmacological approaches. Here we would like to give an overview about the current stage of cytokine therapy and the prospects for dermatological indications. The terminology and immunobiology of cytokines are also briefly discussed, since for a sensible interpretation of the relevant findings a basic knowledge of these biologically highly active messenger substances is essential. [source] Transcriptional regulation of collagenase-3 by interleukin-1 alpha in osteoblastsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2003Samuel Varghese Abstract Interleukin-1 (IL-1), is an autocrine/paracrine agent of the skeletal tissue and it regulates bone remodeling. Collagenase-3 or matrix metalloproteinase (MMP)-13 is expressed in osteoblasts and its expression is modulated by several cytokines including IL-1,. Because the molecular mechanism of increased synthesis of collagenase-3 in bone cells by IL-1, is not known, we investigated if collagenase-3 expression by IL-1, in osteoblasts is mediated by transcriptional or post-transcriptional mechanisms. Exposure of rat osteoblastic cultures (Ob cells) to IL-1, at concentrations higher than 0.5 nM increased the synthesis of collagenase-3 mRNA up to eightfold and the secretion of immunoreactive protein up to 21-fold. The effects of IL-1, on collagenase-3 were time- and dose-dependent. Although prostaglandins stimulate collagenase-3 expression, stimulation of collagenase-3 in Ob cells by IL-1, was not mediated through increased biosynthesis of prostaglandins. The half-life of collagenase-3 mRNA from control and IL-1,-treated Ob cells was similar suggesting that the stabilization of collagenase-3 mRNA did not contribute to the increase in collagenase-3. However, IL-1, stimulated the rate of transcription of the collagenase-3 gene by twofold to fourfold indicating regulation of collagenase-3 expression in Ob cells at the transcriptional level. Stimulation of collagenase-3 by IL-1, in osteoblasts may in part mediate the effects of IL-1, in bone metabolism. © 2003 Wiley-Liss, Inc. [source] Relationship between IL-1A polymorphisms and gingival overgrowth in renal transplant recipients receiving Cyclosporin AJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 11 2006Nagihan Bostanci Abstract Aim: Levels of interleukin-1, (IL-1,) are elevated in periodontal inflammation. IL-1A gene polymorphisms are associated with inflammatory diseases. This study aimed to investigate IL-1A gene polymorphism in Cyclosporin A (CsA)-treated renal transplant patients and investigate the association between this polymorphism and gingival crevicular fluid (GCF) levels of several cytokines. Materials and Methods: Fifty-one renal transplant patients on CsA treatment (25 with and 26 without gingival overgrowth) and 29 healthy controls were recruited for the study. Demographic, pharmacological and periodontal parameters were recorded and gingival overgrowth was assessed. Results: Multiple regression analysis showed that genotype was significantly associated with gingival overgrowth (p=0.02). Carriage of the IL-1A (,889) T allele was strongly protective [95% confidence interval (CI): 0.046,0.77], although not significantly associated with IL-1, protein levels in GCF. IL-1,, IL-1, and IL-8, but not IL-6, were detected in GCF of CsA-treated patients, but none of them was significantly associated with gingival overgrowth. Conclusions: This study is the first to associate a gene polymorphism as a risk factor for CsA-induced gingival overgrowth in renal transplant patients, demonstrating that IL-1A polymorphism might alter individual susceptibility to CsA. However, there was no association between GCF cytokine levels and the presence of gingival overgrowth or patient IL-1A genotype. [source] cDNA-arrays and real-time quantitative PCR techniques in the investigation of chronic achilles tendinosisJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2003Håkan Alfredson The aetiology and pathogenesis of chronic painful Achilles tendinosis are unknown. This investigation aimed to use cDNA arrays and real-time quantitative polymerase chain reaction (real-time PCR) technique to study tendinosis and control tissue samples. Five patients (females mean age 57.1 ± 4.3 (years ±SD)) with chronic painful Achilles tendinosis were included. From all patients, one biopsy was taken from the area with tendinosis and one from a clinically normal area (control) of the tendon. The tissue samples were immediately immersed in RNAlater