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Sample records for encoding interleukin-1 receptor

  1. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...

  2. Soluble interleukin-1 receptor, a potential negative regulator of orange-spotted grouper Epinephelus coioides interleukin-1 system.

    Science.gov (United States)

    Lu, D Q; Yao, M; Yi, S B; Li, Y W; Liu, X C; Zhang, Y; Lin, H R

    2013-09-01

    In this study, the cDNA sequence encoding interleukin-1 (Il-1) receptor-like protein of orange-spotted grouper Epinephelus coioides was obtained. The newly identified sequence was named soluble type I Il-1 receptor (sIl-1rI) owing to its structural composition, which had two Ig-like domains, lack of transmembrane region and the Toll/interleukin-1 receptor (TIR) domain, similar to the brown rat Rattus norvegicus soluble Il-1rI. In addition, sequence comparison and phylogenetic analysis indicated that E. coioides sequence had a closer relationship with Il-1rI than Il-1rII. Real-time PCR revealed that sil-1rI mRNA expression presented a process of decrease, restoration and increase in Cryptocaryon irritans-infected E. coioides. The negative correlation between Il-1β and sil-1rI mRNA in C. irritans-infected head-kidney implied the potential negative regulatory role of sil-1rI in E. coioides Il-1 system. The leucocytes incubated with lipopolysaccharide or polyriboinosinic polyribocytidylic acid exhibited different expression profiles of sil-1rI. Recombinant Il-1β (rIl-1β) protein was capable of inducing sil-1rI mRNA under the concentration of 100 ng ml(-1) , suggesting that high dosage or excess Il-1β would stimulate the expression of sil-1rI to maintain the homoeostasis of E. coioides Il-1 system. For the first time, the role of teleost Il-1rI in parasite infection has been identified, and soluble Il-1r was found in fish. © 2013 The Fisheries Society of the British Isles.

  3. Interleukin 1-β, Interleukin-1 Receptor Antagonist, and Interleukin 18 in Children with Acute Spontaneous Urticaria

    Science.gov (United States)

    Machura, E.; Szczepańska, M.; Mazur, B.; Barć-Czarnecka, M.; Kasperska-Zając, A.

    2013-01-01

    Very little is known about the role of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in urticaria. Material and Methods. Serum levels of IL-1β, IL-1 receptor antagonist (IL-1RA), and IL-18 were measured in 56 children with urticaria and in 41 healthy subjects. Results. Serum IL-1β did not differ between children with acute urticaria and controls. Children with single episode of urticaria had higher levels of IL-1RA and IL-18 than healthy subjects. In children with single episode of urticaria, level of IL-1RA correlated with C-reactive protein (CRP), D-dimer, and IL-1β levels. In subjects with recurrence of urticaria IL-1RA was positively correlated with WBC and D-dimer levels. No correlation of cytokine levels and urticaria severity scores (UAS) in all children with urticaria was observed. In children with single episode of urticaria UAS correlated with CRP level. In the group with single episode of urticaria and in children with symptoms of upper respiratory infection, IL-1RA and IL-18 levels were higher than in controls. The former was higher than in noninfected children with urticaria. In conclusion, this preliminary study documents that serum IL-1RA and IL-18 levels are increased in some children with acute urticaria. However further studies are necessary to define a pathogenic role of IL-1β, IL-1RA, and IL-18 in urticaria. PMID:24490166

  4. Interleukin 1-β, Interleukin-1 Receptor Antagonist, and Interleukin 18 in Children with Acute Spontaneous Urticaria

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    E. Machura

    2013-01-01

    Full Text Available Very little is known about the role of interleukin-1β (IL-1β and interleukin-18 (IL-18 in urticaria. Material and Methods. Serum levels of IL-1β, IL-1 receptor antagonist (IL-1RA, and IL-18 were measured in 56 children with urticaria and in 41 healthy subjects. Results. Serum IL-1β did not differ between children with acute urticaria and controls. Children with single episode of urticaria had higher levels of IL-1RA and IL-18 than healthy subjects. In children with single episode of urticaria, level of IL-1RA correlated with C-reactive protein (CRP, D-dimer, and IL-1β levels. In subjects with recurrence of urticaria IL-1RA was positively correlated with WBC and D-dimer levels. No correlation of cytokine levels and urticaria severity scores (UAS in all children with urticaria was observed. In children with single episode of urticaria UAS correlated with CRP level. In the group with single episode of urticaria and in children with symptoms of upper respiratory infection, IL-1RA and IL-18 levels were higher than in controls. The former was higher than in noninfected children with urticaria. In conclusion, this preliminary study documents that serum IL-1RA and IL-18 levels are increased in some children with acute urticaria. However further studies are necessary to define a pathogenic role of IL-1β, IL-1RA, and IL-18 in urticaria.

  5. DMPD: Modulation of Toll-interleukin 1 receptor mediated signaling. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15662540 Modulation of Toll-interleukin 1 receptor mediated signaling. Li X, Qin J.... J Mol Med. 2005 Apr;83(4):258-66. Epub 2005 Jan 21. (.png) (.svg) (.html) (.csml) Show Modulation of Toll-interleukin... 1 receptor mediated signaling. PubmedID 15662540 Title Modulation of Toll-interleukin 1 receptor

  6. Potential Influence of Interleukin-1 Receptor Antagonist Gene Polymorphism on Knee Osteoarthritis Risk

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    Menha Swellam

    2010-01-01

    Full Text Available Objectives: Genes encoding for cytokines have been associated with susceptibility for joint osteoarthritis (OA and interleukin (IL-1 gene is supposed to be involved in the cartilage destruction process. In this regard, interleukin-1 receptor antagonist (IL-1RA competing with IL-1 for binding to its receptor may act as an inhibitor of cartilage breakdown. We assessed the association of primary knee OA with IL-1RA region as a putative factor of susceptibility to knee OA in Egyptian patients.

  7. Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer

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    Nicole Armbruster

    2017-05-01

    Full Text Available Background: Mesenchymal stem cells (MSCs and their chondrogenic differentiation have been extensively investigated in vitro as MSCs provide an attractive source besides chondrocytes for cartilage repair therapies. Here we established prototype foamyviral vectors (FVV that are derived from apathogenic parent viruses and are characterized by a broad host range and a favorable integration pattern into the cellular genome. As the inflammatory cytokine interleukin 1 beta (IL1β is frequently present in diseased joints, the protective effects of FVV expressing the human interleukin 1 receptor antagonist protein (IL1RA were studied in an established in vitro model (aggregate culture system of chondrogenesis in the presence of IL1β.Materials and Methods: We generated different recombinant FVVs encoding enhanced green fluorescent protein (EGFP or IL1RA and examined their transduction efficiencies and transgene expression profiles using different cell lines and human primary MSCs derived from bone marrow-aspirates. Transgene expression was evaluated by fluorescence microscopy (EGFP, flow cytometry (EGFP, and ELISA (IL1RA. For evaluation of the functionality of the IL1RA transgene to block the inhibitory effects of IL1β on chondrogenesis of primary MSCs and an immortalized MSC cell line (TERT4 cells, the cells were maintained following transduction as aggregate cultures in standard chondrogenic media in the presence or absence of IL1β. After 3 weeks of culture, pellets were harvested and analyzed by histology and immunohistochemistry for chondrogenic phenotypes.Results: The different FVV efficiently transduced cell lines as well as primary MSCs, thereby reaching high transgene expression levels in 6-well plates with levels of around 100 ng/ml IL1RA. MSC aggregate cultures which were maintained in chondrogenic media without IL1β supplementation revealed a chondrogenic phenotype by means of strong positive staining for collagen type II and matrix

  8. Characterization of the interleukin 1 receptor-associated kinase 4 (IRAK4)-encoding gene in salmonid fish: the functional copy is rearranged in Oncorhynchus mykiss and that factor can impair TLR signaling in mammalian cells.

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    Brietzke, Andreas; Goldammer, Tom; Rebl, Henrike; Korytář, Tomáš; Köllner, Bernd; Yang, Wei; Rebl, Alexander; Seyfert, Hans-Martin

    2014-01-01

    The interleukin 1 receptor-associated kinase 4 (IRAK4) is an essential factor for TLR-mediated activation of the host's immune functions subsequent to pathogen contact. We have characterized the respective cDNA and gene sequences from three salmonid species, salmon, rainbow trout and maraena whitefish. The gene from salmon is structured into eleven exons, as is the mammalian homologue, while exons have been fused in the genes from the two other salmonid species. Rainbow trout expresses also a pseudogene at low levels. Its basic structure resembles more closely the primordial gene than the functional copy does. The N-terminal death domain and the C-terminal protein kinase domain of the factors are better conserved throughout evolution than the linker domain. The deduced amino acid sequences of the factors from all three species group together in an evolutionary tree of IRAK4 factors. Scrutinizing expression and function of IRAK4 from rainbow trout, we found its highest expression in head kidney and spleen and lowest expression in muscle tissue. Infecting fish with Aeromonas salmonicida did not modulate its expression during 72 h of observation. Expression of a GFP-tagged trout IRAK4 revealed, expectedly, its cytoplasmic localization in human HEK-293 cells. However, this factor significantly quenched in a dose-dependent fashion not only the pathogen-induced stimulation of NF-κB factors in the HEK-293 reconstitution system of TLR2 signaling, but also the basal NF-κB levels in unstimulated control cells. Our data unexpectedly imply that IRAK4 is involved in establishing threshold levels of active NF-κB in resting cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Elevated serum interleukin-1β levels and interleukin-1β-to-interleukin-1 receptor antagonist ratio 1 week after embryo transfer are associated with ectopic pregnancy.

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    Lekovich, Jovana; Witkin, Steven S; Doulaveris, Georgios; Orfanelli, Theofano; Shulman, Brittney; Pereira, Nigel; Rosenwaks, Zev; Spandorfer, Steven D

    2015-11-01

    To investigate whether interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1RA) serum levels in the early luteal phase differ in IVF cycles that result in an ectopic pregnancy (EP) when compared with other outcomes. Retrospective cohort. Not applicable. A total of 307 women whose serum samples were available, with the following IVF outcomes: 103 live births, 80 negative pregnancy tests, 52 biochemical pregnancies, 47 EPs, and 25 miscarriages. Serum samples were obtained on cycle days 24 and 28 (cycle day 14 = day of egg retrieval). Levels of IL-1β and IL-1RA were determined by quantitative ELISA performed by blinded personnel. IL-1β and IL-1RA levels, IL-1β-to-IL-1RA ratio versus cycle outcome. The IL-1β levels were predictive of an EP. At cycle days 24 and 28 the mean IL-1β levels were higher in patients with an EP (127.1 pg/mL and 166.9 pg/mL, respectively) than in women with any other IVF outcome (15.8-55.3 pg/mL and 14.8-75.5 pg/mL, respectively). At cycle day 24 the IL-1β-to-IL-1RA ratio was 0.18 in the ectopic group versus 0.01-0.09 in the other groups. Elevated IL-1β levels and IL-1β-to-IL-1RA ratio as early as 4 days before the first pregnancy test are associated with an EP. If confirmed by prospective studies, clinical application of these findings could potentially improve EP detection. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  10. DEFICIENCY OF INTERLEUKIN-1 RECEPTOR ANTAGONIST RESPONSIVE TO ANAKINRA

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    SCHNELLBACHER, CHARLOTTE; CIOCCA, GIOVANNA; MENENDEZ, ROXANNA; AKSENTIJEVICH, IVONA; GOLDBACH-MANSKY, RAPHAELA; DUARTE, ANAM.; RIVAS-CHACON, RAFAEL

    2012-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acutephase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. PMID:22471702

  11. Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines.

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    Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy; Mayfield, Jody; Harris, R Adron

    2015-08-01

    Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Role of Interleukin-1 Receptor Signaling in the Behavioral Effects of Ethanol and Benzodiazepines

    Science.gov (United States)

    Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Mayfield, Jody; Harris, R. Adron

    2015-01-01

    Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL-1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway. PMID:25839897

  13. The safety of interleukin-1 receptor antagonist (anakinra in the treatment of rheumatoid arthritis

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    L. Riente

    2011-09-01

    Full Text Available The safety profile of interleukin-1 receptor antagonist (anakinra has been studied with randomised, placebo-controlled trials involving 2932 patients affected by rheumatoid arthritis. The most frequently reported adverse events were represented by injection site reactions (71% and headache (13.6%. No statistically significant difference in the incidence of infections was observed among the patients treated with the interleukin-1 receptor antagonist and the patients receiving placebo. In particular, the incidence of serious infections was 1,8% in rheumatoid arthritis patients on anakinra therapy and 0,7% in patients on placebo. The reported serious infections consisted of pneumonia, cellulitis, bone and joint infections, bursitis. No case of opportunistic infections or tubercolosis was observed. The results of clinical studies suggest that anakinra is a new well-tolerated drug for the treatment of patients affected by rheumatoid arthritis.

  14. Radiolabeling with fluorine-18 of a protein, interleukin-1 receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Prenant, C., E-mail: cprenant@cyclopharma.f [Wolfson Molecular Imaging Centre, University of Manchester, Manchester (United Kingdom); Cawthorne, C. [Academic Department of Radiation Oncology, Christie NHS Foundation Trust, Manchester (United Kingdom); Fairclough, M. [Wolfson Molecular Imaging Centre, University of Manchester, Manchester (United Kingdom); Rothwell, N.; Boutin, H. [Faculty of Life Sciences, University of Manchester, Manchester (United Kingdom)

    2010-09-15

    IL-1RA is a naturally occurring antagonist of the pro-inflammatory cytokine interleukin-1 (IL-1) with high therapeutic promise, but its pharmacokinetic remains poorly documented. In this report, we describe the radiolabeling of recombinant human interleukin-1 receptor antagonist (rhIL-1RA) with fluorine-18 to allow pharmacokinetic studies by positron emission tomography (PET). rhIL-1RA was labeled randomly by reductive alkylation of free amino groups (the {epsilon}-amino group of lysine residues or amino-terminal residues) using [{sup 18}F]fluoroacetaldehyde under mild reaction conditions. Radiosyntheses used a remotely controlled experimental rig within 100 min and the radiochemical yield was in the range 7.1-24.2% (decay corrected, based on seventeen syntheses). We showed that the produced [{sup 18}F]fluoroethyl-rhIL-1ra retained binding specificity by conducting an assay on rat brain sections, allowing its pharmakokinetic study using PET.

  15. Association analysis between variants of the interleukin-1β and the interleukin-1 receptor antagonist gene and antidepressant treatment response in major depression

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    André Tadic

    2008-03-01

    Full Text Available André Tadic1, Dan Rujescu2, Matthias J Müller3, Ralf Kohnen4, Hans H. Stassen5, Armin Szegedi6, Norbert Dahmen11Department of Psychiatry, University of Mainz, Germany; 2Department of Psychiatry, University of Munich, Germany; 3Clinic for Psychiatry and Psychotherapy, Marburg-Sued, Germany, and Clinic for Psychiatry and Psychotherapy, Giessen, Germany; 4IMEREM, Nuernberg, Germany; 5Department of Psychiatry, University of Zurich, Switzerland; 6Organon, Roseland, NJ, USAAbstract: This study investigated the possible association of the interleukin-1 beta (IL-1β C-511T promoter polymorphism and the interleukin-1 receptor antagonist (IL-1Ra (86bpn variable number of tandem repeats (VNTR polymorphism with antidepressant response to paroxetine and mirtazapine treatment. The study group consisted of 101 patients suffering from DSM-IV major depression participating in a randomized double-blind controlled clinical trial. Patients homozygous for the IL-1β-511T allele had a significantly faster and more pronounced response to paroxetine treatment than IL-1β-511C allele carriers. No association was found for the IL-1β C-511T polymorphism with mirtazapine treatment response. The IL-1Ra VNTR showed neither an association with paroxetine nor with mirtazapine treatment response. Our results provide further suggestive evidence that time course of response and antidepressant efficacy of paroxetine, but not of mirtazapine, is influenced in a clinically relevant manner by the IL-1β C-511T gene variant. Our data do not support the hypothesis that the IL-1Ra (86bpn VNTR affects antidepressant treatment response to paroxetine or mirtazapine. An independent replication of our finding is needed. If replicated, the IL-1β C-511T promoter polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.Keywords: major depression, antidepressive agents, treatment outcome, interleukin-1 beta, interleukin-1

  16. DMPD: The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling networks controlling inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18249132 The involvement of the interleukin-1 receptor-associated kinases (IRAKs) i...2008 Jan 30. (.png) (.svg) (.html) (.csml) Show The involvement of the interleukin-1 receptor-associated kin...49132 Title The involvement of the interleukin-1 receptor-associated kinases (IRAKs) incellular signaling ne

  17. MicroRNAs and Toll-like Receptor/Interleukin-1 Receptor Signaling

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    Virtue Anthony

    2012-10-01

    Full Text Available Abstract The discovery of miRNAs has revolutionized the way we examine the genome, RNA products, and the regulation of transcription and translation. Their ability to modulate protein expression through mRNA degradation and translation repression resulted in avid scientific interest in miRNAs over the past decade. This research has led to findings that indicate miRNAs can regulate an array of cellular functions such as cellular apoptosis, proliferation, differentiation, and metabolism. Specifically, the capability of miRNAs to finely-tune gene expression naturally lends itself to immune system regulation which requires precise control for proper activity. In fact, abnormal miRNAs expression is often seen with inflammatory disorders like rheumatoid arthritis, systemic lupus erthematosus, experimental autoimmune encephalomyelitis, and inflammatory cancers. As a result, research investigating miRNAs modulation of immune cell proliferation, differentiation, and cellular signaling has yielded fruitful results. Specifically, in this review, we will examine the impact of miRNAs on toll-like receptor (TLRs and interleukin-1β (IL-1β signaling, which are integral in the proper functioning of the innate immune system. These signaling pathways share several key downstream signaling adaptors and therefore produce similar downstream effects such as the production of pro-inflammatory cytokines, chemokines, and interferons. This review will examine in depth the specific interactions of miRNAs with receptors, adaptor molecules, and regulator molecules within these cellular pathways. In addition, we will discuss the modulation of miRNAs’ expression by TLR and IL-1R signaling through positive and negative feedback loops.

  18. Interleukin 1 receptor antagonist inhibits the augmentation of metastasis induced by interleukin 1 or lipopolysaccharide in a human melanoma/nude mouse system.

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    Chirivi, R G; Garofalo, A; Padura, I M; Mantovani, A; Giavazzi, R

    1993-10-15

    This study examined the ability of the recombinant human interleukin 1 receptor antagonist (IL-1ra) to block interleukin 1 (IL-1)-mediated experimental metastases from the A375M human melanoma. In vivo, IL-1ra administrated at concentrations > or = 200 times IL-1 significantly inhibited the increase in lung colonies induced by IL-1 in nude mice. The response to IL-1 was significantly inhibited when IL-1ra was administered simultaneously with or 1 to 3 h before IL-1. In vitro, the incubation of IL-1-activated endothelial cells with IL-1ra prevented the increase in adhesion of A375M melanoma cells. At the same experimental conditions, IL-1ra inhibited the augmented expression of the intracellular and vascular cell adhesion molecules 1 and E-selectin induced by IL-1 on endothelial cells. Lipopolysaccharide, an IL-1 inducer, increased the number of lung colonies in nude mice. IL-1ra injected with or 1 h after lipopolysaccharide inhibited this augmentation, suggesting a role for host-produced IL-1 in metastasis formation.

  19. Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats

    DEFF Research Database (Denmark)

    Zumsteg, U; Reimers, J I; Pociot, F

    1993-01-01

    The monokines interleukin-1 alpha and -beta have been implicated as effector molecules in the immune-mediated pancreatic beta-cell destruction leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and glucagon release of rat...... thymocytes with a 50% inhibitory concentration of 10- and 100-fold molar excess, respectively. Complete inhibition was obtained with a 100-1,000-fold molar excess. However, at a 100-fold molar excess the interleukin-1 receptor antagonist did not antagonise the potentiating effect of interleukin-1 beta on rat...... islet insulin accumulation during 3 and 6 h of exposure or of interleukin-1 beta-induced inhibition of insulin release after 24 h. In contrast, interleukin-1 beta-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antagonist. A 10,000-fold...

  20. Interleukin-1 Receptors Are Differentially Expressed in Normal and Psoriatic T Cells

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    Attila Bebes

    2014-01-01

    Full Text Available This study was carried out to examine the possible role of interleukin-1 (IL-1 in the functional insufficiency of regulatory T cells in psoriasis, by comparing the expression of IL-1 receptors on healthy control and psoriatic T cells. Patients with moderate-to-severe chronic plaque psoriasis and healthy volunteers, matched in age and sex, were selected for all experiments. CD4+CD25− effector and CD4+CD25+CD127low regulatory T cells were separated and used for the experiments. Expression of the mRNA of IL-1 receptors (IL-1R1, IL-1R2, and sIL-1R2 was determined by quantitative real-time RT-PCR. Cell surface IL-1 receptor expression was assessed by flow cytometry. Relative expression of the signal transmitting IL-1 receptor type 1 (IL-1R1 mRNA is higher in resting psoriatic effector and regulatory T cells, and activation induces higher IL-1R1 protein expression in psoriatic T cells than in healthy cells. Psoriatic regulatory and effector T cells express increased mRNA levels of the decoy IL-1 receptors (IL-1R2 and sIL-1R2 upon activation compared to healthy counterparts. Psoriatic T cells release slightly more sIL-1R2 into their surrounding than healthy T cells. In conclusion, changes in the expression of IL-1 receptors in psoriatic regulatory and effector T cells could contribute to the pathogenesis of psoriasis.

  1. Interleukin Expression after Injury and the Effects of Interleukin-1 Receptor Antagonist

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    Chamberlain, Connie S.; Leiferman, Ellen M.; Frisch, Kayt E.; Brickson, Stacey L.; Murphy, William L.; Baer, Geoffrey S.; Vanderby, Ray

    2013-01-01

    Ligament healing follows a series of complex coordinated events involving various cell types, cytokines, as well as other factors, producing a mechanically inferior tissue more scar-like than native tissue. Macrophages provide an ongoing source of cytokines to modulate inflammatory cell adhesion and migration as well as fibroblast proliferation. Studying interleukins inherent to ligament healing during peak macrophage activation and angiogenesis may elucidate inflammatory mediators involved in subsequent scar formation. Herein, we used a rat healing model assayed after surgical transection of their medial collateral ligaments (MCLs). On days 3 and 7 post-injury, ligaments were collected and used for microarray analysis. Of the 12 significantly modified interleukins, components of the interleukin-1 family were significantly up-regulated. We therefore examined the influence of interleukin-1 receptor antagonist (IL-1Ra) on MCL healing. Transected rat MCLs received PBS or IL-1Ra at the time of surgery. Inhibition of IL-1 activation decreased pro-inflammatory cytokines (IL-1α, IL-1β, IL-12, IL-2, and IFN-γ), myofibroblasts, and proliferating cells, as well as increased anti-inflammatory cytokines (IL-10), endothelial cells/blood vessel lumen, M2 macrophages, and granulation tissue size without compromising the mechanical properties. These results support the concept that IL-1Ra modulates MCL-localized granulation tissue components and cytokine production to create a transient environment that is less inflammatory. Overall, IL-1Ra may have therapeutic potential early in the healing cascade by stimulating the M2 macrophages and altering the granulation tissue components. However, the single dose of IL-1Ra used in this study was insufficient to maintain the more regenerative early response. Due to the transient influence on most of the healing components tested, IL-1Ra may have greater therapeutic potential with sustained delivery. PMID:23936523

  2. Interleukin 1 receptor contributes to methamphetamine- and sleep deprivation-induced hypersomnolence.

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    Schmidt, Michelle A; Wisor, Jonathan P

    2012-04-04

    Methamphetamine-induced wakefulness is dependent on monoamine transporter blockade. Subsequent to methamphetamine-induced wakefulness, the amount of time spent asleep and the depth of sleep are increased relative to baseline sleep. The mechanisms that drive methamphetamine-induced hypersomnolence are not fully understood. We recently observed that methamphetamine exposure elevates the expression of the sleep-promoting cytokine, interleukin-1β in CD11b-positive monocytes within the brain. Here, we sought to determine whether activation of the interleukin 1 receptor (IL1R) drives the increase in the depth and amount of sleep that occurs subsequent to methamphetamine-induced wakefulness. IL1R-deficient mice and wild type control mice were subjected to systemic methamphetamine (1 and 2mg/kg) and saline treatments. The wake-promoting effect of methamphetamine was modestly potentiated by IL1R-deficiency. Additionally, the increase in time spent in NREMS subsequent to methamphetamine-induced wakefulness in wild type mice was abolished in IL1R-deficient mice. The increase in time spent asleep after 3h of behaviorally enforced wakefulness was also abolished in IL1R-deficient mice. Increases in EEG slow wave activity triggered by methamphetamine and sleep deprivation were of equal magnitude in IL1R-deficient and wild type mice. These data demonstrate that IL1R activation contributes to hypersomnolence that occurs after sleep loss, whether that sleep loss is triggered pharmacologically by methamphetamine or through behavioral sleep deprivation. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  3. Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist

    DEFF Research Database (Denmark)

    Klementiev, Boris; Li, Shizhong; Korshunova, Irina

    2014-01-01

    Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide.......Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide....