and frozen at ,80°C until RNA extraction. Portions of pooled RNA from control and tendinosis sites, respectively, were transcribed to cDNA, radioactively labelled (32P), hybridized to cDNA expression arrays, and exposed to phosphoimager screens over night. Expressions of specific genes, shown to be regulated in the cDNA array analysis, were analyzed in the individual samples using real-time PCR. cDNA arrays showed that gene expressions for matrix-metalloproteinase-2 (MMP-2), fibronectin subunit B (FNRB), vascular endothelial growth factor (VEGF), and mitogen-activated protein kinase p38 (MAPKp38) were up-regulated, while matrix-metalloproteinase-3 (MMP-3) and decorin were down-regulated, in tendinosis tissue compared with control tissue. Using real-time PCR, , and , patients showed up-regulation of MMP-2 and FNRB mRNA, respectively. For decorin, VEGF, and MAPKp38, real-time PCR revealed a great variability among patients. Interestingly, the mRNAs for several cytokines and cytokine receptors were not regulated, indicating the absence of an inflammatory process in chronic painful Achilles tendinosis. In conclusion, cDNA-arrays and real-time PCR can be used to study differences in gene expression levels between tendinosis and control tendon tissue. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Focal adhesion kinase mediates human leukocyte histocompatibility antigen class II-induced signaling in gingival fibroblastsJOURNAL OF PERIODONTAL RESEARCH, Issue 6 2007S. Yoshizawa Background and Objective:, The role of human leukocyte antigen class II molecules on nonantigen-presenting cells has been a matter of controversy. We previously reported that human leukocyte antigen class II molecules on human gingival fibroblasts do not present antigens, but transduce signals into the cells by making a complex with antigenic peptide T-cell receptor or by stimulating cell surface human leukocyte antigen-DR molecules with human leukocyte antigen-DR antibody (L243), which mimics the formation of the human leukocyte antigen class II,antigenic peptide T-cell receptor complex, resulting in the expression of several cytokines. The aim of this study was to detect human leukocyte antigen class II-associated molecules mediating human leukocyte antigen class II-induced signals into the cells. Material and Methods:, Antibody-based protein-microarray analysis was performed to detect activated signaling molecules in gingival fibroblasts stimulated via human leukocyte antigen class II molecules. Then, we examined if these molecules structurally associate with human leukocyte antigen class II and actually transduce signals into the cells. Results:, Stimulation of human leukocyte antigen class II on gingival fibroblasts by L243 resulted in enhanced phosphorylation of focal adhesion kinase. Focal adhesion kinase was co-immunoprecipitated with human leukocyte antigen-DR by L243. Stimulation of gingival fibroblasts with L243 induced phosphorylation of focal adhesion kinase. Luteolin, a putative focal adhesion kinase inhibitor, suppressed phosphorylation of focal adhesion kinase and dose dependently inhibited human leukocyte antigen class II-induced cytokine production. Conclusion:, Focal adhesion kinase is structurally associated with human leukocyte antigen-DR and mediates human leukocyte antigen class II-induced signals in gingival fibroblasts. [source] Tumor necrosis factor-, and interferon-, directly impair epithelial barrier function in cultured mouse cholangiocytesLIVER INTERNATIONAL, Issue 1 2003Hanada Shinichiro Abstract:Background/Aims: In primary biliary cirrhosis (PBC), cytokines from CD4 + T lymphocytes were suggested to contribute to the intralobular bile duct damage together with cellular immunity by CD8 + T lymphocytes. Recently, we reported that immunolocalization of 7H6 , a tight junction (TJ)-associated protein , was significantly diminished in cholangiocytes in the PBC liver. In this study, we examined the direct effects of several cytokines , tumor necrosis factor-, (TNF-,), interferon-, (IFN-,), interleukin-2 and 4 (IL-2 and 4) , on TJ in immortalized mouse cholangiocytes. Moreover, we examined the inhibitory effect of ursodeoxycholic acid (UDCA)on cytokine-induced changes in paracellular permeability. Methods: Barrier function of TJ was evaluated by measuring transepithelial electrical resistance (TER) and 3H-inulin flux. We also performed immunostaining and immunoblotting for TJ-associated proteins , claudin-1 and -3, occludin, zonula occluden-1 (ZO-1) and 7H6. Results: TNF-, and IFN-,, but neither IL-2 nor IL-4, significantly decreased TER (P < 0.005). 3H-inulin flux studies confirmed IFN-,-induced increases in paracellular permeability of cholangiocytes (P < 0.001). In immunostaining and immunoblotting studies, TJ-associated proteins were well preserved in TNF-,- or IFN-,-treated cells. Ursodeoxycholic acidhas been found to have no inhibitory effect on increased paracellular permeability induced by TNF-, or IFN-,. Conclusion: These findings show that TNF-, and IFN-, disrupt barrier function of TJ in cholangiocytes without major structural changes to TJ and suggest that disruption of TJ function and subsequent leakage of the bile constituents may influence the aggravation of cholestasis in PBC. [source] Expulsion of the gastrointestinal cestode, Hymenolepis diminuta by tolerant rats: evidence for mediation by a Th2 type immune enhanced goblet cell hyperplasia, increased mucin production and secretionPARASITE IMMUNOLOGY, Issue 1 2007R. A. WEBB SUMMARY The processes underlying expulsion of Hymenolepis diminuta in rats are not known. Expression levels of mRNAs of several cytokines revealed a Th2 response that differed between worm infection levels. IL-4 protein levels decreased while IL-13 levels increased in a 50-worm infection by 30 dpi; the converse was seen with a five-worm infection. A negative correlation was found between IL-4 or IL-13 mRNA expression and worm biomass, between IL-13 protein levels and worm number or worm biomass, and between IL-4 protein levels and worm biomass in 50-worm infections. A negative correlation between IL-4 mRNA or protein expression and worm biomass was observed with five-worm infections. A strong correlation between Muc2 mRNA expression and decreased worm number or biomass in a 50-worm infection was observed. Muc2 protein, goblet cell numbers and mucin decreased in a 50-worm infection by 20 days post-infection. These changes were not seen with five-worm infections where worms are not expelled. The data show that rats infected with 50 H. diminuta mount a Th2 response leading to high levels of IL-13, increased goblet cell numbers and increased mucin2 production and release. The mucus traps the worms, which are progressively expelled from the small intestine. [source] Pulmonary fibrosis: Cellular and molecular eventsPATHOLOGY INTERNATIONAL, Issue 3 2003Mohammed S. Razzaque Connective tissue remodeling of the interstitium is an important feature of chronic lung diseases encompassing interstitial inflammatory changes and subsequent pulmonary fibrosis. The early inflammatory phase is usually associated with the release of several cytokines and chemokines by activated resident cells and infiltrating cells which, in turn, help further recruit inflammatory mononuclear cells. Cytokines and growth factors secreted by inflammatory cells and by interstitial cells (fibroblasts and myofibroblasts) play an important role in the fibrogenic phase of pulmonary fibrosis by inducing matrix synthesis. In addition, matrix-degrading enzymes and their inhibitors also contribute to extracellular matrix (ECM) remodeling in pulmonary fibrosis. This review addresses the pathophysiology of wound healing and different phases of pulmonary fibrosis. [source] Functional immaturity of cord blood monocytes as detected by impaired response to hepatocyte growth factorPEDIATRICS INTERNATIONAL, Issue 4 2001Qi Jiang AbstractBackground: Monocytes as antigen-presenting cells play an important role in host defense and transplantation. However, there are little reports on cord blood monocytes, and the role of monocytes in cord blood transplantation is largely unknown. Methods and Results: There are several cytokines affecting monocyte function. These include interferon-,, interleukin-4, interleukin-10, granulocyte macrophage-colony stimulating factor and hepatocyte growth factor (HGF). We investigated the effect of these cytokines on antigen-presenting capacity (APC) of cord and adult blood monocytes. Using either mononuclear cells or purified CD4+ T cells as responder cells, HGF enhanced APC of adult monocytes most effectively among these cytokines. In contrast, cord blood monocytes failed to respond to HGF. As HLA, costimulatory and adhesion molecules may affect APC function, we examined these antigens of monocytes following HGF stimulation. The HGF upregulated integrin ,5 subunit (CD49e) and intercellular adhesion molecule-1 (CD54) was