  4. The effects of dexamethasone and chlorpromazine on tumour necrosis factor-alpha, interleukin-1 beta, interleukin-1 receptor antagonist and interleukin-10 in human volunteers.

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    Bleeker, M W; Netea, M G; Kullberg, B J; Van der Ven-Jongekrijg, J; Van der Meer, J W

    1997-01-01

    Tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) are pro-inflammatory cytokines that play an important role in severe infections, whereas IL-1 receptor antagonist (IL-1ra) and IL-10 are anti-inflammatory cytokines that counteract their effects. Chlorpromazine and dexamethasone protect mice against lethal endotoxaemia by decreasing circulating concentrations of TNF-alpha and IL-1 beta. We investigated whether administration of chlorpromazine or dexamethasone to human volunteers is able to modulate the lipopolysaccharide (LPS)-stimulated cytokine production capacity in whole blood. Blood samples were taken before and several time-points after medication. Circulating cytokine concentrations were low in all samples. LPS-induced TNF-alpha and IL-1 beta production in whole blood was inhibited by dexamethasone treatment, while chlorpromazine had no effect. When peripheral blood mononuclear cells were stimulated in vitro with LPS, the addition of chlorpromazine (1-100 ng/ml) had no modulatory action on TNF-alpha, IL-1 beta, IL-1ra or IL-10 synthesis. The chlorpromazine concentrations measured in circulation of volunteers were eight to 40 times lower than the concentrations shown to be effective in mice. In conclusion, chlorpromazine inhibits TNF-alpha and IL-1 beta production in mice at concentrations that cannot be reached in humans, thus precluding its usage in clinical anti-cytokine strategies. In contrast, dexamethasone is an effective inhibitor of pro-inflammatory cytokine production. PMID:9378493

  5. Interleukin-1 receptor is a target for adjunctive control of diazepam-refractory status epilepticus in mice.

    Science.gov (United States)

    Xu, Zheng-Hao; Wang, Yi; Tao, An-Feng; Yu, Jie; Wang, Xiao-Yu; Zu, Yun-Yun; Zhang, Shi-Hong; Chen, Zhong

    2016-07-22

    Proinflammatory cytokine interleukin-1 beta (IL-1β) may accumulate in the brain during status epilepticus, but whether it contributes to the progressive refractoriness of SE remains unclear. By using a kainic acid-induced SE mice model, we tested whether pharmacological blockade or knock-out of interleukin-1 receptor type 1 (IL-1R1) could influence the diazepam-refractory phenomenon of prolonged SE. We confirmed diazepam failed to terminate prolonged SE (allowed to continue for 40min before diazepam administration). The expression level of IL-1β in the hippocampus during prolonged SE was significantly higher than that of baseline. Interestingly, prolonged SE was not diazepam-refractory in IL-1R1 knock-out mice. Moreover, administration of interleukin-1 receptor antagonist (IL-1RA) combined with diazepam terminated established prolonged SE, while IL-1RA alone is not capable to terminate prolonged SE. On the contrary, administration of recombinant human IL-1β weakens the efficacy of diazepam by prolonging its latency to terminate non-prolonged SE. Thus, the present study provides direct evidence that accumulated IL-1β contributed to the diazepam refractoriness of prolonged SE, and suggests that interleukin-1 receptor is a target for adjunctive control of diazepam-refractory SE. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Amniotic-fluid-derived mesenchymal stem cells overexpressing interleukin-1 receptor antagonist improve fulminant hepatic failure.

    Directory of Open Access Journals (Sweden)

    Yu-Bao Zheng

    Full Text Available Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of fulminant hepatic failure (FHF. The major acute-phase mediators associated with FHF, including IL-1β, IL-6, and TNF-α, impair the regeneration of liver cells and stem cell grafts. Amniotic-fluid-derived mesenchymal stem cells (AF-MSCs have the capacity, under specific conditions, to differentiate into hepatocytes. Interleukin-1-receptor antagonist (IL-1Ra plays an anti-inflammatory and anti-apoptotic role in acute and chronic inflammation, and has been used in many experimental and clinical applications. In the present study, we implanted IL-1Ra-expressing AF-MSCs into injured liver via the portal vein, using D-galactosamine-induced FHF in a rat model. IL-1Ra expression, hepatic injury, liver regeneration, cytokines (IL-1β, IL-6, and animal survival were assessed after cell transplantation. Our results showed that AF-MSCs over-expressing IL-1Ra prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and increased survival rates after injection with these cells. Using green fluorescent protein as a marker, we demonstrated that the engrafted cells and their progeny were incorporated into injured livers and produced albumin. This study suggests that AF-MSCs genetically modified to over-express IL-1Ra can be implanted into the injured liver to provide a novel therapeutic approach to the treatment of FHF.

  7. Interleukin-1 receptor antagonist prevents embryonic implantation by a direct effect on the endometrial epithelium.

    Science.gov (United States)

    Simón, C; Valbuena, D; Krüssel, J; Bernal, A; Murphy, C R; Shaw, T; Pellicer, A; Polan, M L

    1998-11-01

    To investigate the embryonic and/or endometrial molecular mechanisms underlying the antiimplantation effect of interleukin-1 receptor antagonist (IL-1ra). Controlled experiment. Animal facilities at Stanford University and laboratories of the Instituto Valenciano de Infertilidad and the University of Sydney. Twelve-week-old B6C3F-1 female mice. Intraperitoneal injections of recombinant human IL-1ra during the periimplantation period. Implantation sites, embryonic morphology, and viability. Polymerase chain reaction and immunohistochemistry for integrins and extracellular matrices and transmission electron microscopy of endometrium in IL-1ra-treated versus control animals. Pregnancy rates in control and IL-1ra-injected animals were 60% and 13%, respectively. At day 8 of pregnancy, flushing of uteri obtained from the treated group resulted in 32 blastocysts. Six pseudopregnant animals received IL-1ra-treated blastocysts (left horn) and control blastocysts (right horn), resulting in one pregnancy, with two embryos and one embryo in the left and right horns, respectively. At day 4 of pregnancy, IL- 1ra down-regulated alpha4 mRNA with use of the polymerase chain reaction. Immunohistochemistry showed a decrease of alpha4, alpha v, and beta3, and transmission electron microscopy revealed inhibition of transformation of the plasma membrane. Impairment of embryonic adhesion with IL-1ra is mediated through a direct effect on transformation of the epithelial plasma membrane at the time of implantation as a result of down-regulation of alpha4, alpha v, and beta3.

  8. Human Interleukine-1 receptor antagonist:Cloning, Expression and Optimization in E.coli Host

    Directory of Open Access Journals (Sweden)

    Gh. Barati

    2014-07-01

    Full Text Available Introduction & Objective: Interleukine-1 receptor antagonist (IL-1RA is a powerful anti-inflammatory cytokine which limits the biological effects of IL-1. Due to structural similarity between IL-1 and its antagonist, IL-1RA competitively binds to IL-1 receptor which leads to no signal transduction. Therefore , it is applied in the treatment of patients with inflammatory diseases such as Rheumatoid Arthritis. The aim of this study is cloning, expression and op-timization of IL-1RA in E. coli. Materials & Methods: In this experimental study synthetically prepared cDNA was amplified by PCR. After double digestion with NdeI and XhoI restriction enzymes, this gene was cloned in pET28a expression vector. Expression of desired gene was analyzed at RNA level by RT-PCR and at protein level by SDS-PAGE and followed by western blot to confirm SDS-PAGE results. Optimization of recombinant protein expression was performed in dif-ferent IPTG concentrations and harvesting times after induction. Results: The presence of gene in pET28a was determined by colony-PCR and confirmed by restriction digestion. Transcription of cloned gene and expression of high yield recombinant protein were shown by RT-PCR and SDS-PAGE, respectively. The result of SDS-PAGE was confirmed by western blot. Expression was optimized in different induction time and IPTG concentrations Conclusion: The result of this study demonstrated expression of this recombinant protein at high level in E.coli system by pET28a expression vector. This study also showed a direct as-sociation between the increased level of expression and time of induction . Therefore, an overnight induction time with 0.1 mM IPTG concentration is recommended for a high level expression. (Sci J Hamadan Univ Med Sci 2014; 21 (2:145-151

  9. Structure-function similarities between a plant receptor-like kinase and the human interleukin-1 receptor-associated kinase-4

    NARCIS (Netherlands)

    Klaus-Heisen, D.; Nurisso, A.; Pietraszewska-Bogiel, A.; Mbengue, M.; Camut, S.; Timmers, T.; Pichereaux, C.; Rossignol, M.; Gadella, T.W.J.; Imberty, A.; Lefebvre, B.; Cullimore, J.V.

    2011-01-01

    Phylogenetic analysis has previously shown that plant receptor-like kinases (RLKs) are monophyletic with respect to the kinase domain and share an evolutionary origin with the animal interleukin-1 receptor-associated kinase/Pelle-soluble kinases. The lysin motif domain-containing receptor-like

  10. Controlled Release of Interleukin-1 Receptor Antagonist from Hyaluronic Acid-Chitosan Microspheres Attenuates Interleukin-1β-Induced Inflammation and Apoptosis in Chondrocytes

    Directory of Open Access Journals (Sweden)

    Bo Qiu

    2016-01-01

    Full Text Available This paper investigates the protective effect of interleukin-1 receptor antagonist (IL-1Ra released from hyaluronic acid chitosan (HA-CS microspheres in a controlled manner on IL-1β-induced inflammation and apoptosis in chondrocytes. The IL-1Ra release kinetics was characterized by an initial burst release, which was reduced to a linear release over eight days. Chondrocytes were stimulated with 10 ng/ml IL-1β and subsequently incubated with HA-CS-IL-1Ra microspheres. The cell viability was decreased by IL-1β, which was attenuated by HA-CS-IL-1Ra microspheres as indicated by an MTT assay. ELISA showed that HA-CS-IL-1Ra microspheres inhibited IL-1β-induced inflammation by attenuating increases in NO2- and prostaglandin E2 levels as well as increase in glycosaminoglycan release. A terminal deoxyribonucleotide transferase deoxyuridine triphosphate nick-end labeling assay revealed that the IL-1β-induced chondrocyte apoptosis was decreased by HA-CS-IL-1Ra microspheres. Moreover, HA-CS-IL-1Ra microspheres blocked IL-1β-induced chondrocyte apoptosis by increasing B-cell lymphoma 2 (Bcl-2 and decreasing Bcl-2-associated X protein and caspase-3 expressions at mRNA and protein levels, as indicated by reverse-transcription quantitative polymerase chain reaction and western blot analysis, respectively. The results of the present study indicated that HA-CS-IL-1Ra microspheres as a controlled release system of IL-1Ra possess potential anti-inflammatory and antiapoptotic properties in rat chondrocytes due to their ability to regulate inflammatory factors and apoptosis associated genes.

  11. Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist

    Directory of Open Access Journals (Sweden)

    Hollister J Roger

    2009-12-01

    Full Text Available Abstract Purpose We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA taking Interleukin-1 receptor antagonist (IL1RA. Methods Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS, malignancy, and drug reaction. Results In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month. Conclusions Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.

  12. Interleukin-1 receptor antagonist protects against lipopolysaccharide induced diaphragm weakness in preterm lambs.

    Directory of Open Access Journals (Sweden)

    Kanakeswary Karisnan

    Full Text Available Chorioamnionitis (inflammation of the fetal membranes is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA lipopolysaccharide (LPS is orchestrated via interleukin 1 (IL-1. We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra (Anakinra; 100 mg or saline (Sal 3 h prior to second IA injections of LPS (4 mg or Sal at 119d gestational age (GA. Preterm lambs were killed after delivery at 121d GA (term = 150 d. Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group was 25% lower than in control lambs (Sal/Sal group; p=0.025. LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.

  13. In vivo mucosal delivery of bioactive human interleukin 1 receptor antagonist produced by Streptococcus gordonii

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    Tagliabue Aldo

    2003-09-01

    Full Text Available Abstract Background Interleukin-1 (IL-1 is a cytokine involved in the initiation and amplification of the defence response in infectious and inflammatory diseases. IL-1 receptor antagonist (IL-1ra is an inactive member of the IL-1 family and represents one of the most potent mechanisms for controlling IL-1-dependent inflammation. IL-1ra has proven effective in the therapy of acute and chronic inflammatory diseases in experimental animal models and also in preliminary clinical trials. However, optimisation of therapeutic schedules is still needed. For instance, the use of drug delivery systems targeting specific mucosal sites may be useful to improve topical bioavailability and avoid side effects associated with systemic administration. Results In order to develop systems for the delivery of IL-1ra to mucosal target sites, a Streptococcus gordonii strain secreting human IL-1ra was constructed. The recombinant IL-1ra produced by S. gordonii was composed of the four amino acid residues RVFP of the fusion partner at the N-terminus, followed by the mature human IL-1ra protein. RFVP/IL-1ra displayed full biological activity in vitro in assays of inhibition of IL-1β-induced lymphocyte proliferation and was released by recombinant S. gordonii in vivo both at the vaginal and the gastrointestinal mucosa of mice. RFVP/IL-1ra appeared beneficial in the model of ulcerative colitis represented by IL-2-/- mice (knock-out for the interleukin-2 gene, as shown by the body weight increase of IL-2-/- mice locally treated with S. gordonii producing RFVP/IL-1ra. Conclusions These results indicate that recombinant S. gordonii can be successfully used as a delivery system for the selective targeting of mucosal surfaces with therapeutic proteins.

  14. Good response to infliximab in rheumatoid arthritis following failure of interleukin-1 receptor antagonist.

    Science.gov (United States)

    Bao, Jun; Yue, Tao; Li, Ting; He, Dong-Yi; Bao, Yi-Xiao

    2016-04-01

    To evaluate the efficacy of tumor necrosis factor inhibitor infliximab in patients with rheumatoid arthritis (RA) who were disease-resistant to recombinant human interleukin-1 receptor antagonist (IL-1Ra). A total of 104 patients with active RA despite methotrexate (MTX) treatment were enrolled in the open trial. Among them, 27 IL-1Ra nonresponders 'Switchers' and 51 biologic-naive patients 'Naivers' received an infusion of 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy, while the other 26 patients who had never received any biologics 'Controls' continued MTX monotherapy. Clinical outcomes and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks with the American College of Rheumatology (ACR) core set criteria, the Disease Activity Score in 28 joints, and records of adverse events (AEs) and abnormal laboratory findings. At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers, compared with 23% of Controls (P = 0.0013 and 0.0126, respectively). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient's assessment of pain, patient's and physician's global assessment of disease activity, erythrocyte sedimentation rate and C-reactive protein. Switchers even achieved a greater benefit from health assessment questionnaire (HAQ) scores than Naivers. Infliximab was well tolerated, with a similar incidence of AEs across all study groups. Switching from IL-1Ra to infliximab is effective in improving disease activity and maintaining joint function. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  15. Interleukin-1 receptor antagonist modulates the early phase of liver regeneration after partial hepatectomy in mice.

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    Antonino Sgroi

    Full Text Available BACKGROUND: Cytokine administration is a potential therapy for acute liver failure by reducing inflammatory responses and favour hepatocyte regeneration. The aim of this study was to evaluate the role of interleukin-1 receptor antagonist (IL-1ra during liver regeneration and to study the effect of a recombinant human IL-1ra on liver regeneration. METHODS: We performed 70%-hepatectomy in wild type (WT mice, IL-1ra knock-out (KO mice and in WT mice treated by anakinra. We analyzed liver regeneration at regular intervals by measuring the blood levels of cytokines, the hepatocyte proliferation by bromodeoxyuridin (BrdU incorporation, proliferating cell nuclear antigen (PCNA and Cyclin D1 expression. The effect of anakinra on hepatocyte proliferation was also tested in vitro using human hepatocytes. RESULTS: At 24h and at 48 h after hepatectomy, IL-1ra KO mice had significantly higher levels of pro-inflammatory cytokines (IL-6, IL-1β and MCP-1 and a reduced and delayed hepatocyte proliferation measured by BrdU incorporation, PCNA and Cyclin D1 protein levels, when compared to WT mice. IGFBP-1 and C/EBPβ expression was significantly decreased in IL-1ra KO compared to WT mice. WT mice treated with anakinra showed significantly decreased levels of IL-6 and significantly higher hepatocyte proliferation at 24h compared to untreated WT mice. In vitro, primary human hepatocytes treated with anakinra showed significantly higher proliferation at 24h compared to hepatocytes without treatment. CONCLUSION: IL1ra modulates the early phase of liver regeneration by decreasing the inflammatory stress and accelerating the entry of hepatocytes in proliferation. IL1ra might be a therapeutic target to improve hepatocyte proliferation.

  16. Variant interleukin 1 receptor antagonist gene alleles in sudden infant death syndrome.

    Science.gov (United States)

    Highet, Amanda R; Gibson, Catherine S; Goldwater, Paul N

    2010-12-01

    To investigate if carriage of interleukin 1 (IL-1) receptor antagonist gene variants are associated with sudden infant death syndrome (SIDS) in a large cohort of case-control demographically matched infants. 118 SIDS and 233 control infants, who were matched to each SIDS infant by date of birth, sex, birth weight (±500 g), gestational age and ethnicity, were genotyped for an IL-1RN 89 bp tandem repeat polymorphism and analysed for significant associations. No significant difference in genotype frequencies was observed between low and normal birthweight infants and year of birth (1987-1994, when the SIDS incidence was higher). In infants born between 1987 and 1994, an association was observed with SIDS and allele 2 where 18% of SIDS infants carried the 2/2 genotype compared with 9% of controls (χ(2) p=0.026, OR 2.46). Allele 3 was found at a low frequency, but was significantly more common in SIDS infants (3.1%) compared with controls (0.9%, Fisher's exact p=0.04, OR 3.76). The higher prevalence of IL-1RN allele 2, which predisposes to poor outcomes from infection, in SIDS infants born between 1987 and 1994 (ie, prior to the dramatic decrease in SIDS incidence) suggests that the high incidence during this period could point to infection playing a role in aetiology. An association of IL-1RN allele 3 with SIDS was also found, but should be interpreted with caution due to the low frequency of this variant. The consequence of allele 3 carriage is currently unknown in the absence of functionality studies for this isoform.

  17. Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain.

    Science.gov (United States)

    Semple, Bridgette D; O'Brien, Terence J; Gimlin, Kayleen; Wright, David K; Kim, Shi Eun; Casillas-Espinosa, Pablo M; Webster, Kyria M; Petrou, Steven; Noble-Haeusslein, Linda J

    2017-08-16

    Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by ex vivo magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility. SIGNIFICANCE STATEMENT Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments

  18. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance

    NARCIS (Netherlands)

    Poppel, P.C.M. van; Asseldonk, E.J.P. van; Holst, J.J.M. van der; Vilsboll, T.; Netea, M.G.; Tack, C.J.J.

    2014-01-01

    Inflammation at the level of the beta cell appears to be involved in progressive beta-cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin-1 (IL-1) by anakinra [recombinant human interleukin-1 receptor antagonist (IL-1Ra)] on beta-cell function. Sixteen participants

  19. Cross-linking of the beta-glucan receptor on human monocytes results in interleukin-1 receptor antagonist but not interleukin-1 production

    NARCIS (Netherlands)

    Poutsiaka, D D; Mengozzi, M; Vannier, E; Sinha, B; Dinarello, C A

    1993-01-01

    The beta-glucan receptor, found on monocytes and neutrophils, binds glucose polymers derived from fungi. Ligands for the receptor have various immunomodulatory effects, including increased microbicidal killing activity. We have investigated the effect of beta-glucans on the production of

  20. Interleukin 1 receptor contributes to methamphetamine- and sleep deprivation-induced hypersomnolence

    OpenAIRE

    Schmidt, Michelle A.; Wisor, Jonathan P

    2012-01-01

    Methamphetamine-induced wakefulness is dependent on monoamine transporter blockade. Subsequent to methamphetamine-induced wakefulness, the amount of time spent asleep and the depth of sleep are increased relative to baseline sleep. The mechanisms that drive methamphetamine-induced hypersomnolence are not fully understood. We recently observed that methamphetamine exposure elevates the expression of the sleep-promoting cytokine, interleukin-1 β in CD11b-positive monocytes within the brain. Her...

  1. An Epstein-Barr Virus MicroRNA Blocks Interleukin-1 (IL-1) Signaling by Targeting IL-1 Receptor 1.

    Science.gov (United States)

    Skinner, Camille M; Ivanov, Nikita S; Barr, Sarah A; Chen, Yan; Skalsky, Rebecca L

    2017-11-01

    Epstein-Barr virus (EBV) encodes >44 viral microRNAs (miRNAs) that are differentially expressed throughout infection, can be detected in Epstein-Barr virus (EBV)-positive tumors, and manipulate several biological processes, including cell proliferation, apoptosis, and immune responses. Here, we show that EBV BHRF1-2 miRNAs block NF-κB activation following treatment with proinflammatory cytokines, specifically interleukin-1β (IL-1β). Analysis of EBV PAR-CLIP miRNA targetome data sets combined with pathway analysis revealed multiple BHRF1-2 miRNA targets involved in interleukin signaling pathways. By further analyzing changes in cellular gene expression patterns, we identified the IL-1 receptor 1 (IL1R1) as a direct target of miR-BHRF1-2-5p. Targeting the IL1R1 3' untranslated region (UTR) by EBV miR-BHRF1-2-5p was confirmed using 3'-UTR luciferase reporter assays and Western blot assays. Manipulation of EBV BHRF1-2 miRNA activity in latently infected B cells altered steady-state cytokine levels and disrupted IL-1β responsiveness. These studies demonstrate functionally relevant BHRF1-2 miRNA interactions during EBV infection, which is an important step in understanding their roles in pathogenesis. IMPORTANCE IL-1 signaling plays an important role in inflammation and early activation of host innate immune responses following virus infection. Here, we demonstrate that a viral miRNA downregulates the IL-1 receptor 1 during EBV infection, which consequently alters the responsiveness of cells to IL-1 stimuli and changes the cytokine expression levels within infected cell populations. We postulate that this viral miRNA activity not only disrupts IL-1 autocrine and paracrine signaling loops that can alert effector cells to sites of infection but also provides a survival advantage by dampening excessive inflammation that may be detrimental to the infected cell. Copyright © 2017 American Society for Microbiology.

  2. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance

    DEFF Research Database (Denmark)

    van Poppel, P C M; van Asseldonk, E J P; Holst, Jens Juul

    2014-01-01

    Inflammation at the level of the β cell appears to be involved in progressive β-cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin-1 (IL-1) by anakinra [recombinant human interleukin-1 receptor antagonist (IL-1Ra)] on β-cell function. Sixteen participants with imp......Inflammation at the level of the β cell appears to be involved in progressive β-cell dysfunction in type 2 diabetes. We assessed the effect of blocking interleukin-1 (IL-1) by anakinra [recombinant human interleukin-1 receptor antagonist (IL-1Ra)] on β-cell function. Sixteen participants......-phase insulin secretion improved after anakinra treatment compared with placebo, 148 ± 20 versus 123 ± 14 mU/l, respectively (p = 0.03), and the insulinogenic index was higher after anakinra treatment. These results support the concept of involvement of IL-1β in the (progressive) decrease of insulin secretion...

  3. The experimental treatment of corneal graft rejection with the interleukin-1 receptor antagonist (IL-1ra gene.

    Directory of Open Access Journals (Sweden)

    Jin Yuan

    Full Text Available PURPOSE: To investigate the protective effects of interleukin-1 receptor antagonist (IL-1ra gene transfer in a rat model of corneal graft rejection. METHODS: We constructed a recombinant plasmid (pcDNA3.1-hIL-1ra with high IL-1ra expression in eukaryotic cells. Using a Wistar-SD rat model of corneal graft rejection, we examined the effects of IL-1ra in vivo after cationic polymer jetPEI-mediated nonviral gene delivery. Four groups were included: negative controls (group I, n = 20, pcDNA3.1-hIL-1ra corneal stromal injection (group II, n = 34, pcDNA3.1-hIL-1ra anterior chamber injection (group III, n = 34, and 500 µg/ml IL-1ra protein subconjunctiva injection (group IV, n = 20. IL-1ra expression after transfection was evaluated by real-time polymerase chain reaction (RT-PCR and western blotting. The rejection indices of corneal grafts were analysed in the different groups. The expression levels of transforming growth factor β1 (TGF-β1, inflammatory chemokines including RANTES, interleukin-1 (IL-1 and the numbers of CD4+ and CD8+ T cells in the grafts were determined by biochemical assays at different time points after corneal transplantation. RESULTS: Various degrees of inflammatory cell infiltration and graft neovascularisation were observed by histopathology. After injecting the pcDNA3.1-hIL-1ra plasmid into the cornea, IL-1ra mRNA and protein expression was detected in the corneal stroma and reached a peak on day 3. The graft survival curves indicated that the corneal transparency rates of grafts in the IL-1ra gene-treated group and the IL-1ra protein-treated group were higher compared with the untreated group (P<0.05. During the period of acute rejection, TGF-β1, RANTES, IL-1α and IL-1β levels in the grafts in the IL-1ra treatment groups were lower than the control group (P<0.05. CD4+ and CD8+ T cell counts were reduced significantly in the corneal grafts of groups II, III and IV compared with group I (P<0.05. CONCLUSION

  4. Interleukin-1 contributes to increased concentrations of soluble tumor necrosis factor receptor type I in sepsis

    NARCIS (Netherlands)

    van der Poll, T.; Fischer, E.; Coyle, S. M.; van Zee, K. J.; Pribble, J. P.; Stiles, D. M.; Barie, P. S.; Buurman, W. A.; Moldawer, L. L.; Lowry, S. F.

    1995-01-01

    Studies were done in baboons and humans to assess the role of interleukin (IL)-1 on the release of soluble tumor necrosis factor receptors (sTNFRs) during sepsis. In baboons, IL-1 alpha induced increased levels of sTNFR types I and II. Infusion of Escherichia coli into baboons also led to higher

  5. INCREASED PLASMA-CONCENTRATIONS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN NEONATAL SEPSIS

    NARCIS (Netherlands)

    DEBONT, ESJM; DELEIJ, LHFM; OKKEN, A; BAARSMA, R; KIMPEN, JLL

    Newborns are prone to severe infections and sepsis. Cytokines such as tumor necrosis factor-alpha and IL-1 beta play a major role in the initiation of the host response to infections. IL-1 receptor antagonist (IL-1ra) is a naturally occurring antagonist of IL-1 beta. we hypothesized that low IL-1ra

  6. Interleukin-1 receptor antagonist (IL1RN) is associated with suppression of early carcinogenic events in human oral malignancies.

    Science.gov (United States)

    Shiiba, Masashi; Saito, Kengo; Yamagami, Hitomi; Nakashima, Dai; Higo, Morihiro; Kasamatsu, Atsushi; Sakamoto, Yosuke; Ogawara, Katsunori; Uzawa, Katsuhiro; Takiguchi, Yuichi; Tanzawa, Hideki

    2015-05-01

    Inflammatory abnormalities have been implicated in the pathogenesis of various human diseases, including cancer. Interleukin-1 receptor antagonist (IL1RN) is a potent anti-inflammatory molecule that modulates the biological activity of the proinflammatory cytokine, interleukin-1. The aim of this study was to examine the expression of IL1RN in oral squamous cell carcinomas (OSCCs), and to determine its clinical significance. Expression levels of IL1RN in matched normal and tumor specimens from 39 OSCCs were evaluated using real-time quantitative polymerase chain reaction methods, and immunohistochemical analysis. Protein expression of IL1RN was also examined in 18 oral premalignant lesions (OPLs). Expression of IL1RN mRNA was significantly downregulated in OSCCs compared with normal tissues. Decreased expression of IL1RN protein was also observed in OPLs and OSCCs. The IL1RN expression level was lower in the OPL cases with severe dysplasia compared to those with mild/moderate dysplasia. Significantly downregulated IL1RN expression was observed in all OSCC lesion sites examined when compared with the matched normal tissues. However, the decreased level of IL1RN expression did not correspond with tumor progression. Noteworthy, IL1RN expression was higher in the advanced OSCC cases (T3/T4) compared to early cases (T1/T2). Among OSCC samples, relatively higher IL1RN expression was associated with active tumor development in the OSCCs occurring in the buccal mucosa, oral floor, fauces and gingiva, but not the tongue. These data suggest that IL1RN may exhibit opposing characteristics in oral malignancies depending on the stage of cancer development, suppressing early carcinogenic events, yet promoting tumor development in some lesion sites. Thus, IL1RN could represent a reliable biomarker for the early diagnosis of OSCCs. Furthermore, IL1RN may possess unknown and complex functions in the developed OSCC.

  7. Brain-specific interleukin-1 receptor accessory protein in sleep regulation.

    Science.gov (United States)

    Taishi, Ping; Davis, Christopher J; Bayomy, Omar; Zielinski, Mark R; Liao, Fan; Clinton, James M; Smith, Dirk E; Krueger, James M

    2012-03-01

    Interleukin (IL)-1β is involved in several brain functions, including sleep regulation. It promotes non-rapid eye movement (NREM) sleep via the IL-1 type I receptor. IL-1β/IL-1 receptor complex signaling requires adaptor proteins, e.g., the IL-1 receptor brain-specific accessory protein (AcPb). We have cloned and characterized rat AcPb, which shares substantial homologies with mouse AcPb and, compared with AcP, is preferentially expressed in the brain. Furthermore, rat somatosensory cortex AcPb mRNA varied across the day with sleep propensity, increased after sleep deprivation, and was induced by somnogenic doses of IL-1β. Duration of NREM sleep was slightly shorter and duration of REM sleep was slightly longer in AcPb knockout than wild-type mice. In response to lipopolysaccharide, which is used to induce IL-1β, sleep responses were exaggerated in AcPb knockout mice, suggesting that, in normal mice, inflammation-mediated sleep responses are attenuated by AcPb. We conclude that AcPb has a role in sleep responses to inflammatory stimuli and, possibly, in physiological sleep regulation.

  8. Association study of interleukin-1 family, interleukin-6, and its receptor gene polymorphisms in patients with recurrent aphthous stomatitis.

    Science.gov (United States)

    Izakovicova Holla, Lydie; Valova, Simona; Borilova Linhartova, Petra; Bartova, Jirina; Petanova, Jitka; Kuklinek, Pavel; Fassmann, Antonin

    2017-11-01

    Recurrent aphthous stomatitis (RAS) is one of the most common oral chronic ulcerative disease in which proinflammatory cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6) are thought to play an important role. The aim of this study was to investigate the possible association between polymorphisms in the IL-1 cytokine family, IL-6 or its receptor and RAS in the Czech population. A total of 248 subjects, 184 healthy controls, and 64 patients with RAS were genotyped for IL-1A-889C>T, IL-1B-511C>T, IL-1B+3953C>T, IL-1RN86 bp variable number of tandem repeats (VNTRs) in intron 2, IL-6-597G>A, IL-6-572G>C, IL-6-174G>C, and IL-6R+48992A>C by polymerase chain reaction (PCR) methods. No significant differences between investigated polymorphisms in healthy subjects and patients with RAS were detected (P>.05). In addition, complex analysis also revealed similar IL-1 or IL-6 haplotype frequencies between both groups (P>.05). In conclusion, IL-1 and IL-6 or its receptor gene variants cannot be used as markers for identification of Czech patients with increased risk of recurrent aphthous stomatitis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints.

    Science.gov (United States)

    Watson, R S; Broome, T A; Levings, P P; Rice, B L; Kay, J D; Smith, A D; Gouze, E; Gouze, J-N; Dacanay, E A; Hauswirth, W W; Nickerson, D M; Dark, M J; Colahan, P T; Ghivizzani, S C

    2013-06-01

    With the long-term goal of developing a gene-based treatment for osteoarthritis (OA), we performed studies to evaluate the equine joint as a model for adeno-associated virus (AAV)-mediated gene transfer to large, weight-bearing human joints. A self-complementary AAV2 vector containing the coding regions for human interleukin-1-receptor antagonist (hIL-1Ra) or green fluorescent protein was packaged in AAV capsid serotypes 1, 2, 5, 8 and 9. Following infection of human and equine synovial fibroblasts in culture, we found that both were only receptive to transduction with AAV1, 2 and 5. For these serotypes, however, transgene expression from the equine cells was consistently at least 10-fold higher. Analyses of AAV surface receptor molecules and intracellular trafficking of vector genomes implicate enhanced viral uptake by the equine cells. Following delivery of 1 × 10(11) vector genomes of serotypes 2, 5 and 8 into the forelimb joints of the horse, all three enabled hIL-1Ra expression at biologically relevant levels and effectively transduced the same cell types, primarily synovial fibroblasts and, to a lesser degree, chondrocytes in articular cartilage. These results provide optimism that AAV vectors can be effectively adapted for gene delivery to large human joints affected by OA.

  10. RECOMBINANT HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST IN THE TREATMENT OF PATIENTS WITH SEPSIS SYNDROME - RESULTS FROM A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL

    NARCIS (Netherlands)

    FISHER, C. J.; DHAINAUT, J. F. A.; Opal, S. M.; Pribble, J. P.; BALK, R. A.; SLOTMAN, G. J.; IBERTI, T. J.; RACKOW, E. C.; SHAPIRO, M. J.; GREENMAN, R. L.; REINES, H. D.; SHELLY, M. P.; THOMPSON, B. W.; LABRECQUE, J. F.; Catalano, M. A.; KNAUS, W. A.; Sadoff, J. C.; ASTIZ, M.; CARPATI, C.; BONE, R. C.; FREIDMAN, B.; MURE, A. J.; BRATHWAITE, C.; SHAPIRO, E.; MELHORN, L.; TAYLOR, R.; KEEGAN, M.; OBRIEN, J.; SCHEIN, R.; PENA, M.; WASSERLOUF, M.; OROPELLO, J.; BENJAMIN, E.; DELGUIDICE, R.; EMMANUEL, G.; LIE, T.; Anderson, L.; Marshall, J.; DEMAJO, W.; ROTSTEIN, O.; FOSTER, D.; Abraham, E.; MIDDLETON, H.; Perry, C.; LEVY, H.; FRY, D. E.; SIMPSON, S. Q.; CROWELL, R. E.; Neidhart, M.; Stevens, D.; COFFMAN, T.; NARASIMHAM, N.; MERRICK, D. K.; BERGQUIST, W.; MATZEL, K. E.; HUEBLER, M.; Foulke, G. E.; ALBERTSON, T. E.; WALBY, W. F.; ALLEN, R. P.; Baughman, R.; HASSELGREN, P. O.; Fink, M. P.; FAVORITO, F.; THOMPSON, B. T.; CORBIN, R.; SHELLHORSE, G. Y.; FRAZIER, A.; White, S.; GARRARD, C.; ACOURT, C.; STORER, S.; GERVICH, D. H.; FOSHE, D.; BRASE, R.; BAGDAHN, A.; COONEY, R.; Smith, J. S.; MARTIN, L. F.; Vincent, J. L.; Friedman, G.; Berlot, G.; FLETCHER, J. R.; WILLIAMS, M. D.; WRIGHT, T. F.; Johnson, S.; FEILD, C.; WOLF, K.; MACINTYRE, N.; DUBIN, H. G.; DURKIN, M. R.; DUBIN, P. K.; STAUBACH, K. H.; FEIN, A. M.; SCHULMAN, D. B.; NIEDERMAN, M. S.; CHALFIN, D. B.; van Leeuwen, P. A. M.; Boermeester, M. A.; Schneider, A. J.; BANDER, J.; IMM, A.; BERNARD, G.; Nelson, L.; Stroud, M.; SAFCSAK, K.; CERRA, F.; RINDAL, J.; Mann, H.; HALPERN, N.; SILVERSTEIN, J.; ALICEA, M.; Sibbald, W. J.; MARTIN, C. M.; RUTLEDGE, F. S.; PETTI, K.; RUSSELL, J. A.; KRUGER, R.; DRUMMOND, A.; LANGE, P.; SEIFERT, T.; DUROCHER, A.; TENAILLON, A.; BOITEAU, R.; LHERM, T.; Lowry, S. F.; Coyle, S. M.; Barie, P. S.; DEMARIA, E.; SNYDMAN, D. R.; SCHWAITZBERG, S. D.; NASRAWAY, S. A.; GRINDLINGER, J.; SUMMER, W.; DEBOISBLANC, B.; WAHL, M.; ALESTIG, K.; GROSSMAN, J.; MAKI, D.; PAZ, H. L.; Weiner, M.; BIHARI, D.; Campbell, D.; BLEICHNER, G.; DAHN, M. S.; LANGE, M. P. A.; Hall, J.; POHLMAN, A.; WENZEL, R. P.; GROSSERODE, M.; COSTIGAN, M.; MILESKI, W.; WEIGELT, J.; YESTON, N.; IRIZARRY, C.; Ross, J.; ROBBINS, J.; NIGHTINGALE, P.; OWEN, K.; SANDSTEDT, S.; Berg, S.; SIMON, G. L.; SENEFF, M. G.; CONRY, K. M.; ZIMMERMAN, J. L.; Dellinger, R. P.; Johnston, R.; ALLEE, P.; GRANDE, P. O.; MYHRE, E.; DHAINAUT, J. F.; HAMY, I.; Mira, J. P.; HARMON, J.; White, J.; MCKIE, L.; SILVERMAN, H.; TUMA, P.; Bennett, D.; PORTER, J. C.; LAURELL, M. H.; Jacobs, S.; ASH, S.; Stiles, D. M.; PRIOR, M. J.; KNATTERUD, G.; TERRIN, M.; KUFERA, J.; WILKENS, P.; RA, K.; MONROE, L.; SPRUNG, C.; HAMILTON, C. M.; MATTHAY, R.; MCCABE, W.; TONASCIA, J.; WIEDEMAN, H.; Wittes, J.; CAMPION, G. V.; CROFT, C. R.; LUSTICK, R.; LOOKABAUGH, J.; GORDON, G. S.; NOE, L.; BLOEDOW, D.; SMITH, C. G.; BRANNON, D.; KUSH, R.; NG, D.; MOORE, E.; BAZEMORE, K.; GALVAN, M.; Wagner, D.; HARRELL, F.; STABLEIN, D.

    1994-01-01

    Objective.-To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhlL-1ra) in the treatment of sepsis syndrome. Study Design.-Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. Population.-A total of 893 patients with

  11. Circulating interleukin-1β promotes endoplasmic reticulum stress-induced myocytes apoptosis in diabetic cardiomyopathy via interleukin-1 receptor-associated kinase-2.

    Science.gov (United States)

    Liu, Zhongwei; Zhao, Na; Zhu, Huolan; Zhu, Shunming; Pan, Shuo; Xu, Jing; Zhang, Xuejun; Zhang, Yong; Wang, Junkui

    2015-09-23

    IL-1β was considered as an important inflammatory cytokine in diabetic cardiovascular complications. DCM is one of the major manifestations of diabetic cardiovascular complications whose specific mechanisms are still unclear. In this study, we investigated the role of IL-1β in myocytes apoptosis in DCM. In the in vitro study, high- glucose medium and/or IL-1β were used to incubate the isolated primary myocytes. siRNA was used to knockdown the irak2 gene expression. Apoptosis was evaluated by Hoechst and TUNEL staining. In the in vivo study, DCM in rats was induced by STZ injection and confirmed by cardiac hemodynamic determinations. The IL-1 receptor antagonist, IL-1Ra was also used to treat DCM rats. Myocardial apoptosis was assessed by TUNEL assay. In both in vitro and in vivo studies, expression levels of GRP-78, IRAK-2 and CHOP were analyzed by Western Blotting. ELISA was employed to exam the IL-1β content in serum and cell supernatants. Myocytes were not identified as the source of IL-1β secretion under high- glucose incubation. High glucose incubation and/or IL-1β incubation elevated ER- stress mediated myocytes apoptosis which was attenuated by irak2 silencing. Dramatically increased circulating and myocardial IL-1β levels were found in DCM rats which stimulated activation of ER stress and lead to elevated myocytes apoptosis. The administration of IL-1Ra, however, attenuated IRAK2/CHOP induced apoptosis without affecting fasting blood glucose concentration. Elevated circulating IL-1β contributed to promote ER stress- induced myocytes apoptosis by affecting IRAK-2/CHOP pathway in DCM.

  12. DNA Methyltransferase 3B Gene Promoter and Interleukin-1 Receptor Antagonist Polymorphisms in Childhood Immune Thrombocytopenia

    Directory of Open Access Journals (Sweden)

    Margarita Pesmatzoglou

    2012-01-01

    Full Text Available Primary immune thrombocytopenia (ITP is one of the most common blood diseases as well as the commonest acquired bleeding disorder in childhood. Although the etiology of ITP is unclear, in the pathogenesis of the disease, both environmental and genetic factors including polymorphisms of TNF-a, IL-10, and IL-4 genes have been suggested to be involved. In this study, we investigated the rs2424913 single-nucleotide polymorphism (SNP (C46359T in DNA methyltransferase 3B (DNMT3B gene promoter and the VNTR polymorphism of IL-1 receptor antagonist (IL-1 Ra intron-2 in 32 children (17 boys with the diagnosis of ITP and 64 healthy individuals. No significant differences were found in the genotype distribution of DNMT3B polymorphism between the children with ITP and the control group, whereas the frequency of allele T appeared significantly increased in children with ITP (P = 0.03, OR = 2, 95% CI: 1.06–3.94. In case of IL-1 Ra polymorphism, children with ITP had a significantly higher frequency of genotype I/II, compared to control group (P = 0.043, OR = 2.60, 95% CI: 1.02–6.50. Moreover, genotype I/I as well as allele I was overrepresented in the control group, suggesting that allele I may have a decreased risk for development of ITP. Our findings suggest that rs2424913 DNMT3B SNP as well as IL-1 Ra VNTR polymorphism may contribute to the susceptibility to ITP.

  13. Effects of an interleukin-1 receptor antagonist on human sleep, sleep-associated memory consolidation, and blood monocytes.

    Science.gov (United States)

    Schmidt, Eva-Maria; Linz, Barbara; Diekelmann, Susanne; Besedovsky, Luciana; Lange, Tanja; Born, Jan

    2015-07-01

    Pro-inflammatory cytokines like interleukin-1 beta (IL-1) are major players in the interaction between the immune system and the central nervous system. Various animal studies report a sleep-promoting effect of IL-1 leading to enhanced slow wave sleep (SWS). Moreover, this cytokine was shown to affect hippocampus-dependent memory. However, the role of IL-1 in human sleep and memory is not yet understood. We administered the synthetic IL-1 receptor antagonist anakinra (IL-1ra) in healthy humans (100mg, subcutaneously, before sleep; n=16) to investigate the role of IL-1 signaling in sleep regulation and sleep-dependent declarative memory consolidation. Inasmuch monocytes have been considered a model for central nervous microglia, we monitored cytokine production in classical and non-classical blood monocytes to gain clues about how central nervous effects of IL-1ra are conveyed. Contrary to our expectation, IL-1ra increased EEG slow wave activity during SWS and non-rapid eye movement (NonREM) sleep, indicating a deepening of sleep, while sleep-associated memory consolidation remained unchanged. Moreover, IL-1ra slightly increased prolactin and reduced cortisol levels during sleep. Production of IL-1 by classical monocytes was diminished after IL-1ra. The discrepancy to findings in animal studies might reflect species differences and underlines the importance of studying cytokine effects in humans. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Genetic Polymorphisms of Interleukin-1 Alpha and the Vitamin D Receptor in Mexican Mestizo Patients with Intervertebral Disc Degeneration

    Directory of Open Access Journals (Sweden)

    Salvador Cervin Serrano

    2014-01-01

    Full Text Available Intervertebral disc degeneration (IDD is the most common diagnosis in patients with back pain, a leading cause of musculoskeletal disability worldwide. Several conditions, such as occupational activities, gender, age, and obesity, have been associated with IDD. However, the development of this disease has strong genetic determinants. In this study, we explore the possible association between rs1800587 (c.-949C>T of interleukin-1 alpha (IL1A and rs2228570 (c.2T>V and rs731236 (c.1056T>C of vitamin D receptor (VDR gene polymorphisms and the development of IDD in northwestern Mexican Mestizo population. Gene polymorphisms were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism, in two groups matched by age and gender: patients with symptomatic lumbar IDD n=100 and subjects with normal lumbar-spine MRI-scans n=100. Distribution of the mutated alleles in patients and controls was 27.0% versus 28.0% P=0.455 for T of rs1800587 (IL1A; 53.0% versus 58.0% P=0.183 for V of rs2228570 (VDR; and 18.0% versus 21.0% P=0.262 for C of rs731236 (VDR. Our results showed no association between the studied polymorphisms and IDD in this population. This is the first report on the contribution of gene polymorphisms on IDD in a Mexican population.

  15. Association between interleukin 1 receptor antagonist gene 86-bp VNTR polymorphism and sepsis: a meta-analysis.

    Science.gov (United States)

    Fang, Fang; Pan, Jian; Li, Yiping; Xu, Lixiao; Su, Guanghao; Li, Gang; Wang, Jian

    2015-01-01

    Many studies have focused on the relationship between interleukin 1 receptor antagonist (IL1RN) gene 86-bp VNTR polymorphism and sepsis, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between IL1RN 86-bp VNTR polymorphism and risk of sepsis and sepsis-related mortality. Relevant publications were searched in several widely used databases and six eligible studies were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between IL1RN 86-bp VNTR polymorphism and risk of sepsis and sepsis-related mortality. Significant associations between IL1RN 86-bp VNTR polymorphism and sepsis risk were observed in both overall meta-analysis for L2 versus 22 (OR=0.75, 95% CI=0.59-0.94) and severe sepsis subgroup for LL+L2 versus 22 (OR=0.67, 95% CI=0.47-0.93). L stands for long alleles containing three to six repeats; 2 stands for short allele containing two repeats. However, no significant sepsis mortality variation was detected for all genetic models. According to the results of our meta-analysis, the IL1RN 86-bp VNTR polymorphism probably associates with sepsis risk but not with sepsis-related mortality. Copyright © 2014. Published by Elsevier Inc.