expressed in adult blood monocytes, but not in cord blood. In kinetic studies, HGF downregulated c-met protein/HGF receptor expression of adult monocytes in lower concentrations and at shorter incubation time as compared with that of cord blood. Conclusions: The results suggest that impaired response of cord blood monocytes to HGF may be responsible, in large part, for their functional immaturity. [source] Albumin depletion of human plasma also removes low abundance proteins including the cytokinesPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 18 2005Jill Granger Abstract The use of proteomics for efficient, accurate, and complete analysis of clinical samples poses a variety of technical challenges. The presence of higher abundance proteins in the plasma, such as albumin, may mask the detection of lower abundance proteins such as the cytokines. Methods have been proposed to deplete the sample of these higher abundance proteins to facilitate detection of those with lower abundance. In this study, a commercially available albumin depletion kit was used to determine if removal of albumin would measurably reduce detection of lower abundance cytokine proteins in human plasma. The Montage® Albumin Deplete Kit (Millipore) was used to deplete albumin from LPS-stimulated whole blood from 15 normal human donors. Albumin depletion was measured using the BCG reagent and SDS-PAGE, and cytokine recovery was determined by a microassay immunoassay that measures both pro- and anti-inflammatory cytokines. Average albumin depletion from the samples was 72%. However, several cytokines were also significantly reduced when the albumin was removed from the plasma. Additionally, there was a variable reduction in cytokine recovery from a known mixture of cytokines in a minimal amount of plasma that were loaded onto the columns. These data demonstrate that there may be a non-specific loss of cytokines following albumin depletion, which may confound subsequent proteomic analysis. [source] ORIGINAL ARTICLE: IL-10 Modulates Placental Responses to TLR LigandsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2009Mehmet Bayraktar Problem, Intra-uterine infections increase production of pro-inflammatory cytokines. It is unclear whether different infectious agents determine the relative expression of pro-and anti-inflammatory cytokines. Methods of study, We compared the placental inflammatory response induced by bacterial lipopolysaccharide (LPS, endotoxin from Gram-negative bacteria) with those induced by lipoteichoic acid (LTA, a cell wall component of Gram-positive bacteria). Placental explants from term delivery were treated with either LPS or LTA, in the presence or absence of IL-10, for 24 hrs. Cytokines, prostaglandin E2 (PGE2) production and cyclo-oxygenase-2 (COX-2) expression were quantified. Results, Both LTA and LPS significantly induced several cytokines with LPS eliciting more potent effects. IL-6 and IL-8 were induced to comparable levels in response to both LTA and LPS whereas monocyte chemotactic protein-1 (MCP-1) production was induced more by LTA, demonstrating a differential placental response to a specific toll-like receptor (TLR) ligand. IL-10 treatment significantly reduced most pro-inflammatory cytokines as well as PGE2 induced by both LPS and LTA. Interestingly, IL-10 down-regulated LTA-mediated MCP1 induction, but not that mediated by LPS. Moreover, IL-10 was more effective in down-regulating PGE2 after LPS- when compared with LTA stimulation. Conclusions, Our results demonstrate that placental exposure to LTA and LPS appear to trigger distinct cytokine responses that can be modulated by IL-10. [source] 1141636674 Differential serine and tyrosine phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) in Jeg-3 choriocarcinoma cell linesAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2006J Roediger Background:, Signal Transducer and Activator of Transcription 3 (STAT3) is an intracellular signalling molecule, which is used by several cytokines, including leukemia inhibitory factor (LIF), epithelial growth factor (EGF), and interleukin-6 (IL-6). It induces a variety of gene transcripts and cell functions. In trophoblast cells and in tumor cells, its tyrosine phosphorylation is directly linked to their invasiveness. The regulation and function of STAT3 serine phosphorylation is still widely unclear. Material and Methods:, Jeg-3 choriocarcinoma cells were stimulated with different concentrations of EGF, IL-6 and LIF. STAT3 serine (727) and tyrosine (705) phosphorylation were analyzed 5,60 min after stimulation by SDS-PAGE electrophoresis followed by Western blotting. Results:, Jeg-3 cells display spontaneous STAT3 serine phosphorylation. 100 ng/mL EGF induces a time-dependent reduction starting 15 min after stimulation. Tyrosine phosphorylation does not occur spontaneously, but is strongly induced by EGF at all analyzed time points. LIF induces tyrosine phosphorylation, but affects serine phosphorylation only very slightly. IL-6 did not influence neither serine phosphorylation nor tyrosine phosphorylation. Discussion:, The EGF induced STAT3 tyrosine phosphorylation may be responsible for its invasion triggering capacities. The parallel reduction of serine phosphorylation may enhance this effect. LIF was formerly shown to enhance trophoblast invasion via STAT3 tyrosine phosphorylation. IL-6 displays very little effects on STAT3 and seems to use other pathways for signalling. [source] Dysregulation of the Cytokine Network in the Uterus of the Diabetic RatAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2001SERGE PAMPFER Insulin-dependent (type 1) diabetes is an auto-immune disorder that produces secondary complications in numerous non-immunological systems. Changes in the synthesis and action pattern of several cytokines have been associated with the development of these alterations. Based on the clinical facts that the pregnant and non-pregnant functions of the reproductive system are also disrupted by diabetes, our laboratory has decided to concentrate its research activities on the hypothesis that cytokines may be implicated in the uteropathy and embryopathy associated with the metabolic disorder. This review article summarizes our major findings concerning the synthesis of TNF-, and IL-1, in the uterus of diabetic rats, and in cultures of rodent uterine cells upon their exposure to high concentrations of glucose. The paper also reviews evidence that both the peri-implanting embryo and the epithelial cell layer lining the uterine lumen are targets for the deleterious influence of excess TNF-,. If confirmed in the uterus of diabetic patients, these observations may explain how cytokines contribute to the dysregulation of crucial reproductive events like menstruation and embryo implantation in humans. [source] Over-expression of I,B-kinase-, (IKK,/IKKi) induces secretion of inflammatory cytokines in prostate cancer cell linesTHE PROSTATE, Issue 7 2009Benjamin Péant Abstract BACKGROUND Elevated inflammatory cytokine levels in serum have been associated with advanced stage metastasis-related morbidity in prostate cancer. Several studies have shown that IL-6 and IL-8 can accelerate the growth of human prostate cancer cell lines. Previous studies, in murine embryonic fibroblasts, have shown that I,-B kinase-epsilon (IKK,/IKKi)-deficiency results in the reduction of lipopolysaccharide-mediated expression of IL-6. RESULTS In this study, we report that over-expression of IKK, in hormone-sensitive 22Rv1 and LNCaP prostate cancer cells induces the secretion of several inflammatory cytokines including IL-6 and IL-8. Both of these cytokines are secreted by hormone-refractory PC-3 prostate cancer cells and IKK, knock-down in these cells correlates with a strong decrease in IL-6 secretion. Furthermore, we demonstrate that IKK, over-expression does not induce the activation of the IKK, classical targets NF-,B and IRF-3, two transcription factors involved in the regulation of several cytokines. Finally, we observe that high IKK, expression results in its nuclear translocation, a phenomena that is TBK1-independent. CONCLUSIONS This study identifies IKK, as a potential prostate cancer gene that may favor chronic inflammation and create a tumor-supporting microenvironment that promotes prostate cancer progression, particularly by the induction of IL-6 secretion that may act as a positive growth factor in prostate cancer. Prostate 69: 706,718, 2009. © 2009 Wiley-Liss, Inc. [source] Regulation of uterine function by cytokines in cows: Possible actions of tumor necrosis factor-,, interleukin-1, and interferon-,ANIMAL SCIENCE JOURNAL, Issue 3 2006Kiyoshi OKUDA ABSTRACT When animals do not become pregnant, regression of the corpus luteum (CL) is essential for normal cyclicity because it allows the development of a new ovulatory follicle. Luteal regression is caused by a pulsatile release of prostaglandin (PG) F2, from the uterus in the