  16. Identification of five new genes, closely related to the interleukin-1beta converting enzyme gene, that do not encode functional proteases.

    Science.gov (United States)

    Rocher, C; Faucheu, C; Blanchet, A M; Claudon, M; Hervé, F; Durand, L; Harnois, M; Diu-Hercend, A; Lalanne, J L

    1997-06-01

    Interleukin-1beta converting enzyme (ICE) was the first identified member of a growing family of cysteine proteases that now includes ten mammalian homologs. Within this large family, two functional proteins, denoted TX and TY share 60% amino-acid identity with ICE in the mature protein and, together with ICE, constitute the ICE subfamily. The present study describes the identification of five new gene sequences, denoted S1-S5, closely related to ICE and TX and belonging to this subfamily. Sequences were identified using genomic Southern-blot analysis of human DNA with probes corresponding to ICE and TX exon 6. Using PCR amplification and cloning, the complete exon-6 sequence of these new genes was identified; three exhibit around 90% identity with Ice within exon 6, whereas the two others share about 70% identity with Ice. Examination of open reading frames and of amino acids essential for ICE activity indicate that none of these genes encodes for a functional protease. In conclusion, extensive analysis of the genes closely related to Ice shows that the Ice subfamily is constituted of eight members. Three of them encode for functional proteases (ICE, TX and TY) whereas the remaining members probably correspond to pseudogenes.

  17. A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist.

    Directory of Open Access Journals (Sweden)

    Mark S Gresnigt

    2014-03-01

    Full Text Available The galactosaminogalactan (GAG is a cell wall component of Aspergillus fumigatus that has potent anti-inflammatory effects in mice. However, the mechanisms responsible for the anti-inflammatory property of GAG remain to be elucidated. In the present study we used in vitro PBMC stimulation assays to demonstrate, that GAG inhibits proinflammatory T-helper (Th1 and Th17 cytokine production in human PBMCs by inducing Interleukin-1 receptor antagonist (IL-1Ra, a potent anti-inflammatory cytokine that blocks IL-1 signalling. GAG cannot suppress human T-helper cytokine production in the presence of neutralizing antibodies against IL-1Ra. In a mouse model of invasive aspergillosis, GAG induces IL-1Ra in vivo, and the increased susceptibility to invasive aspergillosis in the presence of GAG in wild type mice is not observed in mice deficient for IL-1Ra. Additionally, we demonstrate that the capacity of GAG to induce IL-1Ra could also be used for treatment of inflammatory diseases, as GAG was able to reduce severity of an experimental model of allergic aspergillosis, and in a murine DSS-induced colitis model. In the setting of invasive aspergillosis, GAG has a significant immunomodulatory function by inducing IL-1Ra and notably IL-1Ra knockout mice are completely protected to invasive pulmonary aspergillosis. This opens new treatment strategies that target IL-1Ra in the setting of acute invasive fungal infection. However, the observation that GAG can also protect mice from allergy and colitis makes GAG or a derivative structure of GAG a potential treatment compound for IL-1 driven inflammatory diseases.

  18. Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology

    Directory of Open Access Journals (Sweden)

    Andrew D. Greenhalgh

    2012-11-01

    Subarachnoid haemorrhage (SAH is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1 represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1 was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC. Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease.

  19. Interleukin-1 Receptor Antagonist and Interleukin-4 Genes Variable Number Tandem Repeats Are Associated with Adiposity in Malaysian Subjects

    Directory of Open Access Journals (Sweden)

    Yung-Yean Kok

    2017-01-01

    Full Text Available Interleukin-1 receptor antagonist (IL1RA intron 2 86 bp repeat and interleukin-4 (IL4 intron 3 70 bp repeat are variable number tandem repeats (VNTRs that have been associated with various diseases, but their role in obesity is elusive. The objective of this study was to investigate the association of IL1RA and IL4 VNTRs with obesity and adiposity in 315 Malaysian subjects (128 M/187 F; 23 Malays/251 ethnic Chinese/41 ethnic Indians. The allelic distributions of IL1RA and IL4 were significantly different among ethnicities, and the alleles were associated with total body fat (TBF classes. Individuals with IL1RA I/II genotype or allele II had greater risk of having higher overall adiposity, relative to those having the I/I genotype or I allele, respectively, even after controlling for ethnicity [Odds Ratio (OR of I/II genotype = 12.21 (CI = 2.54, 58.79; p=0.002; II allele = 5.78 (CI = 1.73, 19.29; p=0.004]. However, IL4 VNTR B2 allele was only significantly associated with overall adiposity status before adjusting for ethnicity [OR = 1.53 (CI = 1.04, 2.23; p=0.03]. Individuals with IL1RA II allele had significantly higher TBF than those with I allele (31.79±2.52 versus 23.51±0.40; p=0.005. Taken together, IL1RA intron 2 VNTR seems to be a genetic marker for overall adiposity status in Malaysian subjects.

  20. Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters.

    Science.gov (United States)

    Zhu, Chong-Bin; Lindler, Kathryn M; Owens, Anthony W; Daws, Lynette C; Blakely, Randy D; Hewlett, William A

    2010-12-01

    Serotonin (5-hydroxytryptamine, 5-HT) has long been implicated in regulation of mood. Medications that block the neuronal 5-HT transporter (SERT) are used as major pharmacological treatment for mood disorders. Conversely, stimuli that enhance SERT activity might be predicted to diminish synaptic 5-HT availability and increase the risk for 5-HT-related CNS disorders. We have shown that the inflammatory cytokines enhance brain SERT activity in cultured serotonergic cells and nerve terminal preparations in vitro. In this study, we establish that intraperitoneal injection of the cytokine-inducer lipopolysaccharide (LPS) stimulates brain SERT activity, acting at doses below those required to induce overt motor suppression. SERT stimulation by LPS is paralleled by increased immobility in both the tail suspension test (TST) and the forced swim test (FST); antidepressant-sensitive alterations are thought to model aspects of behavioral despair. Both the stimulation of SERT activity and induced immobility are absent when LPS is administered to interleukin-1 receptor (IL-1R)-deficient mice and in the presence of SB203580, an inhibitor of IL-1R-stimulated p38 MAPK. Moreover, the ability of LPS to enhance immobility in TST is lost in SERT knockout mice. These findings reveal an ability of peripheral inflammatory stimuli to enhance brain SERT activity through IL-1R and p38 MAPK pathways in vivo and identify a requirement for SERT expression in immune-system-modulated despair behaviors. Our studies identify IL-1R- and p38 MAPK-dependent regulation of SERT as one of the mechanisms by which environmentally driven immune system activation can trigger despair-like behavior in an animal model, encouraging future analysis of the pathway for risk factors in neuropsychiatric disorders.

  1. Cytokines and Bone Loss in a 5-Year Longitudinal Study—Hormone Replacement Therapy Suppresses Serum Soluble Interleukin-6 Receptor and Increases Interleukin-1-Receptor Antagonist

    DEFF Research Database (Denmark)

    Abrahamsen, B.; Bonnevie-Nielsen, V.; Ebbesen, E.N.

    2000-01-01

    The proinflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-6 may play a central role in the acceleration of postmenopausal bone loss, but observational studies have led to contradictory results. Estrogen-dependent changes in the production of IL-1 receptor antagonist (IL-1ra...... observed in the control group. IL-1ra was inversely correlated with bone loss at the ultradistal forearm (r = 0.29; p bone loss at the ultradistal forearm (r = 0.26; p ....05). High IL-6 levels were associated with slower bone loss (spine r = 0.31, p bone loss at the femoral neck (r = -0.29; p bone loss in the spine (r = -0...

  2. Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice.

    Science.gov (United States)

    Wu, Zhen-Qian; Han, Xiao-Dong; Wang, Yu; Yuan, Ke-Li; Jin, Zhi-Ming; Di, Jian-Zhong; Yan, Jun; Pan, Ye; Zhang, Pin; Huang, Xin-Yu; Wang, Zhi-Gang; Zheng, Qi

    2011-07-01

    The aim of this study was to investigate the relationship between changes in IL-1β expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine. Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200 mg/kg). IL-1Ra (1 mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1β induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining. The variation of IL-1β expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1β and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice. Our studies elucidate that IL-1β is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy

  3. Expression of an insulin/interleukin-1 receptor antagonist hybrid gene in insulin-producing cell lines (HIT-T15 and NIT-1) confers resistance against interleukin-1-induced nitric oxide production.

    Science.gov (United States)

    Welsh, N; Bendtzen, K; Welsh, M

    1995-01-01

    A hybrid gene consisting of the insulin gene enhancer/promoter region, the signal sequence, the insulin B- and C-chains, and the human interleukin-1 receptor antagonist (IL-1ra) gene was constructed. This hybrid gene was transfected together with the pSV2-neo construct into the insulin-producing cell lines HIT-T15 and NIT-1. One of the geneticin-selected clones, HITra2, expressed a 1.4-kb mRNA, which hybridized both to insulin and IL-1ra-cDNA in Northern blot analysis. Three proteins, with the mol wt 23, 17, and 14 kD, were immunoprecipitated with anti-IL-1ra antibodies from [35S]methionine-labeled HITra2 cells. Both at a low and at a high glucose concentration, 4-5 ng of IL-1ra/10(6) cells (ELISA) was released from these cells. On the other hand, a high glucose concentration evoked a three-fold increase in the release of insulin, suggesting that IL-1ra was released constitutively. Measured by nitrite production, transfected HIT, and NIT-1 cells exhibited a more than 10-fold decrease in IL-1 beta sensitivity. Since the conditioned culture media from the HITra2 cells exhibited an anti-IL-1 beta activity of only 0.5 U/ml, and mixed culture of HITra2 cells and isolated rat islets prevented IL-1 beta induced inhibition of insulin release, it is likely that IL-1ra acts locally at the cell surface. It is concluded that expression of a hybrid insulin/IL-1ra gene confers resistance to IL-1 and that this technique may be used to elucidate the role of IL-1 in autoimmune disorders such as insulin-dependent diabetes mellitus. Images PMID:7706480

  4. Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4

    Energy Technology Data Exchange (ETDEWEB)

    McElroy, William T.; Seganish, W. Michael; Herr, R. Jason; Harding, James; Yang, Jinhai; Yet, Larry; Komanduri, Venukrishnan; Prakash, Koraboina Chandra; Lavey, Brian; Tulshian, Deen; Greenlee, William J.; Sondey, Christopher; Fischmann, Thierry O.; Niu, Xiaoda (Merck); (Albany MR)

    2015-05-01

    Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities.

  5. Increased concentrations of interleukin-6 and interleukin-1 receptor antagonist and decreased concentrations of beta-2-glycoprotein I in Gambian children with cerebral malaria

    DEFF Research Database (Denmark)

    Jakobsen, P H; McKay, V; Morris-Jones, S D

    1994-01-01

    receptors of tumor necrosis factor and IL-6 (sIL-6R) in serum of Gambian children with cerebral malaria, mild or asymptomatic malaria, or other illnesses unrelated to malaria. Because cytokine secretion may be triggered by toxic structures containing phosphatidylinositol (PI), we also measured......To investigate the pathogenic versus the protective role of cytokines and toxin-binding factors in Plasmodium falciparum infections, we measured the concentrations of tumor necrosis factor alpha, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist, and IL-6, as well as soluble...... concentrations of anti-PI antibodies and the PI-binding serum protein beta-2-glycoprotein I. We found increased concentrations of IL-6, sIL-6R, IL-1ra, and some immunoglobulin M antibodies against PI in children with cerebral malaria, but those who died had decreased concentrations of beta-2-glycoprotein I. We...

  6. Identification of the promoter region of human interleukin 1 type I receptor gene: multiple initiation sites, high G+C content, and constitutive expression.

    Science.gov (United States)

    Ye, K; Dinarello, C A; Clark, B D

    1993-01-01

    To better understand the role of interleukin 1 (IL-1) and its receptor in disease, we have isolated a genomic clone of the human IL-1 type I receptor and have identified the promoter region. There are multiple transcriptional initiation sites as demonstrated by primer extension. DNA sequence analysis shows that the promoter region contains neither a TATA nor a CAAT box; however, the 5' upstream regulatory elements contain two AP-1-like binding sites. The internal regulatory sequences found immediately downstream to the 5' transcriptional start site contain four Sp1 binding domains and have a high G+C content of 75%. This portion of the 5' untranslated region of the mRNA can form stable secondary structure as predicted by computer modeling. Base pairs -4 to + 10 share striking resemblance to an initiator sequence that directs basal expression of certain TATA-less genes-e.g., terminal deoxynucleotidyltransferase in lymphocytes. The IL-1 receptor promoter directs basal expression of chloramphenicol acetyltransferase in transiently transfected cells. Overall, the promoter of the IL-1 type I receptor gene resembles that of constitutively expressed genes that have housekeeping- and/or growth-related functions. The constitutive nature of the promoter may account for this gene being expressed at low levels in diverse cell types. Our finding sheds more understanding into the mechanisms governing the regulation of the IL-1 receptor in health and disease. Images Fig. 2 Fig. 6 PMID:8460136

  7. Levels of circulating soluble receptor activator of NF-κB and interleukins-1 predicting outcome of locally advanced basal cell carcinoma.

    Science.gov (United States)

    Lin, Quan; Li, Yan; Zhang, Duo; Jin, Hongjuan

    2016-12-01

    Decreasing levels of cytokines are associated with better responses to therapies, while increasing levels are related to progression or recurrence and decreased survival. NF-κB's role in the cell cycle and its ubiquity are only stressed out by the evidence for the importance of activation (aberrant activation in the majority of cancers) of both canonical and non-canonical pathways in advanced basal cell carcinomas (aBCCs), a subset of basal cell carcinoma (BCC). NF-κB acts through its canonical, or classical, form activated by interleukin-1 (IL-1), regulates cytoprotective, innate, and adaptive immune responses. However, NF-κB2 often acts through its non-canonical or alternate pathway. During the two-year study period, we selected 21 patients presenting with aBCCs due to delay in accessing medical attention with an advanced form of BCCs (n = 19) and infiltrative BCCs (n = 2). Initial diagnosis of BCCs of head and neck was made clinically and verified by skin biopsy. Venous blood was drawn and serum was obtained. Samples were collected at baseline and every three days thereafter (days 3, 6, 9, etc. until surgery). Antigenes' quantities (cytokines) were determined by ELISA kits. Initially, the mean value of all cytokine subjects was significantly different related to the control group (P <0.05). Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) were observed following the surgery. Changes in serum levels of circulating soluble receptor activator of NF-κB and interleukins-1 (α and β) are evident throughout our study period and a certain regularity in its dynamics is evident as the follow-up period moves away. It was therefore concluded that measurement of these factors might be useful in predicting the overall outcome of patients with aBCCs. This study highlights the systemic effects of aBCCs, but further studies are required on this topic. © The Author(s) 2016.

  8. Interleukin-1 beta down-regulates the expression of metabotropic glutamate receptor 5 in cultured human astrocytes

    NARCIS (Netherlands)

    Aronica, E.; Gorter, J.A.; Rozemuller, A.J.M.; Yankaya, B.; Troost, D.

    2005-01-01

    Expression of metabotropic glutamate receptor 5 (mGluR5) protein is known to be plastic and to depend critically on the astrocytes' microenvironment. In the present study we investigated whether interleukins, which are involved in the immune response following brain injury, could contribute to the

  9. Interleukin-1 beta down-regulates the expression of metabotropic glutamate receptor 5 in cultured human astrocytes

    NARCIS (Netherlands)

    Aronica, Eleonora; Gorter, Jan A.; Rozemuller, Annemieke J.; Yankaya, Bulent; Troost, Dirk

    2005-01-01

    Expression of metabotropic glutamate receptor 5 (mGluR5) protein is known to be plastic and to depend critically oil the astrocytes' microenvironment. In the present study we investigated whether interleukins, which are involved in the immune response following brain injury, could contribute to the

  10. Role of murine intestinal interleukin-1 receptor 1-expressing lymphoid tissue inducer-like cells in Salmonella infection.

    Directory of Open Access Journals (Sweden)

    Vincent L Chen

    Full Text Available Interleukin (IL-1 signaling plays a critical role in intestinal immunology. Here, we report that the major population of intestinal lamina propria lymphocytes expressing IL-1 receptor 1 (IL-1R1 is the lymphoid tissue inducer (LTi-like cell, a type of innate lymphoid cell. These cells are significant producers of IL-22, and this IL-22 production depends on IL-1R1 signaling. LTi-like cells are required for defense against Salmonella enterica serovar Typhimurium. Moreover, colonic LTi-like cell numbers depend on the presence of the intestinal microbiota. LTi-like cells require IL-1R1 for production of protective cytokines and confer protection in infectious colitis, and their cell numbers in the colon depend upon having a microbiome.

  11. Changes in plasma concentrations of interleukin-6 and interleukin-1 receptor antagonists in response to adrenaline infusion in humans

    DEFF Research Database (Denmark)

    Søndergaard, S R; Ostrowski, K.; Ullum, H

    2000-01-01

    To investigate the possible role of adrenaline in the response of interleukin (IL)-6 and IL-1 receptor antagonists (ra) to extreme physiological conditions such as trauma and exercise, we examined the concentrations in the plasma of these cytokines during an adrenaline infusion. Given the fact...... that HIV infected patients have elevated levels of IL-6 in plasma, 12 HIV seropositive subjects and 6 HIV seronegative control subjects received a 1-h adrenaline infusion. Baseline concentrations of IL-6 and IL-1ra were higher in the HIV patients compared with the controls (P...), being most pronounced in the untreated subgroup of HIV infected patients (n = 6). The plasma concentration of adrenaline had increased 24-fold after 15 min of adrenaline infusion. The plasma concentration of IL-6 had increased by two- to threefold after 45 min of adrenaline infusion (P

  12. Interleukin-1 receptor antagonist ribonucleic acid and protein expression by cultured Graves' and normal orbital fibroblasts is differentially modulated by dexamethasone and irradiation.

    Science.gov (United States)

    Mühlberg, T; Joba, W; Spitzweg, C; Schworm, H D; Heberling, H J; Heufelder, A E

    2000-02-01

    Recent data have indicated that orbital fibroblasts (OF) can be stimulated to produce marked quantities of interleukin-1 receptor antagonist (IL-1RA), a powerful inhibitor of the proinflammatory activities of interleukin-1 in the orbital tissues in Graves' ophthalmopathy (GO). We examined whether the beneficial effects of dexamethasone or irradiation, the two main therapeutic modalities applied in patients with active GO, may be related to their capacity to alter IL-1RA ribonucleic acid (RNA) and protein expression in OF. Early passages of cultured OF were obtained from orbital connective tissue and extraocular muscle of patients with severe active GO and five control subjects. Modulation of the two variants of IL-1RA, intracellular IL-1RA (icIL-1RA) and soluble IL-1RA (sIL-1RA), was studied after exposure of OF to increasing concentrations of dexamethasone (10(-10)-(10(-6) mol/L)), the glucocorticoid receptor antagonist RU 38486 (10(-3) mol/L), or combinations thereof. Alternatively, cell monolayers were exposed to increasing doses of UV irradiation (0.1-1 J/cm2) or ionizing irradiation (0.2-2 Gy). The IL-1RA gene and protein variants were analyzed by RT-PCR, immunocytochemistry, immunoblotting, and enzyme-linked immunosorbent assay. Dexamethasone inhibited IL-1RA RNA steady state levels in GO OF and control OF in a dose-dependent manner. Combined exposure of OF to dexamethasone and RU 38486 completely restored baseline levels of IL-1RA RNA. By contrast, low doses of UV and ionizing irradiation dose dependently up-regulated IL-1RA-specific transcripts in GO OF and control OF, whereas higher doses were less effective. Immunoblotting and enzyme-linked immunosorbent assay revealed suppression of IL-1RA immunoreactivity after treatment with dexamethasone and enhanced expression of IL-1RA by GO OF and normal OF after low doses of UV and ionizing irradiation. Our results indicate that, in contrast to dexamethasone, low doses of irradiation stimulate expression of the IL

  13. Thyrocyte-interleukin-1 interactions

    DEFF Research Database (Denmark)

    Rasmussen, A K; Bendtzen, K; Feldt-Rasmussen, U

    2000-01-01

    characterized by massive infiltration of lymphoid cells. The interleukin-1 (IL-1) family of molecules is together with other cytokines an integral component of the complex intercellular communication required to mount and control an immune response. IL-1alpha/beta in moderate and high concentrations reversibly...... inhibit thyroid cell function, while IL-1beta in low concentrations stimulates thyroid cell function. The biphasic, non-cytotoxic and reversible influence of IL-1 supports a role of IL-1 in the physiological regulation of thyroid cell function. IL-1 stimulates the guanylate mediated pathways and inhibits...... the adenylate cyclase mediated pathways. All IL-1 effects are counteracted by IL-1 receptor antagonist indicating that the effects are exerted through activation of specific IL-1 receptors on thyrocytes. Furthermore, IL-1 induces or enhances expression of a number of immunologically active molecules...

  14. Down syndrome candidate region-1 protein interacts with Tollip and positively modulates interleukin-1 receptor-mediated signaling.

    Science.gov (United States)

    Lee, Jae Youn; Lee, Hyun Jung; Lee, Eun Jung; Jang, Sung Hee; Kim, Hyeyoung; Yoon, Joo-Heon; Chung, Kwang Chul

    2009-12-01

    The Down syndrome candidate region-1 gene (DSCR1, also known as RCAN1) is situated close to the Down Syndrome Critical Region (DSCR), which contains genes responsible for many features of Down syndrome. DSCR1 modulates calcineurin phosphatase activity, though its functional role is incompletely understood. Here we investigated the role of DSCR1-1S isoform in IL-1 receptor (IL-1R)-mediated signaling by analyzing interaction between DSCR1-1S and the IL-1R pathway components Tollip, IRAK-1, and TRAF6. Co-immunoprecipitation analyses of HEK293 cells revealed that DSCR1-1S interacted with Tollip, an IRAK-1 inhibitor, leading to the dissociation of IRAK-1 from Tollip. Similarly, both DSCR1-1S and Tollip interacted with TRAF6, with DSCR1 reducing interaction between Tollip and TRAF6. DSCR1-1S also stimulated IL-1R-mediated signaling pathways, TAK1 activation, NF-kappaB transactivation, and IL-8 production, all downstream consequences of IL-1R activation. Together, these results suggest that DSCR1-1S isoform positively modulates IL-1R-mediated signaling pathways by regulating Tollip/IRAK-1/TRAF6 complex formation.

  15. Effect of serum interleukin-1 receptor antagonist level on survival of patients with non-small cell lung cancer.

    Science.gov (United States)

    Yigit, Murat; Değirmencioğlu, Serkan; Ugurlu, Erhan; Yaren, Arzu

    2017-05-01

    Due to poor prognosis in advanced non-small cell lung cancer (NSCLC), new effective markers are required in the monitoring of the disease. The present study aimed to investigate the association between the serum IL-1 receptor antagonist (IL-1Ra) level, overall survival (OS), and treatment response in NSCLC, and to evaluate the usefulness of the serum IL-1Ra level as a prognostic marker for NSCLC. Eighty patients (72 men and 8 women) and 40 healthy volunteers (13 men and 27 women) were included in the present study. The median progression-free survival was 16 weeks for patients with high serum IL-1Ra levels, and 35 weeks for patients with low serum IL-1Ra levels (P=0.027). The median OS was 38 weeks in patients with a high serum IL-1Ra level, and 62 weeks in patients with a low serum IL-1Ra level (P=0.065). The results of the present study have demonstrated that there was a significant correlation between IL-1Ra levels and NSCLC progression and survival, although the correlation between IL-1Ra levels and the response to treatment was not statistically significant. Therefore, the pre-treatment IL-1Ra level has been identified as a putative prognostic factor for NSCLC.

  16. Deletion of interleukin 1 receptor-associated kinase 1 (Irak1) improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle.

    Science.gov (United States)

    Sun, Xiao-Jian; Kim, Soohyun Park; Zhang, Dongming; Sun, Helen; Cao, Qi; Lu, Xin; Ying, Zhekang; Li, Liwu; Henry, Robert R; Ciaraldi, Theodore P; Taylor, Simeon I; Quon, Michael J

    2017-07-21

    Chronic inflammation may contribute to insulin resistance via molecular cross-talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor-associated kinase 1 (IRAK-1) mediates pro-inflammatory signaling via IL-1 receptor/Toll-like receptors, which may contribute to insulin resistance, but this hypothesis is untested. Here, we used male Irak1 null (k/o) mice to investigate the metabolic role of IRAK-1. C57BL/6 wild-type (WT) and k/o mice had comparable body weights on low-fat and high-fat diets (LFD and HFD, respectively). After 12 weeks on LFD (but not HFD), k/o mice (versus WT) had substantially improved glucose tolerance (assessed by the intraperitoneal glucose tolerance test (IPGTT)). As assessed with the hyperinsulinemic euglycemic glucose clamp technique, insulin sensitivity was 30% higher in the Irak1 k/o mice on chow diet, but the Irak1 deletion did not affect IPGTT outcomes in mice on HFD, suggesting that the deletion did not overcome the impact of obesity on glucose tolerance. Moreover, insulin-stimulated glucose-disposal rates were higher in the k/o mice, but we detected no significant difference in hepatic glucose production rates (± insulin infusion). Positron emission/computed tomography scans indicated higher insulin-stimulated glucose uptake in muscle, but not liver, in Irak1 k/o mice in vivo Moreover, insulin-stimulated phosphorylation of Akt was higher in muscle, but not in liver, from Irak1 k/o mice ex vivo In conclusion, Irak1 deletion improved muscle insulin sensitivity, with the effect being most apparent in LFD mice. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Interleukin-1 Receptor Antagonist Reduces Neonatal Lipopolysaccharide-Induced Long-Lasting Neurobehavioral Deficits and Dopaminergic Neuronal Injury in Adult Rats

    Directory of Open Access Journals (Sweden)

    Yi Pang

    2015-04-01

    Full Text Available Our previous study showed that a single lipopolysaccharide (LPS treatment to neonatal rats could induce a long-lasting neuroinflammatory response and dopaminergic system injury late in life. This is evidenced by a sustained activation of microglia and elevated interleukin-1β (IL-1β levels, as well as reduced tyrosine hydroxylase (TH expression in the substantia nigra (SN of P70 rat brain. The object of the current study was to test whether co-administration of IL-1 receptor antagonist (IL-1ra protects against LPS-induced neurological dysfunction later in life. LPS (1 mg/kg with or without IL-1ra (0.1 mg/kg, or sterile saline was injected intracerebrally into postnatal day 5 (P5 Sprague-Dawley male rat pups. Motor behavioral tests were carried out from P7 to P70 with subsequent examination of brain injury. Our results showed that neonatal administration of IL-1ra significantly attenuated LPS-induced motor behavioral deficits, loss of TH immunoreactive neurons, as well as microglia activation in the SN of P70 rats. These data suggest that IL-1β may play a pivotal role in mediating a chronic neuroinflammation status by a single LPS exposure in early postnatal life, and blockading IL-1β might be a novel approach to protect the dopaminergic system against perinatal infection/inflammation exposure.

  18. Association of interleukin-1 receptor-associated kinase (IRAK1) gene polymorphisms (rs3027898, rs1059702) with systemic lupus erythematosus in a Chinese Han population.

    Science.gov (United States)

    Zhai, Yu; Xu, Ke; Leng, Rui-Xue; Cen, Han; Wang, Wei; Zhu, Yan; Zhou, Mo; Feng, Chen-Chen; Ye, Dong-Qing

    2013-06-01

    The purpose of this study was to examine the association of interleukin-1 receptor-associated kinase (IRAK1) polymorphisms (rs3027898, rs1059702) with systemic lupus erythematosus (SLE) in a Chinese Han population. A total of 667 SLE patients and 667 healthy controls were collected in this study. The genotyping of polymorphisms (rs3027898, rs1059702) was determined by TaqMan allele discrimination assay on the 7300 real-time polymerase chain reaction system. The statistical analysis was conducted by chi square test or Fisher's exact test. The frequency of C allele for rs3027898 in patients was significantly higher than in controls (C versus A: OR = 1.438, 95 % CI = 1.180-1.753, p oral ulcers. However, no significant difference was detected in IRAK1 rs1059702 polymorphism and the clinical manifestations. Our data demonstrate that the polymorphisms rs3027898 and rs1059702 of IRAK1 gene are associated with SLE in the Chinese Han population.

  19. Alternate splicing of interleukin-1 receptor type II (IL1R2 in vitro correlates with clinical glucocorticoid responsiveness in patients with AIED.

    Directory of Open Access Journals (Sweden)

    Andrea Vambutas

    Full Text Available Autoimmune Inner Ear Disease (AIED is poorly characterized clinically, with no definitive laboratory test. All patients suspected of having AIED are given glucocorticoids during periods of acute hearing loss, however, only half initially respond, and still fewer respond over time.We hypothesized that AIED is a systemic autoimmune disease characterized by dysfunctional peripheral blood mononuclear cells (PBMC responses to a unique cochlear antigen(s. To test this hypothesis, we examined end-stage AIED patients undergoing cochlear implant surgery and compared autologous perilymph stimulated PBMC from AIED patients to controls. We determined that autologous perilymph from AIED patients was unable to induce expression of a long membrane-bound Interleukin-1 Receptor Type II (mIL1R2 transcript in PBMC as compared with controls, despite similar expression of the short soluble IL1R2 (sIL1R2 transcript (p<0.05. IL1R2 is a molecular decoy that traps interleukin-1beta (IL-1beta and does not initiate subsequent signaling events, thereby suppressing an inflammatory response. IL1R2 transcript length is regulated by alternate splicing, and the major inhibitory function is attributed to the full-length mIL1R2. In addition, IL1R2 expression is induced by dexamethasone.Separately, we prospectively examined patients with newer onset glucocorticoid-responsive AIED. Immediately prior to clinical treatment for acute deterioration of hearing thresholds, their PBMC demonstrated a robust induction of mIL1R2 in PBMC in response to dexamethasone in vitro that correlated with a clinical response to prednisone in vivo (p<0.0001 as measured by hearing restoration. In contrast, clinically steroid unresponsive patients demonstrated high basal levels of mIL1R2 in their PBMC and only minimally augmented expression in response to dexamethasone. Thus, induced expression of mIL1R2 appears to be a protective mechanism in hearing homeostasis and warrants further investigation in a

  20. Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA: regulation by CB2 receptors and implications for neurotoxicity

    Directory of Open Access Journals (Sweden)

    O'Shea Esther

    2011-05-01

    Full Text Available Abstract Background 3,4-Methylenedioxymethamphetamine (MDMA produces a neuroinflammatory reaction in rat brain characterized by an increase in interleukin-1 beta (IL-1β and microglial activation. The CB2 receptor agonist JWH-015 reduces both these changes and partially protects against MDMA-induced neurotoxicity. We have examined MDMA-induced changes in IL-1 receptor antagonist (IL-1ra levels and IL-1 receptor type I (IL-1RI expression and the effects of JWH-015. The cellular location of IL-1β and IL-1RI was also examined. MDMA-treated animals were given the soluble form of IL-1RI (sIL-1RI and neurotoxic effects examined. Methods Dark Agouti rats received MDMA (12.5 mg/kg, i.p. and levels of IL-1ra and expression of IL-1RI measured 1 h, 3 h or 6 h later. JWH-015 (2.4 mg/kg, i.p. was injected 48 h, 24 h and 0.5 h before MDMA and IL-1ra and IL-1RI measured. For localization studies, animals were sacrificed 1 h or 3 h following MDMA and stained for IL-1β or IL-1RI in combination with neuronal and microglial markers. sIL-1RI (3 μg/animal; i.c.v. was administered 5 min before MDMA and 3 h later. 5-HT transporter density was determined 7 days after MDMA injection. Results MDMA produced an increase in IL-ra levels and a decrease in IL-1RI expression in hypothalamus which was prevented by CB2 receptor activation. IL-1RI expression was localized on neuronal cell bodies while IL-1β expression was observed in microglial cells following MDMA. sIL-1RI potentiated MDMA-induced neurotoxicity. MDMA also increased IgG immunostaining indicating that blood brain-barrier permeability was compromised. Conclusions In summary, MDMA produces changes in IL-1 signal modulators which are modified by CB2 receptor activation. These results indicate that IL-1β may play a partial role in MDMA-induced neurotoxicity.

  1. Interleukin-1 antagonism in type 1 diabetes of recent onset

    DEFF Research Database (Denmark)

    Moran, Antoinette; Bundy, Brian; Becker, Dorothy J

    2013-01-01

    Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1...... antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes....

  2. A phase I study of recombinant human soluble interleukin-1 receptor (rhu IL-1R) in patients with relapsed and refractory acute myeloid leukemia.

    Science.gov (United States)

    Bernstein, S H; Fay, J; Frankel, S; Christiansen, N; Baer, M R; Jacobs, C; Blosch, C; Hanna, R; Herzig, G

    1999-01-01

    The recombinant human interleukin-1 receptor (rhu IL-1R) is a soluble truncated form of the type 1 full-length membrane-bound receptor that binds IL-1 with identical affinity to that of the membrane form. As such, it may have clinical potential by sequestering IL-1, thereby preventing it from binding to its membrane-bound receptor and eliciting a biological effect. As IL-1 has been shown to regulate leukemic cell proliferation in an autocrine fashion, a phase I trial of rhu IL-1R was conducted in patients with relapsed and refractory acute myeloid leukemia (AML). The study group comprised 11 patients who were sequentially treated on one of three dose levels, receiving a single intravenous (i.v.) bolus dose on day 1 followed by 13 days of daily subcutaneous (s.c.) injections with the option of an additional 14 days of treatment if a response of stable disease or better was achieved. Dose level 1 i.v. bolus 500 microg/m2, s.c. dose 250 microg/m2 per day (five patients); dose level 2 i.v. bolus 1000 microg/m2, s.c. dose 500 microg/m2 per day (three patients); dose level 3 i.v. bolus 2000 microg/m2, s.c. dose 1000 microg/m2 per day (three patients). Owing to limited drug availability, the study was designed to only examine these three dose levels. rhu IL-IR was well tolerated. There was no grade 3 or 4 non-hematological toxicity related to the study drug and the maximum tolerated dose was not reached. No IL-1R-blocking antibodies developed during the course of the study. Serum levels of IL-1beta, IL-6 and TNF were undetectable before, during and after rhu IL-IR administration. The terminal half-life after i.v. dosing was at least 7-12 h, and after s.c. dosing 2-4 days. Serum levels of rhu IL-1R up to 360- and 25-fold those of pretreatment levels were achieved after i.v. and s.c. dosing respectively. No patient had a complete, partial or minor response to treatment; four had stable disease and seven had progressive disease. rhu IL-1R therapy was safe but did not have

  3. Analysis of Polymorphisms in Interleukin-10, Interleukin-6, and Interleukin-1 Receptor Antagonist in Mexican-Mestizo Women with Pre-eclampsia

    Science.gov (United States)

    Valencia Villalvazo, Elith Yazmin; Canto-Cetina, Thelma; Romero Arauz, Juan Fernando; Coral-Vázquez, Ramón Mauricio; Canizales-Quinteros, Samuel; Coronel, Agustín; Carlos Falcón, Juan; Hernández Rivera, Jaime; Ibarra, Roberto; Polanco Reyes, Lucila

    2012-01-01

    Due to the fact that studies seeking associations of polymorphisms in regulatory regions of cytokine genes with pre-eclampsia (PE) have not always been consistent in different population analyses, the aim of this study was to investigate the possible association between rs1800896 of interleukin-10 (IL-10), rs1800795 of interleukin-6 (IL-6), and the variable number of tandem repeats (VNTR) in intron 2 of interleukin-1 receptor antagonist (IL-1Ra), as well as gene–gene interactions between these three polymorphisms with the presence of PE in Mexican-Mestizo women and one Amerindian population from México (Maya). A case–control study was performed where 411 pre-eclamptic cases and 613 controls were genotyped. For the rs1800896 of IL-10 and rs1800795 of IL-6, we used real-time polymerase chain reaction (PCR) allelic discrimination and for the VNTR of IL-1Ra, PCR. Allele frequency differences were assessed by Chi-squared test; logistic regression was used to test for associations; a gene–gene interaction was conducted. Genotypic and allelic distribution of the polymorphisms was similar in our population. The estimated of the gene–gene interaction between the polymorphisms did not differ significantly. However, we observed important differences in the distribution of the alleles and genotypes of the three polymorphisms analyzed between Mestiza-Mexicanas and Maya-Mestizo women. In conclusion, we did not find an association between polymorphisms in IL-10, IL-6, and IL-1Ra and PE in Mexican-Mestizo and Maya-Mestizo women. To our knowledge, this is the first time that these three polymorphisms were analyzed together with gene–gene interaction in women with PE. PMID:23013217

  4. Experimental transmission of AA amyloidosis by injecting the AA amyloid protein into interleukin-1 receptor antagonist knockout (IL-1raKO) mice.

    Science.gov (United States)

    Watanabe, K; Uchida, K; Chambers, J K; Tei, M; Shoji, A; Ushio, N; Nakayama, H

    2015-05-01

    The incidence of AA amyloidosis is high in humans with rheumatoid arthritis and several animal species, including cats and cattle with prolonged inflammation. AA amyloidosis can be experimentally induced in mice using severe inflammatory stimuli and a coinjection of AA amyloid; however, difficulties have been associated with transmitting AA amyloidosis to a different animal species, and this has been attributed to the "species barrier." The interleukin-1 receptor antagonist knockout (IL-1raKO) mouse, a rodent model of human rheumatoid arthritis, has been used in the transmission of AA amyloid. When IL-1raKO and BALB/c mice were intraperitoneally injected with mouse AA amyloid together with a subcutaneous pretreatment of 2% AgNO3, all mice from both strains that were injected with crude or purified murine AA amyloid developed AA amyloidosis. However, the amyloid index, which was determined by the intensity of AA amyloid deposition, was significantly higher in IL-1raKO mice than in BALB/c mice. When IL-1raKO and BALB/c mice were injected with crude or purified bovine AA amyloid together with the pretreatment, 83% (5/6 cases) and 38% (3/8 cases) of IL-1raKO mice and 17% (1/6 cases) and 0% (0/6 cases) of BALB/c mice, respectively, developed AA amyloidosis. Similarly, when IL-1raKO and BALB/c mice were injected with crude or purified feline AA amyloid, 33% (2/6 cases) and 88% (7/8 cases) of IL-1raKO mice and 0% (0/6 cases) and 29% (2/6 cases) of BALB/c mice, respectively, developed AA amyloidosis. These results indicated that IL-1raKO mice are a useful animal model for investigating AA amyloidogenesis. © The Author(s) 2014.

  5. Interleukin-1 receptor antagonist: characterisation of its gene expression in rabbit tissues and large-scale expression in eucaryotic cells using a baculovirus expression system.

    Science.gov (United States)

    Apostolopoulos, J; Ross, S; Davenport, P; Matsukawa, A; Yoshinaga, M; Tipping, P G

    1996-11-29

    The gene expression of rabbit interleukin-1 receptor antagonist (RbIL-lra) was examined in rabbit tissues. RNA was isolated from heart, lung, kidney, muscle, liver, spleen, brain, and peripheral blood monocytes (PBMs), and RbIL-lra mRNA was identified as a single species by Northern analysis using a RbIL-lra probe. RbIL-lra was abundantly expressed in lung, brain, heart, and liver, expressed at low levels in spleen, and undetectable in kidney and unstimulated PBMs. Expression of large scale recombinant production of RbIL-lra was achieved by subcloning the cDNA into a baculovirus expression vector. Recombination of this vector was completed with the BacPAK6 baculovirus genome. The recombinant virus, containing the RbIL-lra cDNA, was used to infect Spodoptera frugiperda (Sf21) insect cells in a spinner flask system and in monolayers in cell culture flasks. Recombinant rabbit IL-lra (rRbIL-lra) was secreted into the culture medium in this system at very high levels (35 mg/l). The protein was identified by reducing SDS-PAGE electrophoresis, was variably glycosylated and had a molecular weight between 19-25 kDa. It was then purified by size exclusion HPLC on a Du Pont Gf-250 column. The rRbIL-lra was demonstrated to be functionally active by inhibiting recombinant human IL-1 alpha in a mouse thymocyte proliferation assay. 20 ng/ml (6.7 U/ml) of rRbIL-lra inhibited 95% of the activity of 2 ng/ml IL-1 alpha.

  6. Insight into Phosphatidylinositol-Dependent Membrane Localization of the Innate Immune Adaptor Protein Toll/Interleukin 1 Receptor Domain-Containing Adaptor Protein

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    Mahesh Chandra Patra

    2018-01-01

    Full Text Available The toll/interleukin 1 receptor (TIR domain-containing adaptor protein (TIRAP plays an important role in the toll-like receptor (TLR 2, TLR4, TLR7, and TLR9 signaling pathways. TIRAP anchors to phosphatidylinositol (PI 4,5-bisphosphate (PIP2 on the plasma membrane and PI (3,4,5-trisphosphate (PIP3 on the endosomal membrane and assists in recruitment of the myeloid differentiation primary response 88 protein to activated TLRs. To date, the structure and mechanism of TIRAP’s membrane association are only partially understood. Here, we modeled an all-residue TIRAP dimer using homology modeling, threading, and protein–protein docking strategies. Molecular dynamics simulations revealed that PIP2 creates a stable microdomain in a dipalmitoylphosphatidylcholine bilayer, providing TIRAP with its physiologically relevant orientation. Computed binding free energy values suggest that the affinity of PI-binding domain (PBD for PIP2 is stronger than that of TIRAP as a whole for PIP2 and that the short PI-binding motif (PBM contributes to the affinity between PBD and PIP2. Four PIP2 molecules can be accommodated by distinct lysine-rich surfaces on the dimeric PBM. Along with the known PI-binding residues (K15, K16, K31, and K32, additional positively charged residues (K34, K35, and R36 showed strong affinity toward PIP2. Lysine-to-alanine mutations at the PI-binding residues abolished TIRAP’s affinity for PIP2; however, K34, K35, and R36 consistently interacted with PIP2 headgroups through hydrogen bond (H-bond and electrostatic interactions. TIRAP exhibited a PIP2-analogous intermolecular contact and binding affinity toward PIP3, aided by an H-bond network involving K34, K35, and R36. The present study extends our understanding of TIRAP’s membrane association, which could be helpful in designing peptide decoys to block TLR2-, TLR4-, TLR7-, and TLR9-mediated autoimmune diseases.

  7. Emerging Role of Interleukin-1 in Cardiovascular Diseases

    Czech Academy of Sciences Publication Activity Database

    Vicenová, B.; Vopálenský, D.; Burýšek, L.; Pospíšek, Martin

    2009-01-01

    Roč. 58, č. 4 (2009), s. 481-498 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M06014 Keywords : interleukin-1 * interleukin-1 receptor antagonist protein * signal pathways * cardiovascular diseases Subject RIV: ED - Physiology Impact factor: 1.430, year: 2009 http://www.biomed.cas.cz/physiolres/pdf/58/58_481.pdf

  8. Anti-interleukin-1 alpha autoantibodies in humans: Characterization, isotype distribution, and receptor-binding inhibition--higher frequency in Schnitzler's syndrome (urticaria and macroglobulinemia)

    Energy Technology Data Exchange (ETDEWEB)

    Saurat, J.H.; Schifferli, J.; Steiger, G.; Dayer, J.M.; Didierjean, L. (Department of Dermatology, University Hospital, Geneva (Switzerland))

    1991-08-01

    Since autoantibodies (Abs) to cytokines may modify their biologic activities, high-affinity binding factors for interleukin-1 alpha (IL-1 alpha BF) were characterized in human sera. IL-1 alpha BF was identified as IgG (1) by sucrose density-gradient centrifugation followed by immunodiffusion autoradiography, (2) by ligand-blotting method, (3) by ligand binding to affinity-immobilized serum IgG, and (4) by IgG affinity purification followed by sucrose density-gradient centrifugation. IL-1 alpha binding activity resided in the F(ab)2 fragment. The apparent equilibrium constant was in the range of IgG found after immunization with conventional antigens (i.e., 10(-9) to 10(-10) mol/L). Anti-IL-1 alpha IgG auto-Abs represented only an extremely small fraction of total IgG (less than 1/10(-5)). Some sera with IL-1 alpha BF and purified IgG thereof were able to inhibit by 96% to 98% the binding of human recombinant IL-1 alpha to its receptor on murine thymoma EL4-6.1 cells, whereas other sera did not. When 125I-labeled anti-IL-1 alpha IgG complexes were injected into rats, they prolonged the plasma half-life of 125I-labeled IL-1 alpha several fold and altered its tissue distribution. The predominant class was IgG (12/19), mainly IgG4 (9/19), but in five of the sera, anti-IL-1 alpha IgA was also detected. In a screening of 271 sera, IL-1 alpha BF was detected in 17/98 normal subjects and was not more frequent in several control groups of patients, except in patients with Schnitzler's syndrome (fever, chronic urticaria, bone pain, and monoclonal IgM paraprotein) (6/9; p less than 0.005). The pathologic significance of these auto-Abs remains to be determined.

  9. Interleukin-1 receptor mediates the interplay between CD4+ T cells and ocular resident cells to promote keratinizing squamous metaplasia in Sjögren's syndrome.

    Science.gov (United States)

    Chen, Ying-Ting; Lazarev, Stanislav; Bahrami, Ahmad F; Noble, Lisa B; Chen, Feeling Y T; Zhou, Delu; Gallup, Marianne; Yadav, Mahesh; McNamara, Nancy A

    2012-04-01

    Keratinizing squamous metaplasia (SQM) of the ocular mucosal epithelium is a blinding corneal disease characterized by the loss of conjunctival goblet cells (GCs), pathological ocular surface keratinization and tissue recruitment of immune cells. Using the autoimmune regulator (Aire)-deficient mouse as a model for Sjögren's syndrome (SS)-associated SQM, we identified CD4(+) T lymphocytes as the main immune effectors driving SQM and uncovered a pathogenic role for interleukin-1 (IL-1). IL-1, a pleiotropic cytokine family enriched in ocular epithelia, governs tissue homeostasis and mucosal immunity. Here, we used adoptive transfer of autoreactive CD4(+) T cells to dissect the mechanism whereby IL-1 promotes SQM. CD4(+) T cells adoptively transferred from both Aire knockout (KO) and Aire/IL-1 receptor type 1 (IL-1R1) double KO donors conferred SQM to severe-combined immunodeficiency (scid) recipients with functional IL-1R1, but not scid recipients lacking IL-1R1. In the lacrimal gland, IL-1R1 was primarily immunolocalized to ductal epithelium surrounded by CD4(+) T cells. In the eye, IL-1R1 was expressed on local mucosal epithelial and stromal cells, but not on resident antigen-presenting cells or infiltrating immune cells. In both tissues, autoreactive CD4(+) T-cell infiltration was only observed in the presence of IL-1R1-postive resident cells. Moreover, persistent activation of IL-1R1 signaling led to chronic immune-mediated inflammation by retaining CD4(+) T cells in the local microenvironment. Following IL-1R1-dependent infiltration of CD4(+) T cells, we observed SQM hallmarks in local tissues-corneal keratinization, conjunctival GC mucin acidification and epithelial cell hyperplasia throughout the ocular surface mucosa. Proinflammatory IL-1 expression in ocular epithelial cells significantly correlated with reduced tear secretion, while CD4(+) T-cell infiltration of the lacrimal gland predicted the development of ocular SQM. Collectively, data in this study

  10. Plasma Levels of the Interleukin-1-Receptor Antagonist Are Lower in Women with Gestational Diabetes Mellitus and Are Particularly Associated with Postpartum Development of Type 2 Diabetes.