late luteal phase in most mammals including cattle. Although it has been proposed in ruminants that pulsatile PGF2, secretion is generated by a positive feedback loop between luteal and/or hypophyseal oxytocin and uterine PGF2,, the bovine endometrium may possess other mechanisms for initiation of luteolytic PGF2, secretion. There is increasing evidence that several cytokines mainly produced by immune cells modulate CL and uterine function in many species. Tumor necrosis factor-, (TNF-,) stimulates PGF2, output from bovine endometrium not only at the follicular phase but also at the late luteal phase. Administration of TNF-, at a high concentration prolongs luteal lifespan, whereas administration of a low concentration of TNF-, accelerates luteal regression in cows. The data obtained from the authors' previous in vitro and in vivo studies strongly suggest that TNF-, is a crucial factor in regulating luteolysis in cows. The authors' recent study has shown that interleukin-1, mediates PG secretion from bovine endometrium as a local regulator. Furthermore, interferon-, (IFN-,) suppresses the action of TNF-, on PGF2, synthesis by the bovine endometrium in vitro, suggesting that IFN-, plays a luteoprotective role by inhibiting TNF-,-induced PGF2, production in early pregnancy. The purpose of the present review is to summarize current understanding of the endocrine mechanisms that regulate uterine function by cytokines during the estrous cycle and early pregnancy in cows. [source] Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 2 2010Heidi Kokkonen Objective To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA). Methods A nested case,control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system. Results The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1, [IL-1,], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-,, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow,derived factors (IL-7, granulocyte,macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1,). The levels were particularly increased in anti,cyclic citrullinated peptide antibody, and rheumatoid factor,positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell,related cytokines, while chemokines, stromal cell,derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA. Conclusion Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell,related factors); after disease onset, the involvement and activation of the immune system was more general and widespread. [source] Native and transformed ,2 -macroglobulin in plasma from patients with multiple sclerosisACTA NEUROLOGICA SCANDINAVICA, Issue 1 2003M. Gunnarsson Multiple sclerosis (MS) is an inflammatory demyelinating disease with unknown etiology. Various proteinases have been observed in increased levels in the central nervous system of patients with MS, which may contribute to the release of immunogenic myelin components. ,2 -Macroglobulin (,2M) inhibits a broad spectrum of proteinases sterically, undergoing major conformational changes induced by the proteinases themselves. Moreover, ,2M acts as a carrier of several cytokines in the systemic circulation. By use of radial immunodiffusion, we determined the total ,2M levels in plasma from 28 MS patients and 15 control subjects [14 patients with other neurologic diseases (OND) and one healthy individual]. No significant differences in total ,2M concentration were observed between the MS patients and the control subjects. A comparison of the degree of ,2M transformation in MS patients with different disease courses and controls was performed, using monoclonal antibodies (mAbs) specific for binding to native and transformed ,2M, respectively. The fractions of transformed ,2M were significantly increased in patients with secondary or primary progressive disease course compared with the controls. No significant differences were obtained using a native-specific mAb. At least a major proportion of ,2M from the MS patients was able to change conformation from its native to its transformed state, as demonstrated by a shift in mAb reactivity, following methylamine treatment of the plasma samples. In conclusion, the results indicate that plasma ,2M may be inactivated at a higher degree in patients with chronic progressive MS compared with patients with OND. This may influence the levels of proteinases and cytokines in the systemic circulation and may furthermore have diagnostic implications. 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