    Science.gov (United States)

    Katra, Pernilla; Dereke, Jonatan; Nilsson, Charlotta; Hillman, Magnus

    2016-01-01

    Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia. Women who develops hyperglycemia for the first time during pregnancy receive the diagnosis gestational diabetes mellitus (GDM). Presently, there is no consensus about the diagnostic criteria for GDM. A majority of these women subsequently develop postpartum overt diabetes making it important to identify these patients as early as possible. In this study we investigated if plasma levels of the interleukin-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1 signaling, can be used as a complementary biomarker for diagnosing GDM and predicting postpartum development of overt diabetes mellitus. Patients participating in this study (n = 227) were diagnosed with their first GDM 2004-2013 at Lund University Hospital, Lund, Sweden. Healthy pregnant volunteers (n = 156) were recruited from women's welfare centers in the same region 2014-2015. Levels of IL-1Ra and C-peptide were analyzed in ethylenediaminetetraacetic acid (EDTA)-plasma or serum using enzyme linked immunosorbent assay (ELISA). GDM patients had significantly lower levels of IL-1Ra than the control group (p = 0.012). In addition, GDM patients that had developed impaired glucose tolerance (IGT) or type 2 diabetes mellitus postpartum had significantly lower levels of IL-1Ra, and significantly higher levels of C-peptide than GDM patients that had not developed diabetes mellitus postpartum (p = 0.023) and (p = 0.0011) respectively. An inverse correlation was found between IL-1Ra and serum C-peptide levels in the control group (rs = -0.31 p = 0.0001). Our results show that IL-1Ra might be included in a future panel of biomarkers, both for diagnosing GDM to complement blood glucose, and also identifying GDM patients that are at risk of developing type 2 diabetes mellitus postpartum. However, the ROC curve analysis provided a sensitivity of 52.2% and specificity of 67.1%, which nonetheless may not be sufficient enough to use IL

  11. Plasma Levels of the Interleukin-1-Receptor Antagonist Are Lower in Women with Gestational Diabetes Mellitus and Are Particularly Associated with Postpartum Development of Type 2 Diabetes.

    Directory of Open Access Journals (Sweden)

    Pernilla Katra

    Full Text Available Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia. Women who develops hyperglycemia for the first time during pregnancy receive the diagnosis gestational diabetes mellitus (GDM. Presently, there is no consensus about the diagnostic criteria for GDM. A majority of these women subsequently develop postpartum overt diabetes making it important to identify these patients as early as possible. In this study we investigated if plasma levels of the interleukin-1 receptor antagonist (IL-1Ra, an endogenous inhibitor of IL-1 signaling, can be used as a complementary biomarker for diagnosing GDM and predicting postpartum development of overt diabetes mellitus. Patients participating in this study (n = 227 were diagnosed with their first GDM 2004-2013 at Lund University Hospital, Lund, Sweden. Healthy pregnant volunteers (n = 156 were recruited from women's welfare centers in the same region 2014-2015. Levels of IL-1Ra and C-peptide were analyzed in ethylenediaminetetraacetic acid (EDTA-plasma or serum using enzyme linked immunosorbent assay (ELISA. GDM patients had significantly lower levels of IL-1Ra than the control group (p = 0.012. In addition, GDM patients that had developed impaired glucose tolerance (IGT or type 2 diabetes mellitus postpartum had significantly lower levels of IL-1Ra, and significantly higher levels of C-peptide than GDM patients that had not developed diabetes mellitus postpartum (p = 0.023 and (p = 0.0011 respectively. An inverse correlation was found between IL-1Ra and serum C-peptide levels in the control group (rs = -0.31 p = 0.0001. Our results show that IL-1Ra might be included in a future panel of biomarkers, both for diagnosing GDM to complement blood glucose, and also identifying GDM patients that are at risk of developing type 2 diabetes mellitus postpartum. However, the ROC curve analysis provided a sensitivity of 52.2% and specificity of 67.1%, which nonetheless may not be sufficient enough

  12. Variable number of tandem repeat polymorphisms of the interleukin-1 receptor antagonist gene IL-1RN: a novel association with the athlete status

    Directory of Open Access Journals (Sweden)

    Ryckman Kelli K

    2010-02-01

    Full Text Available Abstract Background The interleukin-1 (IL-1 family of cytokines is involved in the inflammatory and repair reactions of skeletal muscle during and after exercise. Specifically, plasma levels of the IL-1 receptor antagonist (IL-1ra increase dramatically after intense exercise, and accumulating evidence points to an effect of genetic polymorphisms on athletic phenotypes. Therefore, the IL-1 family cytokine genes are plausible candidate genes for athleticism. We explored whether IL-1 polymorphisms are associated with athlete status in European subjects. Methods Genomic DNA was obtained from 205 (53 professional and 152 competitive non-professional Italian athletes and 458 non-athlete controls. Two diallelic polymorphisms in the IL-1β gene (IL-1B at -511 and +3954 positions, and a variable number tandem repeats (VNTR in intron 2 of the IL-1ra gene (IL-1RN were assessed. Results We found a 2-fold higher frequency of the IL-1RN 1/2 genotype in athletes compared to non-athlete controls (OR = 1.93, 95% CI = 1.37-2.74, 41.0% vs. 26.4%, and a lower frequency of the 1/1 genotype (OR = 0.55, 95% CI = 0.40-0.77, 43.9% vs. 58.5%. Frequency of the IL-1RN 2/2 genotype did not differ between groups. No significant differences between athletes and controls were found for either -511 or +3954 IL-1B polymorphisms. However, the haplotype (-511C-(+3954T-(VNTR2 was 3-fold more frequent in athletes than in non-athletes (OR = 3.02, 95% CI = 1.16-7.87. Interestingly, the IL-1RN 1/2 genotype was more frequent in professional than in non-professional athletes (OR = 1.92, 95% CI = 1.02-3.61, 52.8% vs. 36.8%. Conclusions Our study found that variants at the IL-1ra gene associate with athletic status. This confirms the crucial role that cytokine IL-1ra plays in human physical exercise. The VNTR IL-1RN polymorphism may have implications for muscle health, performance, and/or recovery capacities. Further studies are needed to assess these specific issues. As VNTR IL-1RN

  13. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-α induction

    OpenAIRE

    Uematsu, Satoshi; Sato, Shintaro; Yamamoto, Masahiro; Hirotani, Tomonori; Kato, Hiroki; Takeshita, Fumihiko; Matsuda, Michiyuki; Coban, Cevayir; Ishii, Ken J.; Kawai, Taro; Takeuchi, Osamu; Akira, Shizuo

    2005-01-01

    Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-α in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7...

  14. Sleep-wake behavior and responses to sleep deprivation of mice lacking both interleukin-1 beta receptor 1 and tumor necrosis factor-alpha receptor 1.

    Science.gov (United States)

    Baracchi, Francesca; Opp, Mark R

    2008-08-01

    Data indicate that interleukin (IL)-1 beta and tumor necrosis factor-alpha (TNFalpha) are involved in the regulation of non-rapid eye movement sleep (NREMS). Previous studies demonstrate that mice lacking the IL-1 beta type 1 receptor spend less time in NREMS during the light period, whereas mice lacking the p55 (type 1) receptor for TNFalpha spend less time in NREMS during the dark period. To further investigate roles for IL-1 beta and TNFalpha in sleep regulation we phenotyped sleep and responses to sleep deprivation of mice lacking both the IL-1 beta receptor 1 and TNFalpha receptor 1 (IL-1R1/TNFR1 KO). Male adult mice (IL-1R1/TNFR1 KO, n=14; B6129SF2/J, n=14) were surgically instrumented with EEG electrodes and with a thermistor to measure brain temperature. After recovery and adaptation to the recording apparatus, 48 h of undisturbed baseline recordings were obtained. Mice were then subjected to 6h sleep deprivation at light onset by gentle handling. IL-1R1/TNFR1 KO mice spent less time in NREMS during the last 6h of the dark period and less time in rapid eye movement sleep (REMS) during the light period. There were no differences between strains in the diurnal timing of delta power during NREMS. However, there were strain differences in the relative power spectra of the NREMS EEG during both the light period and the dark period. In addition, during the light period relative power in the theta frequency band of the REMS EEG differed between strains. After sleep deprivation, control mice exhibited prolonged increases in NREMS and REMS, whereas the duration of the NREMS increase was shorter and there was no increase in REMS of IL-1R1/TNFR1 KO mice. Delta power during NREMS increased in both strains after sleep deprivation, but the increase in delta power during NREMS of IL-1R1/TNFR1 KO mice was of greater magnitude and of longer duration than that observed in control mice. These results provide additional evidence that the IL-1 beta and TNFalpha cytokine systems

  15. Serum amyloid A induces interleukin-6 in dermal fibroblasts via Toll-like receptor 2, interleukin-1 receptor-associated kinase 4 and nuclear factor-κB

    Science.gov (United States)

    O'Reilly, Steven; Cant, Rachel; Ciechomska, Marzena; Finnigan, James; Oakley, Fiona; Hambleton, Sophie; van Laar, Jacob M

    2014-01-01

    Systemic sclerosis is an autoimmune idiopathic connective tissue disease, characterized by vasculopathy, inflammation and fibrosis. There appears to be a link between inflammation and fibrosis, although the exact nature of the relationship is unknown. Serum amyloid A (SAA) is an acute-phase protein that is elevated up to 1000-fold in times of infection or inflammation. This acute-phase reactant, as well as being a marker of inflammation, may initiate signals in a cytokine-like manner, possibly through toll-like receptors (TLRs) promoting inflammation. This study addressed the role of SAA in initiating interleukin-6 (IL-6) production in dermal fibroblasts and the role of TLR2 in this system. We show that SAA induces IL-6 secretion in healthy dermal fibroblasts and that blockade of TLR2 with a neutralizing antibody to TLR2 or specific small interfering RNA attenuated the SAA-induced IL-6 secretion and that this was also mediated through the TLR adaptor protein IL-1 receptor-associated kinase 4. The effect is nuclear factor-κB-mediated because blockade of nuclear factor-κB reduced the induction. We also demonstrate that dermal fibroblasts express TLR2; this is functional and over-expressed in the fibroblasts of patients with systemic sclerosis. Taken together these data suggest that SAA is a danger signal that initiates IL-6 signalling in systemic sclerosis via enhanced TLR2 signalling. PMID:24476318

  16. Enhanced interleukin-1beta production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals

    NARCIS (Netherlands)

    Mylona, E.E.; Mouktaroudi, M.; Crisan, T.O.; Makri, S.; Pistiki, A.; Georgitsi, M.; Savva, A.; Netea, M.G.; van der Meer, J.W.; Giamarellos-Bourboulis, E.J.; Joosten, L.A.B.

    2012-01-01

    ABSTRACT: INTRODUCTION: Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using

  17. An anti-inflammatory property of Candida albicans beta-glucan: Induction of high levels of interleukin-1 receptor antagonist via a Dectin-1/CR3 independent mechanism

    NARCIS (Netherlands)

    Smeekens, S.P.; Gresnigt, M.S.; Becker, K.L.; Cheng, S.C.; Netea, S.A.; Jacobs, L.; Jansen, T.; Veerdonk, F.L. van de; Williams, D.L.; Joosten, L.A.B.; Dinarello, C.A.; Netea, M.G.

    2014-01-01

    BACKGROUND: Candida albicans is an opportunistic fungal pathogen that induces strong proinflammatory responses, such as IL-1beta production. Much less is known about the induction of immune modulatory cytokines, such as the IL-1 receptor antagonist (IL-1Ra) that is the main natural antagonist of

  18. An anti-inflammatory property of Candida albicans beta-glucan: Induction of high levels of interleukin-1 receptor antagonist via a Dectin-1/CR3 independent mechanism

    NARCIS (Netherlands)

    Smeekens, S.P.; Gresnigt, M.S.; Becker, K.L.; Cheng, S.C.; Netea, S.A.; Jacobs, L.; Jansen, T.J.G.; Veerdonk, F.L. van de; Williams, D.L.; Joosten, L.A.B.; Dinarello, C.A.; Netea, M.G.

    2015-01-01

    BACKGROUND: Candida albicans is an opportunistic fungal pathogen that induces strong proinflammatory responses, such as IL-1beta production. Much less is known about the induction of immune modulatory cytokines, such as the IL-1 receptor antagonist (IL-1Ra) that is the main natural antagonist of

  19. Virus-Encoded 7 Transmembrane Receptors

    DEFF Research Database (Denmark)

    Mølleskov-Jensen, Ann-Sofie; Oliveira, MarthaTrindade; Farrell, Helen Elizabeth

    2015-01-01

    chemokine receptors (CKRs). Conserved families of v7TMRs distinguish between beta- versus gammaherpesviruses; furthermore, significant divisions within these subfamilies, such as between genera of the gammaherpesviruses or between the primate and rodent cytomegaloviruses, coincide with specific v7TMR gene...... families. Divergence of functional properties between the viral 7TMR and their cellular counterparts is likely, therefore, to reflect adaptation supporting various aspects of the viral lifecycle with concomitant effects upon viral pathogenesis. Consistent with their long evolutionary history, the v7TMRs...... activation. Indeed, many of the v7TMRs have been shown to signal constitutively, associated in some cases with notable divergence of highly conserved regulatory elements such as the “DRY” motif of TMIII. The availability of rodent models for v7TMR functional studies has provided evidence for important...

  20. Blockade of adenosine A2A receptors prevents interleukin-1β-induced exacerbation of neuronal toxicity through a p38 mitogen-activated protein kinase pathway

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    Simões Ana

    2012-08-01

    Full Text Available Abstract Background and purpose Blockade of adenosine A2A receptors (A2AR affords robust neuroprotection in a number of brain conditions, although the mechanisms are still unknown. A likely candidate mechanism for this neuroprotection is the control of neuroinflammation, which contributes to the amplification of neurodegeneration, mainly through the abnormal release of pro-inflammatory cytokines such as interleukin(IL-1β. We investigated whether A2AR controls the signaling of IL-1β and its deleterious effects in cultured hippocampal neurons. Methods Hippocampal neuronal cultures were treated with IL-1β and/or glutamate in the presence or absence of the selective A2AR antagonist, SCH58261 (50 nmol/l. The effect of SCH58261 on the IL-1β-induced phosphorylation of the mitogen-activated protein kinases (MAPKs c-Jun N-terminal kinase (JNK and p38 was evaluated by western blotting and immunocytochemistry. The effect of SCH58261 on glutamate-induced neurodegeneration in the presence or absence of IL-1β was evaluated by nucleic acid and by propidium iodide staining, and by lactate dehydrogenase assay. Finally, the effect of A2AR blockade on glutamate-induced intracellular calcium, in the presence or absence of IL-1β, was studied using single-cell calcium imaging. Results IL-1β (10 to 100 ng/ml enhanced both JNK and p38 phosphorylation, and these effects were prevented by the IL-1 type 1 receptor antagonist IL-1Ra (5 μg/ml, in accordance with the neuronal localization of IL-1 type 1 receptors, including pre-synaptically and post-synaptically. At 100 ng/ml, IL-1β failed to affect neuronal viability but exacerbated the neurotoxicity induced by treatment with 100 μmol/l glutamate for 25 minutes (evaluated after 24 hours. It is likely that this resulted from the ability of IL-1β to enhance glutamate-induced calcium entry and late calcium deregulation, both of which were unaffected by IL-1β alone. The selective A2AR antagonist, SCH58261 (50 nmol

  1. Lack of interleukin-1 type 1 receptor enhances the accumulation of mutant huntingtin in the striatum and exacerbates the neurological phenotypes of Huntington's disease mice

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    Wang Chuan-En

    2010-11-01

    Full Text Available Abstract Huntington's disease results from expansion of a glutamine repeat (>36 glutamines in the N-terminal region of huntingtin (htt and is characterized by preferential neurodegeneration in the striatum of the brain. N171-82Q mice that express N-terminal 171 amino acids of htt with an 82-glutamine repeat show severe neurological phenotypes and die early, suggesting that N-terminal mutant htt is pathogenic. In addition, various cellular factors and genetic modifiers are found to modulate the cytotoxicity of mutant htt. Understanding the contribution of these factors to HD pathogenesis will help identify therapeutics for this disease. To investigate the role of interleukin type 1 (IL-1, a cytokine that has been implicated in various neurological diseases, in HD neurological symptoms, we crossed N171-82Q mice to type I IL-1 receptor (IL-1RI knockout mice. Mice lacking IL-1RI and expressing N171-82Q show more severe neurological symptoms than N171-82Q or IL-1RI knockout mice, suggesting that lack of IL-1RI can promote the neuronal toxicity of mutant htt. Lack of IL-1RI also increases the accumulation of transgenic mutant htt in the striatum in N171-82Q mice. Since IL-1RI signaling mediates both toxic and protective effects on neurons, its basal function and protective effects may be important for preventing the neuropathology seen in HD.

  2. Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids

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    Pedro Escoll

    2015-01-01

    Full Text Available Clinical treatment with glucocorticoids (GC can be complicated by cytokine-induced glucocorticoid low-responsiveness (GC-resistance, GCR, a condition associated with a homogeneous reduction in the expression of GC-receptor- (GR- driven anti-inflammatory genes. However, GR level and phosphorylation changes modify the expression of individual GR-responsive genes differently. As sustained IL-1β exposure is key in the pathogenesis of several major diseases with prevalent GCR, we examined GR signaling and the mRNA expression of six GR-driven genes in cells cultured in IL-1β and afterwards challenged with GC. After a GC challenge, sustained IL-1β exposure reduced the cytoplasmic GR level, GRSer203 and GRSer211 phosphorylation, and GR nuclear translocation and led to selective GCR in the expression of the studied genes. Compared to GC alone, in a broad range of GC doses plus sustained IL-1β, FKBP51 mRNA expression was reduced by 1/3, TTP by 2/3, and IRF8 was completely knocked down. In contrast, high GC doses did not change the expression of GILZ and DUSP1, while IGFBP1 was increased by 5-fold. These effects were cytokine-selective, IL-1β dose- and IL-1R1-dependent. The integrated gain and loss of gene functions in the “split GCR” model may provide target cells with a survival advantage by conferring resistance to apoptosis, chemotherapy, and GC.

  3. Toll/Interleukin-1 receptor member ST2 exhibits higher soluble levels in type 2 diabetes, especially when accompanied with left ventricular diastolic dysfunction

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    Fousteris Evangelos

    2011-11-01

    Full Text Available Abstract Background Soluble ST2, a member of the of the Toll/IL-1 superfamily, is a novel biomarker with exceptional predictive value in heart failure and myocardial infarction- related mortality as well as in acute dyspneic states. Soluble ST2 is considered a decoy receptor of IL 33 that blocks the protective effects of the cytokine in atherosclerosis and cardiac remodeling. In the present study we investigated the differences in the levels of soluble ST2, BNP and hs-CRP between healthy controls and patients with type 2 diabetes with and without left ventricular diastolic dysfunction. A secondary aim was to investigate correlations between sST2 and other biomarkers of type 2 diabetes, such as HbA1c. Methods 158 volunteers were recruited and underwent a complete Doppler-echocardiographic evaluation of both systolic & diastolic cardiac function. All subjects with ejection fraction Results Patients with type 2 diabetes with (p Conclusions Patients with type 2 diabetes exhibit higher sST2 levels compared to healthy controls. The presence of LVDD in patients with type 2 diabetes is associated with even higher sST2 levels. A significant correlation between glycemic control and sST2 levels was also revealed.

  4. Interleukin-1/toll-like receptor-induced nuclear factor kappa B signaling participates in intima hyperplasia after carotid artery balloon injury in goto-kakizaki rats: a potential target therapy pathway.

    Directory of Open Access Journals (Sweden)

    Xiaotian Zhang

    Full Text Available The value of restenosis after percutaneous coronary intervention (PCI is recognized worldwide, especially for diabetic patients. Interleukin-1/Toll-like receptor (IL-1/TLR signaling is involved in innate and adaptive immune responses, but whether and how the IL-1/TLR-induced nuclear factor kappa B (NFκB pathway plays key roles in intimal formation is unclear. The underlying mechanism of intima hyperplasia was investigated with a model of carotid balloon injury in Goto-Kakizaki (GK and Wistar rats and with lipopolysaccharide-stimulated macrophages. Elastic-van Gieson staining showed the medial area peakedon Day 3 post-injury and decreased by Day 7 post-injury in both GK and Wistar rats. The N/M at Day 7 in GK rats was significantly higher than in Wistar rats (p<0.001. The percent of 5-ethynyl-2'-deoxyuridine (EdU staining-positive cells on Day 3 post-injury was greater than seen on Day 7 post-injury in GK and Wistar rats. The percent of EdU-positive cells on Days 3 and 7 post-injury in Wistar rats was less than that found in GK rats (p<0.01; p<0.05. NFκBp65 immunostaining had increased by Day 7 post-injury. Agilent Whole Genome Oligo Microarray verified that the IL-1/TLR-induced NFκB pathway was activated by carotid balloon injury. TLR4, IL-1 receptor associated kinase, inhibitors α of NFκB, human antigen R, c-Myc (Proto-Oncogene Proteins, EGF-like module-containing mucin-like hormone receptor-like 1 and Interleukin-6 were up-regulated or down-regulated according to immunochemistry, quantitative real-time PCR, Western blotting and Enzyme linked immunosorbent assay. Overall, we conclude that the IL-1/TLR-induced NFκB pathway participates in the intimal hyperplasia after carotid injury in GK and Wistar rats and that GK rats respond more intensely to the inflammation than Wistar rats.

  5. Dexamethasone or interleukin-10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys.

    Science.gov (United States)

    Sadowsky, Drew W; Novy, Miles J; Witkin, Steven S; Gravett, Michael G

    2003-01-01

    The purpose of this study was to determine whether treatment with the immune modulators dexamethasone or interleukin-10 prevents interleukin-1beta-induced uterine contractions in a nonhuman primate model. Thirteen chronically instrumented rhesus monkeys at 135 +/- 1 days of gestation (term, 167 days) received one of three interventions: (1) intra-amniotic interleukin-1beta (10 microg) infusion with maternal dexamethasone (1 mg/kg) intravenously every 6 hours for 1 day before interleukin-1beta and for 2 days thereafter (n = 4), (2) intra-amniotic interleukin-1beta infusion with maternal interleukin-10 (25 microg/kg) given intravenously and 100 microg interleukin-10 given intra-amniotically before the interleukin-1beta and continued every 8 hours for 3 days (n = 5), and (3) intra-amniotic interleukin-1beta administered alone (n = 5). Uterine activity was monitored continuously and quantified as the hourly contraction area (millimeters of mercury times seconds per hour) in all groups until delivery. Amniotic fluid was sampled for leukocyte counts and assayed for prostaglandins E(2) and F(2)alpha, cytokines interleukin-1beta, interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1 receptor antagonist by specific assays. Maternal and fetal blood were assayed for cortisol, dehydroepiandrosterone sulfate, and estradiol. Interleukin-1beta infusion in the absence of immune modulators resulted in an increase in uterine activity and amniotic fluid proinflammatory cytokines, prostaglandins, and leukocytes. Dexamethasone and interleukin-10 treatment significantly reduced interleukin-1beta-induced uterine contractility (P dexamethasone (P Dexamethasone and interleukin-10 exert similar inhibitory effects on interleukin-1beta-induced uterine activity, which appears to be mediated by a decrease in prostaglandin production. Reduced estrogen biosynthesis or suppression of tumor necrosis factor-alpha and leukocyte migration may contribute to the

  6. Structure, function and physiological consequences of virally encoded chemokine seven transmembrane receptors

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Smit, M J; Waldhoer, M

    2008-01-01

    A number of human and animal herpes viruses encode G-protein coupled receptors with seven transmembrane (7TM) segments-most of which are clearly related to human chemokine receptors. It appears, that these receptors are used by the virus for immune evasion, cellular transformation, tissue targeting...... pathogenesis is still poorly understood. Here we focus on the current knowledge of structure, function and trafficking patterns of virally encoded chemokine receptors and further address the putative roles of these receptors in virus survival and host -cell and/or -immune system modulation. Finally, we...

  7. Interleukin-1Ra rs2234663 and Interleukin-4 rs79071878 Polymorphisms in Familial Mediterranean Fever.

    Science.gov (United States)

    Nursal, Ayse Feyda; Tekcan, Akin; Kaya, Suheyla Uzun; Sezer, Ozlem; Yigit, Serbulent

    2016-05-15

    Familial Mediterranean Fever (FMF) is an autosomal recessively inherited auto inflammatory disorder. MEFV gene, causing FMF, encodes pyrin that is associated with the interleukin-1 (IL-1) related inflammation cascade. The aim of this study was to investigate the relationship of interleukin-1 receptor antagonist (IL-1Ra) and interleukin-4 (IL-4) polymorphisms with the risk of FMF in the Turkish population. This study included 160 patients with FMF (74 men, 86 women) and 120 healthy controls (50 men, 70 women), respectively. Genotyping of IL-1Ra rs2234663 polymorphism was evaluated by gel electrophoresis after polymerase chain reaction (PCR). The IL-4 rs79071878 polymorphism was determined by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis. The results of analyses were evaluated for statistical significance. There was no significant difference in IL-1Ra genotype and allele distributions between FMF and the control groups (p>0.05). However, a significant association was observed between FMF patients and control groups according to IL-4 genotype distribution (p=0.016), but no association was found in the allelic frequency of IL-4 between FMF patients and the controls (p>0.05, OR: 1.131, CI 95%: 0.71-1.81). The IL-4 rs79071878 polymorphism, was associated whereas the IL-1Ra rs2234663 polymorphism was not associated with FMF risk in the Turkish population. Larger studies with different ethnicities are needed to determine the impact of IL-1Ra and IL-4 polymorphism on the risk of developing FMF. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Functional properties of Virus-Encoded and Virus-Regulated 7TM Receptors

    DEFF Research Database (Denmark)

    Spiess, Katja; Rosenkilde, Mette Marie

    2014-01-01

    -herpesvirus-encoded BILF1 receptors, the human cytomegalovirus (HCMV)-encoded US28 receptor and the Epstein-Barr virus (EBV)-regulated EBI2 (or GPR183), 2) the tissue tropism and virus-dissemination properties, exemplified by the murine CMV-encoded M33, and 3) the tumorigenic properties, exemplified...... by the human herpesvirus 8 (HHV8)-encoded ORF74, HCMV-US28 and EBV-BILF1. Given the general high “druggability” of 7TM receptors, and the recent progress in the understanding of in particular immune evasive functions of the virus-exploited 7TM receptors, we put a special emphasis on the progress of novel anti...

  9. Preterm Birth and Neonatal Injuries: Importance of Interleukin-1 and Potential of Interleukin-1 Receptor Antagonists.

    Science.gov (United States)

    Nadeau-Vallée, Mathieu; Obari, Dima; Beaudry-Richard, Alexandra; Sierra, Estefania Marin; Beaulac, Alexandre; Maurice, Noémie; Olson, David M; Chemtob, Sylvain

    2017-08-25

    Preterm birth (PTB) is a leading cause of neonatal mortality and morbidity worldwide, and surviving infants are at increased risks of lifelong complications. PTB has been firmly linked to inflammation regardless of infection, specific aetiology or timing of birth. Deleterious inflammation is observed in maternal and fetal tissue, and correlates with the severity of perinatal complications. At present, PTB is treated with tocolytics as though it is exclusively a myometrial contractile disorder. These agents do not address underlying inflammatory processes and are thus vastly ineffective at improving neonatal outcomes. Of all inflammatory mediators, IL-1 is central to the pathophysiology of PTB and most adverse neonatal outcomes. We thus present herein a review of the various effects of IL-1 in utero, with a brief overview of its mechanism of action. We then discuss the potential of different IL-1-targeting agents based on pre-clinical testing in relevant models of PTB and neonatal inflammatory injuries. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Hippocampal interleukin-1 mediates stress-enhanced fear learning: A potential role for astrocyte-derived interleukin-1β.

    Science.gov (United States)

    Jones, Meghan E; Lebonville, Christina L; Paniccia, Jacqueline E; Balentine, Megan E; Reissner, Kathryn J; Lysle, Donald T

    2018-01-01

    Post-traumatic stress disorder (PTSD) is associated with immune dysregulation. We have previously shown that severe stress exposure in a preclinical animal model of the disorder, stress-enhanced fear learning (SEFL), is associated with an increase in hippocampal interleukin-1β (IL-1β) and that blocking central IL-1 after the severe stress prevents the development of SEFL. Here, we tested whether blocking hippocampal IL-1 signaling is sufficient to prevent enhanced fear learning and identified the cellular source of stress-induced IL-1β in this region. Experiment 1 tested whether intra-dorsal hippocampal (DH) infusions of interleukin-1 receptor antagonist (IL-1RA, 1.25µg per hemisphere) 24 and 48h after stress exposure prevents the development of enhanced fear learning. Experiment 2 used triple fluorescence immunohistochemistry to examine hippocampal alterations in IL-1β, glial fibrillary acidic protein (GFAP), an astrocyte-specific marker, and ionized calcium binding adaptor molecule -1 (Iba-1), a microglial-specific marker, 48h after exposure to the severe stressor of the SEFL paradigm. Intra-DH IL-1RA prevented SEFL and stress-induced IL-1β was primarily colocalized with astrocytes in the hippocampus. Further, hippocampal GFAP immunoreactivity was not altered, whereas hippocampal Iba-1 immunoreactivity was significantly attenuated following severe stress. These data suggest that hippocampal IL-1 signaling is critical to the development of SEFL and that astrocytes are a predominant source of stress-induced IL-1β. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Transient receptor potential (TRP gene superfamily encoding cation channels

    Directory of Open Access Journals (Sweden)

    Pan Zan

    2011-01-01

    Full Text Available Abstract Transient receptor potential (TRP non-selective cation channels constitute a superfamily, which contains 28 different genes. In mammals, this superfamily is divided into six subfamilies based on differences in amino acid sequence homology between the different gene products. Proteins within a subfamily aggregate to form heteromeric or homomeric tetrameric configurations. These different groupings have very variable permeability ratios for calcium versus sodium ions. TRP expression is widely distributed in neuronal tissues, as well as a host of other tissues, including epithelial and endothelial cells. They are activated by environmental stresses that include tissue injury, changes in temperature, pH and osmolarity, as well as volatile chemicals, cytokines and plant compounds. Their activation induces, via intracellular calcium signalling, a host of responses, including stimulation of cell proliferation, migration, regulatory volume behaviour and the release of a host of cytokines. Their activation is greatly potentiated by phospholipase C (PLC activation mediated by coupled GTP-binding proteins and tyrosine receptors. In addition to their importance in maintaining tissue homeostasis, some of these responses may involve various underlying diseases. Given the wealth of literature describing the multiple roles of TRP in physiology in a very wide range of different mammalian tissues, this review limits itself to the literature describing the multiple roles of TRP channels in different ocular tissues. Accordingly, their importance to the corneal, trabecular meshwork, lens, ciliary muscle, retinal, microglial and retinal pigment epithelial physiology and pathology is reviewed.

  12. The herpesvirus 8-encoded chemokine vMIP-II, but not the poxvirus-encoded chemokine MC148, inhibits the CCR10 receptor

    DEFF Research Database (Denmark)

    Lüttichau, H R; Lewis, I C; Gerstoft, J

    2001-01-01

    The viral chemokine antagonist vMIP-II encoded by human herpesvirus 8 (HHV8) and MC148 encoded by the poxvirus - Molluscum contagiosum - were tested against the newly identified chemokine receptor CCR10. As the CCR10 ligand ESkine / CCL27 had the highest identity to MC148 and because both...

  13. Cloning of human genes encoding novel G protein-coupled receptors

    Energy Technology Data Exchange (ETDEWEB)

    Marchese, A.; Docherty, J.M.; Heiber, M. [Univ. of Toronto, (Canada)] [and others

    1994-10-01

    We report the isolation and characterization of several novel human genes encoding G protein-coupled receptors. Each of the receptors contained the familiar seven transmembrane topography and most closely resembled peptide binding receptors. Gene GPR1 encoded a receptor protein that is intronless in the coding region and that shared identity (43% in the transmembrane regions) with the opioid receptors. Northern blot analysis revealed that GPR1 transcripts were expressed in the human hippocampus, and the gene was localized to chromosome 15q21.6. Gene GPR2 encoded a protein that most closely resembled an interleukin-8 receptor (51% in the transmembrane regions), and this gene, not expressed in the six brain regions examined, was localized to chromosome 17q2.1-q21.3. A third gene, GPR3, showed identity (56% in the transmembrane regions) with a previously characterized cDNA clone from rat and was localized to chromosome 1p35-p36.1. 31 refs., 5 figs., 1 tab.

  14. The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice

    NARCIS (Netherlands)

    Bongers, G.; Maussang, D.; Muniz, L.R.; Noriega, V.M.; Fraile-Ramos, A.; Barker, N.; Marchesi, F.; Thirunarayanan, N.; Vischer, H.F.; Qin, L.; Mayer, L.; Harpaz, N.; Leurs, R.; Furtado, G.C.; Clevers, H.; Tortorella, D.; Smit, M.J.; Lira, S.A.

    2010-01-01

    US28 is a constitutively active chemokine receptor encoded by CMV (also referred to as human herpesvirus 5), a highly prevalent human virus that infects a broad spectrum of cells, including intestinal epithelial cells (IECs). To study the role of US28 in vivo, we created transgenic mice (VS28 mice)

  15. Changes in gene expression induced by histamine, fexofenadine and osthole: Expression of histamine H1 receptor, COX-2, NF-κB, CCR1, chemokine CCL5/RANTES and interleukin-1β in PBMC allergic and non-allergic patients.

    Science.gov (United States)

    Kordulewska, Natalia Karolina; Kostyra, Elżbieta; Cieślińska, Anna; Matysiewicz, Michał; Fiedorowicz, Ewa; Sienkiewicz-Szłapka, Edyta

    2017-03-01

    Fexofenadine (FXF) is a third-generation antihistamine drug and osthole is assumed as a natural antihistamine alternative. This paper compares results of histamine, FXF and osthole impact on HRH-1, COX-2, NF-κB-p50, CCR1 mRNA expression. We also measured mRNA expression of IL-1β and CCL5/RANTES in incubated peripheral blood mononuclear cells (PBMC) to compared how histamine, FXF and osthole had influence on expression level and interacts on product secretion. The purpose was to investigate expression pattern in asthma PBMC. The cultures were treated 72h with FXF and osthole. We measured mRNA expression of histamine HRH-1, COX-2, NF-κB-p50, CCR1, IL-1β and CCL5/RANTES with Real-Time PCR (RT-PCR). The present study suggest that osthole may be a potential inhibitor of histamine H1 receptor activity. We also demonstrated that cells cultured with histamine increase COX-2 mRNA expression and osthole reduce it. Allergy remains one of the most common chronic diseases in Europe and it is rapidly approaching epidemic proportions; with current predictions estimating that the number of allergy-afflicted will equal the healthy population by 2020. It is therefore paramount to find new pharmaceuticals which successfully combat allergic disease. Copyright © 2016 Elsevier GmbH. All rights reserved.

  16. TARM1 Is a Novel Leukocyte Receptor Complex-Encoded ITAM Receptor That Costimulates Proinflammatory Cytokine Secretion by Macrophages and Neutrophils

    DEFF Research Database (Denmark)

    Radjabova, Valeria; Mastroeni, Piero; Skjødt, Karsten

    2015-01-01

    We identified a novel, evolutionarily conserved receptor encoded within the human leukocyte receptor complex and syntenic region of mouse chromosome 7, named T cell-interacting, activating receptor on myeloid cells-1 (TARM1). The transmembrane region of TARM1 contained a conserved arginine residu...

  17. Human Cytomegalovirus Encoded Homologs of Cytokines, Chemokines and their Receptors: Roles in Immunomodulation

    Science.gov (United States)

    McSharry, Brian P.; Avdic, Selmir; Slobedman, Barry

    2012-01-01

    Human cytomegalovirus (HCMV), the largest human herpesvirus, infects a majority of the world’s population. Like all herpesviruses, following primary productive infection, HCMV establishes a life-long latent infection, from which it can reactivate years later to produce new, infectious virus. Despite the presence of a massive and sustained anti-HCMV immune response, productively infected individuals can shed virus for extended periods of time, and once latent infection is established, it is never cleared from the host. It has been proposed that HCMV must therefore encode functions which help to evade immune mediated clearance during productive virus replication and latency. Molecular mimicry is a strategy used by many viruses to subvert and regulate anti-viral immunity and HCMV has hijacked/developed a range of functions that imitate host encoded immunomodulatory proteins. This review will focus on the HCMV encoded homologs of cellular cytokines/chemokines and their receptors, with an emphasis on how these virus encoded homologs may facilitate viral evasion of immune clearance. PMID:23202490

  18. The orphan G-protein-coupled receptor-encoding gene V28 is closely related to genes for chemokine receptors and is expressed in lymphoid and neural tissues.

    Science.gov (United States)

    Raport, C J; Schweickart, V L; Eddy, R L; Shows, T B; Gray, P W

    1995-10-03

    A polymerase chain reaction (PCR) strategy with degenerate primers was used to identify novel G-protein-coupled receptor-encoding genes from human genomic DNA. One of the isolated clones, termed V28, showed high sequence similarity to the genes encoding human chemokine receptors for monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 alpha (MIP-1 alpha)/RANTES, and to the rat orphan receptor-encoding gene RBS11. When RNA was analyzed by Northern blot, V28 was found to be most highly expressed in neural and lymphoid tissues. Myeloid cell lines, particularly THP.1 cells, showed especially high expression of V28. We have mapped V28 to human chromosome 3p21-3pter, near the MIP-1 alpha/RANTES receptor-encoding gene.

  19. A novel human gene encoding a G-protein-coupled receptor (GPR15) is located on chromosome 3

    Energy Technology Data Exchange (ETDEWEB)

    Heiber, M.; Marchese, A.; O`Dowd, B.F. [Univ. of Toronto, Ontario (Canada)] [and others

    1996-03-05

    We used sequence similarities among G-protein-coupled receptor genes to discover a novel receptor gene. Using primers based on conserved regions of the opioid-related receptors, we isolated a PCR product that was used to locate the full-length coding region of a novel human receptor gene, which we have named GPR15. A comparison of the amino acid sequence of the receptor gene, which we have named GPR15. A comparison of the amino acid sequence of the receptor encoded by GPR15 with other receptors revealed that it shared sequence identity with the angiotensin II AT1 and AT2 receptors, the interleukin 8b receptor, and the orphan receptors GPR1 and AGTL1. GPR15 was mapped to human chromosome 3q11.2-q13.1. 12 refs., 2 figs.

  20. Interleukin 6, interleukin 1β, estradiol and testosterone ...

    African Journals Online (AJOL)

    Jane

    2011-08-22

    Aug 22, 2011 ... at the time of oocyte retrieval and concentration of testosterone, estradiol, interleukin 6 and interleukin. 1β were measured. ..... J. Clin. Endocrinol. Metabolism. 53: 128-134. Brannstrom M and Norman RJ (1993). Involvement of leukocytes and cytokines in the ovulatory process and corpus luteum function.

  1. Hydrochlorothiazide increases interleukin-1 beta (IL-1β) secretion ...

    African Journals Online (AJOL)

    Previous studies showed that individuals with essential hypertension had increased interleukin-1beta (IL-1β) secretion by peripheral blood mononuclear cells (PBMCs) and also valsartan and simvastatin reduced this inflammatory marker. In this study, the effect of hydrochlorothiazide on IL-1β secretion by PBMCs in healthy ...

  2. Interleukin-1 is essential for systemic inflammatory bone loss.

    NARCIS (Netherlands)

    Polzer, K.; Joosten, L.A.B.; Gasser, J.; Distler, J.H.; Ruiz, G.; Baum, W.; Redlich, K.; Bobacz, K.; Smolen, J.S.; Berg, W. van den; Schett, G.; Zwerina, J.

    2010-01-01

    OBJECTIVES: Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of

  3. Targeting the interleukin-1 pathway in patients with hematological disorders

    NARCIS (Netherlands)

    Mooij, C.E.M. de; Netea, M.G.; Velden, W.J.F.M. van der; Blijlevens, N.M.A.

    2017-01-01

    Interleukin-1alpha (IL-1alpha) and IL-1beta are potent inflammatory cytokines that activate local and systemic inflammatory processes and are involved in protective immune responses against infections. However, their dysregulated production and signaling can aggravate tissue damage during infection,

  4. Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Zumsteg, U; Reimers, J

    1993-01-01

    In this review we propose that the balance between the action of interleukin 1 (IL-1) and its natural antagonist IL-1ra on the level of the insulin-producing pancreatic beta-cell may play a decisive role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We argue that IL-1...

  5. The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis

    DEFF Research Database (Denmark)

    Waldhoer, Maria; Casarosa, Paola; Rosenkilde, Mette M

    2003-01-01

    US28 is one of four 7 transmembrane (7TM) chemokine receptors encoded by human cytomegalovirus and has been shown to both signal and endocytose in a ligand-independent, constitutively active manner. Here we show that the constitutive activity and constitutive endocytosis properties of US28...... that the cytoplasmic tail domain of US28 per se regulates receptor endocytosis, independent of the signaling ability of the core domain of US28. The constitutive endocytic property of the US28 c-tail was transposable to other 7TM receptors, the herpes virus 8-encoded ORF74 and the tachykinin NK1 receptor (ORF74-US28......-ctail and NK1-US28-ctail). Deletion of the US28 C terminus resulted in reduced constitutive endocytosis and consequently enhanced signaling capacity of all receptors tested as assessed by inositol phosphate turnover, NF-kappa B, and cAMP-responsive element-binding protein transcription assays. We...

  6. Interleukin-1ß, seizures and neuronal cell death

    OpenAIRE

    Medel-Matus, Jesús S.; Postgrado en Neuroetología, Universidad Veracruzana. Xalapa, México. Centro de Investigaciones Cerebrales, Universidad Veracruzana. Xalapa, México. Químico clínico maestro en Neuroetología.; Cortijo-Palacios, Libia X.; Postgrado en Neuroetología, Universidad Veracruzana. Xalapa, México. química clínica.; Álvarez-Croda, Dulce M.; Postgrado en Neuroetología, Universidad Veracruzana. Xalapa, México. Centro de Investigaciones Cerebrales, Universidad Veracruzana. Xalapa, México. química farmacéutica bióloga.; Martínez-Quiroz, Joel; Facultad de Química Farmacéutica Biológica, Universidad Veracruzana. Xalapa, México. químico farmacéutico biólogo maestro en Ciencias Químico-Biológicas.; López-Meraz, María L.; Centro de Investigaciones Cerebrales, Universidad Veracruzana. Xalapa, México. Facultad de Medicina, Universidad Veracruzana. Xalapa, México. química farmacéutica bióloga doctora en Neurofarmacología y Terapéutica Experimental.

    2014-01-01

    Epilepsy is a neurological disorder affecting almost 1% of the world population. Experimental human and animal studies suggest that inflammation mediators, like cytokines, participate in the physiopathology of epilepsy. Interleukin-1beta (IL-1β) could influence susceptibility for seizures, as well as neuronal death caused by seizures, although some findings are contradictory. This document reviews the current knowledge establishing a connection between IL-1β, seizures and neuronal death. L...

  7. Genetically encoding an electrophilic amino acid for protein stapling and covalent binding to native receptors.

    Science.gov (United States)

    Chen, Xiao-Hua; Xiang, Zheng; Hu, Ying S; Lacey, Vanessa K; Cang, Hu; Wang, Lei

    2014-09-19

    Covalent bonds can be generated within and between proteins by an unnatural amino acid (Uaa) reacting with a natural residue through proximity-enabled bioreactivity. Until now, Uaas have been developed to react mainly with cysteine in proteins. Here we genetically encoded an electrophilic Uaa capable of reacting with histidine and lysine, thereby expanding the diversity of target proteins and the scope of the proximity-enabled protein cross-linking technology. In addition to efficient cross-linking of proteins inter- and intramolecularly, this Uaa permits direct stapling of a protein α-helix in a recombinant manner and covalent binding of native membrane receptors in live cells. The target diversity, recombinant stapling, and covalent targeting of endogenous proteins enabled by this versatile Uaa should prove valuable in developing novel research tools, biological diagnostics, and therapeutics by exploiting covalent protein linkages for specificity, irreversibility, and stability.

  8. Roles of inflammatory caspases during processing of zebrafish interleukin-1β in Francisella noatunensis infection

    Science.gov (United States)

    Vojtech, Lucia N.; Scharping, Nichole; Woodson, James C.; Hansen, John D.

    2012-01-01

    The interleukin-1 family of cytokines are essential for the control of pathogenic microbes but are also responsible for devastating autoimmune pathologies. Consequently, tight regulation of inflammatory processes is essential for maintaining homeostasis. In mammals, interleukin-1 beta (IL-1β) is primarily regulated at two levels, transcription and processing. The main pathway for processing IL-1β is the inflammasome, a multiprotein complex that forms in the cytosol and which results in the activation of inflammatory caspase (caspase 1) and the subsequent cleavage and secretion of active IL-1β. Although zebrafish encode orthologs of IL-1β and inflammatory caspases, the processing of IL-1β by activated caspase(s) has never been examined. Here, we demonstrate that in response to infection with the fish-specific bacterial pathogen Francisella noatunensis, primary leukocytes from adult zebrafish display caspase-1-like activity that results in IL-1β processing. Addition of caspase 1 or pancaspase inhibitors considerably abrogates IL-1β processing. As in mammals, this processing event is concurrent with the secretion of cleaved IL-1β into the culture medium. Furthermore, two putative zebrafish inflammatory caspase orthologs, caspase A and caspase B, are both able to cleave IL-1β, but with different specificities. These results represent the first demonstration of processing and secretion of zebrafish IL-1β in response to a pathogen, contributing to our understanding of the evolutionary processes governing the regulation of inflammation.                   

  9. The Potential Negative Effects of Interleukin 1 B in Multiple Sclerosis Patients with MEFV Mutation

    Directory of Open Access Journals (Sweden)

    Mahmut Alpayci

    2013-10-01

    Full Text Available Multiple sclerosis patients, who are carriers of MEditerranean FeVer (MEFV gene mutation, have faster progression than the non-carriers. However, its underlying mechanism is not well understood. This article proposes the potential role of interleukin-1β (IL-1β that may be responsible for this rapid progression. Mutations in MEFV, the gene encoding for protein pyrin, cause familial Mediterranean fever, lead to gain of pyrin function, resulting in inappropriate IL-1β release. Interleukin-1β is a major mediator of systemic inflammation and fever, and also it contributes to permeability of the blood-brain barrier in active lesions of multiple sclerosis. Moreover, IL-1β promotes apoptosis of neurons and oligodendrocytes that produce the myelin sheath, which insulates axons. Thus, inflammatory damage, the blood-brain barrier disfunction, effects of fever on the central nervous system (or Uhthoff’s phenomenon, and apoptosis of neurons and oligodendrocytes, which play an important role in the pathogenesis and clinical course of multiple sclerosis, can be induced by increased activation and release of IL-1β in the presence of MEFV gene mutations. Therefore, screening for MEFV mutations in patients with multiple sclerosis and treatment planning with IL-1β targeting drugs for the carriers, may be a logical idea that will be a source of inspiration for scientific studies.

  10. Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74

    DEFF Research Database (Denmark)

    McLean, Katherine A; Holst, Peter J; Martini, Lene

    2004-01-01

    The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding...... viral gene expression similarly. As ORF74 is a known inducer of neoplasia, these findings may have important implications for cytomegalovirus-associated pathogenicity....

  11. Genomic organization and chromosomal localization of the human and mouse genes encoding the {alpha} receptor component for ciliary neurotrophic factor

    Energy Technology Data Exchange (ETDEWEB)

    Valenzuela, D.M.; Rojas, E.; McClain, J. [Regeneron Pharmaceuticals, Inc., Tarrytown, NY (United States)] [and others

    1995-01-01

    Ciliary neurotrophic factor (CNTF) has recently been found to share receptor components with, and to be structurally related to, a family of broadly acting cytokines, including interleukin-6, leukemia inhibitory factor, and oncostatin M. However, the CNTF receptor complex also includes a CNTF-specific component known as CNTF receptor {alpha} (CNTFR{alpha}). Here we describe the molecular cloning of the human and mouse genes encoding CNTFR. We report that the human and mouse genes have an identical intron-exon structure that correlates well with the domain structure of CNTFR{alpha}. That is, the signal peptide and the immunoglobulin-like domain are each encoded by single exons, the cytokine receptor-like domain is distributed among 4 exons, and the C-terminal glycosyl phosphatidylinositol recognition domain in encoded by the final coding exon. The position of the introns within the cytokine receptor-like domain corresponds to those found in other members of the cytokine receptor superfamily. Confirming a recent study using radiation hybrids, we have also mapped the human CNTFR gene to chromosome band 9p13 and the mouse gene to a syntenic region of chromosome 4. 24 refs., 4 figs.

  12. Alternative splicing produces two transcripts encoding female-biased pheromone subfamily receptors in the navel orangeworm, Amyelois transitella

    Directory of Open Access Journals (Sweden)

    Stephen F Garczynski

    2015-10-01

    Full Text Available Insect odorant receptors are key sensors of environmental odors and members of the lepidopteran pheromone receptor subfamily are thought to play important roles in mate finding by recognizing sex pheromones. Much research has been done to identify putative pheromone receptors in lepidopteran males, but little attention has been given to female counterparts. In this study, degenerate oligonucleotide primers designed against a conserved amino acid region in the C-terminus of lepidopteran pheromone receptors were used in 3’ RACE reactions to identify candidate pheromone receptors expressed in the antennae of female navel orangeworm. Two near full-length transcripts of 1469 nt and 1302 nt encoding the complete open reading frames for proteins of 446 and 425 amino acids, respectively, were identified. Based on BLAST homology and phylogenetic analyses, the putative proteins encoded by these transcripts are members of the lepidopteran pheromone receptor subfamily. Characterization of these transcripts indicates that they are alternatively spliced products of a single gene. Tissue expression studies indicate that the transcripts are female-biased with detection mainly in female antennae. To the best of our knowledge, these transcripts represent the first detection of alternatively spliced female-biased members of the lepidopteran pheromone receptor subfamily.

  13. Activation of protein kinase C or cAMP-dependent protein kinase increases phosphorylation of the c-erbA-encoded thyroid hormone receptor and of the v-erbA-encoded protein

    DEFF Research Database (Denmark)

    Goldberg, Y; Glineur, C; Gesquière, J C

    1988-01-01

    The c-erbA proto-oncogene encodes a nuclear receptor for thyroid hormone (T3), which is believed to stimulate transcription from specific target promoters upon binding to cis-acting DNA sequence elements. The v-erbA oncogene of avian erythroblastosis virus (AEV) encodes a ligand-independent version...... of this nuclear receptor. The v-erbA product inhibits terminal differentiation of avian erythroblasts, presumably by affecting the transcription of specific genes. We show here that the c-erbA-encoded nuclear receptor (p46c-erbA) is phosphorylated on serine residues on two distinct sites. One of these sites...

  14. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2.

    Directory of Open Access Journals (Sweden)

    Catherine Dodé

    2006-10-01

    Full Text Available Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2 and one of its ligands, prokineticin-2 (PROK2, respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.

  15. ASGR1 and ASGR2, the Genes that Encode the Asialoglycoprotein Receptor (Ashwell Receptor, Are Expressed in Peripheral Blood Monocytes and Show Interindividual Differences in Transcript Profile

    Directory of Open Access Journals (Sweden)

    Rebecca Louise Harris

    2012-01-01

    Full Text Available Background. The asialoglycoprotein receptor (ASGPR is a hepatic receptor that mediates removal of potentially hazardous glycoconjugates from blood in health and disease. The receptor comprises two proteins, asialoglycoprotein receptor 1 and 2 (ASGR1 and ASGR2, encoded by the genes ASGR1 and ASGR2. Design and Methods. Using reverse transcription amplification (RT-PCR, expression of ASGR1 and ASGR2 was investigated in human peripheral blood monocytes. Results. Monocytes were found to express ASGR1 and ASGR2 transcripts. Correctly spliced transcript variants encoding different isoforms of ASGR1 and ASGR2 were present in monocytes. The profile of transcript variants from both ASGR1 and ASGR2 differed among individuals. Transcript expression levels were compared with the hepatocyte cell line HepG2 which produces high levels of ASGPR. Monocyte transcripts were 4 to 6 orders of magnitude less than in HepG2 but nonetheless readily detectable using standard RT-PCR. The monocyte cell line THP1 gave similar results to monocytes harvested from peripheral blood, indicating it may provide a suitable model system for studying ASGPR function in this cell type. Conclusions. Monocytes transcribe and correctly process transcripts encoding the constituent proteins of the ASGPR. Monocytes may therefore represent a mobile pool of the receptor, capable of reaching sites remote from the liver.

  16. Interleukin-1 (IL-1 system gene expression in granulosa cells: kinetics during terminal preovulatory follicle maturation in the mare

    Directory of Open Access Journals (Sweden)

    Gérard Nadine

    2003-05-01

    Full Text Available Abstract Background A growing body of evidences suggests that the ovary is a site of inflammatory reactions, and thus, ovarian cells could represent sources and targets of the interleukin-1 (IL-1 system. The purpose of this study was to examine the IL-1 system gene expressions in equine granulosa cells, and to study the IL-1β content in follicular fluid during the follicle maturation. For this purpose, granulosa cells and follicular fluids were collected from the largest follicle at the early dominance stage (diameter 24 ± 3 mm or during the preovulatory maturation phase, at T0 h, T6 h, T12 h, T24 h and T34 h after induction of ovulation. Cells were analysed by RT-PCR and follicular fluids were studied by gel electrophoresis and immunoblotting. Results We demonstrated that interleukin-1β (IL-1β, interleukin-1 receptor 2 (IL-1R2 and interleukin-1 receptor antagonist (IL-1RA genes are expressed in equine granulosa cells. We observed that the IL-1β and IL-1RA mRNA content changed in granulosa cells during the terminal follicular maturation whereas IL-1R2 mRNA did not vary. In follicular fluid, IL-1β content fluctuated few hours after induction of ovulation. Conclusions The expression of IL-1β gene in granulosa cells and the follicular fluid IL-1β content seem to be regulated by gonadotropins suggesting that IL-1β could be an intermediate paracrine factor involved in ovulation.

  17. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.

    NARCIS (Netherlands)

    Dinarello, C.A.

    2011-01-01

    More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Toll-like receptor, the

  18. Tumor-produced, active Interleukin-1 {beta} regulates gene expression in carcinoma-associated fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Dudas, Jozsef, E-mail: Jozsef.Dudas@i-med.ac.at [Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Fullar, Alexandra, E-mail: fullarsz@gmail.com [Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); 1st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Ulloei ut 26, H-1085 Budapest (Hungary); Bitsche, Mario, E-mail: Mario.Bitsche@i-med.ac.at [Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Schartinger, Volker, E-mail: Volker.Schartinger@i-med.ac.at [Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Kovalszky, Ilona, E-mail: koval@korb1.sote.hu [1st Institute of Pathology and Experimental Cancer Research, Semmelweis University, Ulloei ut 26, H-1085 Budapest (Hungary); Sprinzl, Georg Mathias, E-mail: Georg.Sprinzl@i-med.ac.at [Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria); Riechelmann, Herbert, E-mail: Herbert.Riechelmann@i-med.ac.at [Department of Otorhinolaryngology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck (Austria)

    2011-09-10

    Recently we described a co-culture model of periodontal ligament (PDL) fibroblasts and SCC-25 lingual squamous carcinoma cells, which resulted in conversion of normal fibroblasts into carcinoma-associated fibroblasts (CAFs), and in epithelial-mesenchymal transition (EMT) of SCC-25 cells. We have found a constitutive high interleukin-1{beta} (IL1-{beta}) expression in SCC-25 cells in normal and in co-cultured conditions. In our hypothesis a constitutive IL1-{beta} expression in SCC-25 regulates gene expression in fibroblasts during co-culture. Co-cultures were performed between PDL fibroblasts and SCC-25 cells with and without dexamethasone (DEX) treatment; IL1-{beta} processing was investigated in SCC-25 cells, tumor cells and PDL fibroblasts were treated with IL1-{beta}. IL1-{beta} signaling was investigated by western blot and immunocytochemistry. IL1-{beta}-regulated genes were analyzed by real-time qPCR. SCC-25 cells produced 16 kD active IL1-{beta}, its receptor was upregulated in PDL fibroblasts during co-culture, which induced phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1), and nuclear translocalization of NF{kappa}B{alpha}. Several genes, including interferon regulatory factor 1 (IRF1) interleukin-6 (IL-6) and prostaglandin-endoperoxide synthase 2 (COX-2) were induced in CAFs during co-culture. The most enhanced induction was found for IL-6 and COX-2. Treatment of PDL fibroblasts with IL1-{beta} reproduced a time- and dose-dependent upregulation of IL1-receptor, IL-6 and COX-2. A further proof was achieved by DEX inhibition for IL1-{beta}-stimulated IL-6 and COX-2 gene expression. Constitutive expression of IL1-{beta} in the tumor cells leads to IL1-{beta}-stimulated gene expression changes in tumor-associated fibroblasts, which are involved in tumor progression. -- Graphical abstract: SCC-25 cells produce active, processed IL1-{beta}. PDL fibroblasts possess receptor for IL1-{beta}, and its expression is increased 4.56-times in the

  19. Ultrastructural studies of time-course and cellular specificity of interleukin-1 mediated islet cytotoxicity

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, T; Egeberg, J; Nerup, J

    1987-01-01

    Previous electron-microscopic studies of isolated islets of Langerhans exposed to the monokine interleukin-1 for 7 days have indicated that interleukin-1 is cytotoxic to all islet cells. To study the time-course and possible cellular specificity of interleukin-1 cytotoxicity to islets exposed...... to interleukin-1 for short time periods, isolated rat or human islets were incubated with or without 25 U/ml highly purified human interleukin-1 for 24 h. Samples of rat islets were taken after 5 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 16, 20 and 24 h and samples of human islets after 5 min, 30 min and 24 h...... of incubation and examined by electron microscopy in a blinded fashion. Already after 30 min, accumulation of opaque intracytoplasmic bodies without apparent surrounding membranes, and autophagic vacuoles were seen in about 20% of the beta cells examined in rat islets exposed to interleukin-1. After 16 h...

  20. Microglia and CNS Interleukin-1: Beyond Immunological Concepts

    Directory of Open Access Journals (Sweden)

    Xiaoyu Liu

    2018-01-01

    Full Text Available Activation of microglia and expression of the inflammatory cytokine interleukin-1 (IL-1 in the CNS have become almost synonymous with neuroinflammation. In numerous studies, increased CNS IL-1 expression and altered microglial morphology have been used as hallmarks of CNS inflammation. A central concept of how CNS IL-1 and microglia influence functions of the nervous system was derived from the notion initially generated in the peripheral immune system: IL-1 stimulates monocyte/macrophage (the peripheral counterparts of microglia to amplify inflammation. It is increasingly clear, however, CNS IL-1 acts on other targets in the CNS and microglia participates in many neural functions that are not related to immunological activities. Further, CNS exhibits immunological privilege (although not as absolute as previously thought, rendering amplification of inflammation within CNS under stringent control. This review will analyze current literature to evaluate the contribution of immunological and non-immunological aspects of microglia/IL-1 interaction in the CNS to gain insights for how these aspects might affect health and disease in the nervous tissue.

  1. After-effects of stress on crevicular interleukin-1beta.

    Science.gov (United States)

    Deinzer, R; Kottmann, W; Förster, P; Herforth, A; Stiller-Winkler, R; Idel, H

    2000-01-01

    In a previous study, we found stress to increase crevicular interleukin-1beta (Il-1beta) secretion induced by supragingival plaque. While in that study, stress and plaque were presented concomitantly, we now wondered whether a consecutive presentation of these 2 factors would still exert stress effects. 39 medical students participated in the study; 18 took part in a major exam while the remaining 21 served as controls. From the day after the last exam, students neglected oral hygiene in 2 antagonistic quadrants for 21 days (experimental gingivitis), while they maintained perfect hygiene at the remaining sites. Crevicular fluid samples were taken at days 0, 5, 8, 15, 18, and 21 of experimental gingivitis. A significant effect of pre-exposure to academic stress on crevicular Il-1beta concentration was found (area under the curve: p=0.042), the effect size, however, being smaller than in our previous study when stress and plaque were presented concomitantly. It is concluded that pre-exposure to stress may persistently alter the immunological effects of microbial challenge to the periodontium.

  2. Role of interleukin-1 in pathogenesis of radicular cyst.

    Science.gov (United States)

    Qureshi, Waqar ur Rehman; Asif, Muhammad; Qari, Iftikhar Hossein; Qazi, Javed Akhtar

    2010-01-01

    Interleukin-1 (IL-1) is one of the cytokines produced by macrophages, monocytes and dentritc cells. Macrophages are present in apical granuloma and the wall of the radicular cyst. This cytokine causes the cyst expansion and is involved in proliferation of fibroblasts in the cyst wall and stimulate the fibroblasts to produce more prostaglandin. Radicular cyst is the most common cyst of the jaws which is usually associated with necrotic pulp of the tooth. The cyst formation requires proliferation of the epithelial rest cells of Malassez present in the periodontal ligament. Proliferation of epithelial rest cells of Malassez is an essential event in the Pathogenesis of radicular cyst. Objective of the study was to investigate the effect of IL-1 on epithelial cell proliferation which is an important factor in the pathogenesis of radicular cyst. The cyst walls of 20 radicular cysts were removed and were cultured in vitro to grow the epithelial cells. The culture were rapidly contaminated and dominated by growth of fibroblasts. Therefore another cell line was used for the experiments. The result showed that proliferation was stimulated with increased in a biphasic manner with maximum stimulation at 1.25 nanog/ml, beyond this concentration proliferation was decreased. IL-1 had a proliferative effect on epithelial cells at low concentrations which may be playing a role in evoking an inflammatory reaction and stimulating the epithelial cell rests of Malassez to proliferate to form radicular cyst.

  3. Purification and characterization of human recombinant interleukin-1 beta.

    Science.gov (United States)

    Meyers, C A; Johanson, K O; Miles, L M; McDevitt, P J; Simon, P L; Webb, R L; Chen, M J; Holskin, B P; Lillquist, J S; Young, P R

    1987-08-15

    A human interleukin-1 (IL-1) beta cDNA was cloned, and the region coding for the mature protein was expressed in Escherichia coli. The 17-kDa biologically active product was purified in 40% yield to apparent homogeneity, without chaotropes, from the soluble fraction of sonicated cell lysates. The recombinant IL-1 beta was characterized by amino acid analysis, NH2- and COOH-terminal sequence analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, spectroscopy, and biological assay. Specific biological activity was 4.6 X 10(8) units/mg in a co-mitogenic IL-2 induction assay using cultured EL-4 T-lymphocytes. The molar extinction coefficient was determined to be 10,300 cm-1 M-1 at 280 nm. NH2-terminal sequence analysis revealed that 70% of the product begins with the Ala corresponding to the NH2 terminus of the natural protein, while 30% begins with the following Pro. No initiator Met was observed. Both of the sulfhydryl groups are reactive to Ellman's reagent and to iodoacetamide under nonreducing conditions, indicating that the Cys residues do not form disulfide bonds. S-Carboxamidomethyl-Cys-rIL-1 beta retained biological activity in the IL-2 induction assay. Circular dichroism suggested an extensive beta sheet structure for rIL-1 beta.

  4. Interleukin-1 antagonism moderates the inflammatory state associated with Type 1 diabetes during clinical trials conducted at disease onset

    DEFF Research Database (Denmark)

    Cabrera, Susanne M; Wang, Xujing; Chen, Yi-Guang

    2016-01-01

    It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured...... a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1β additively contribute to the T1D inflammatory state...

  5. The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity.

    Science.gov (United States)

    Martin, Tammy M; Zhang, Zili; Kurz, Paul; Rosé, Carlos D; Chen, Hong; Lu, Huiying; Planck, Stephen R; Davey, Michael P; Rosenbaum, James T

    2009-02-01

    Blau syndrome is a rare, autosomal-dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetics studies have shown that the disease is caused by single nonsynonymous substitutions in NOD-2, a member of the NOD-like receptor or NACHT-leucine-rich repeat (NLR) family of intracellular proteins. Several NLRs function in the innate immune system as sensors of pathogen components and participate in immune-mediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD-2, NLRP3, are responsible for excess caspase 1-dependent interleukin-1beta (IL-1beta) in cryopyrinopathies such as Muckle-Wells syndrome. Furthermore, functional studies demonstrate that caspase 1-mediated release of IL-1beta also involves NOD-2. The aim of this study was to test the hypothesis that IL-1beta may mediate the inflammation seen in patients with Blau syndrome. IL-1beta release was measured in peripheral blood mononuclear cells cultured in vitro, obtained from 5 Blau syndrome individuals with a NOD2 (CARD15) mutation. We observed no evidence for increased IL-1beta production in cells obtained from subjects with Blau syndrome compared with healthy control subjects. Furthermore, we presented 2 cases of Blau syndrome in which recombinant human IL-1 receptor antagonist (anakinra) was ineffective treatment. Taken together, these data suggest that in contrast to related IL-1beta-dependent autoinflammatory cryopyrinopathies, Blau syndrome is not mediated by excess IL-1beta or other IL-1 activity.

  6. Peripheral lipopolysaccharide stimulation induces interleukin-1β messenger RNA in rat brain microglial cells

    NARCIS (Netherlands)

    Buttini, M.; Boddeke, H.

    1995-01-01

    The inflammatory cytokine interleukin-1 acts as an endogenous pyrogenin organisms affected by infectious diseases and has been shown to influence the activity of the central nervous system. Using in situ hybridization histochemistry, we have examined the cellular source of interleukin-1β in rat

  7. Autoantibodies against interleukin 1alpha in rheumatoid arthritis: association with long term radiographic outcome

    DEFF Research Database (Denmark)

    Graudal, N A; Svenson, M; Tarp, Ulrik

    2002-01-01

    To investigate the possible association of interleukin 1alpha autoantibodies (IL1alpha aAb) with the long term course of joint erosion in patients with rheumatoid arthritis (RA).......To investigate the possible association of interleukin 1alpha autoantibodies (IL1alpha aAb) with the long term course of joint erosion in patients with rheumatoid arthritis (RA)....

  8. Redox-control of the alarmin, Interleukin-1α

    Directory of Open Access Journals (Sweden)

    Donald A. McCarthy

    2013-01-01

    Full Text Available The pro-inflammatory cytokine Interleukin-1α (IL-1α has recently emerged as a susceptibility marker for a wide array of inflammatory diseases associated with oxidative stress including Alzheimer's, arthritis, atherosclerosis, diabetes and cancer. In the present study, we establish that expression and nuclear localization of IL-1α are redox-dependent. Shifts in steady-state H2O2 concentrations (SS-[H2O2] resulting from enforced expression of manganese superoxide dismutase (SOD2 drive IL-1α mRNA and protein expression. The redox-dependent expression of IL-1α is accompanied by its increased nuclear localization. Both IL-1α expression and its nuclear residency are abrogated by catalase co-expression. Sub-lethal doses of H2O2 also cause IL-1α nuclear localization. Mutagenesis revealed IL-1α nuclear localization does not involve oxidation of cysteines within its N terminal domain. Inhibition of the processing enzyme calpain prevents IL-1α nuclear localization even in the presence of H2O2. H2O2 treatment caused extracellular Ca2+ influx suggesting oxidants may influence calpain activity indirectly through extracellular Ca2+ mobilization. Functionally, as a result of its nuclear activity, IL-1α overexpression promotes NF-kB activity, but also interacts with the histone acetyl transferase (HAT p300. Together, these findings demonstrate a mechanism by which oxidants impact inflammation through IL-1α and suggest that antioxidant-based therapies may prove useful in limiting inflammatory disease progression.

  9. Interleukin-1β expression on periodontitis patients in Surabaya

    Directory of Open Access Journals (Sweden)

    Chiquita Prahasanti

    2010-12-01

    Full Text Available Background: Periodontal disease, commonly known as periodontitis is an infectious disease which has multifactorial etiologic factors. It may affect everybody in any ages with no gender nor sex predilection and usually can be detected under routine clinical examination. This disease is a manifestation of local factors, host factor and environmental factors, resulting in periodontal tissue damage which may cause tooth mobility and tooth loss. Interleukin-1 is a pro-inflammatory protein which functions primarily as inflammatory mediator in host innate immune responses. IL-1 is a regulator, affecting many biological activities including proliferation, development, homeostasis, regeneration, repair and inflammation which contribute to tissue damage and alveolar bone resorption. Purpose: This research was aimed to reveal the basic pathogenesis of periodontitis and could determine the future definitive treatment for patients with periodontitis. Methods: Data were obtained from 40 patients with aggressive periodontitis and 40 patients with chronic periodontitis. Samples were collected from periodontal tissue patients and protein expression of IL-1β was performed with immunohistochemistry. Results: Most female patient suffer aggressive periodontitis and chronic periodontitis. The datas were analyzed with t-test. The t values result was -8623, significance 0.001, with α = 5%, which indicated there was significant difference in IL-1β expression between aggressive and chronic periodontitis. The box plot diagram showed marked difference in distribution of protein expression of IL-1β between patients with aggressive periodontitis and chronic periodontitis. With a regression equation, it might be concluded that the protein expression of IL-1β might affect the incidence of aggressive periodontitis and chronic periodontitis. The OR value was calculated for 0.746 (sign.= 0.001, which indicate each increment of one unit protein expression of IL-1β will lead

  10. Duodenal enteroendocrine I-cells contain mRNA transcripts encoding key endocannabinoid and fatty acid receptors.

    Directory of Open Access Journals (Sweden)

    Alexandros G Sykaras

    Full Text Available Enteroendocrine cells have a critical role in regulation of appetite and energy balance. I-cells are a subtype of enteroendocrine cells localized in duodenum that release cholecystokinin in response to ingested fat and amino-acids. Despite their potentially pivotal role in nutrient sensing and feeding behaviour, native I-cells have previously been difficult to isolate and study. Here we describe a robust protocol for the isolation and characterization of native duodenal I-cells and additionally, using semi-quantitative RT-PCR we determined that mouse duodenal I-cells contain mRNA transcripts encoding key fatty acid and endocannabinoid receptors including the long chain fatty acid receptors GPR40/FFAR1, GPR120/O3FAR1; short chain fatty acid receptors GPR41/FFAR3 and GPR43/FFAR2; the oleoylethanolamide receptor GPR119 and the classic endocannabinoid receptor CB1. These data suggest that I-cells sense a wide range of gut lumen nutrients and also have the capacity to respond to signals of fatty-acid derivatives or endocannabinoid peptides.

  11. Polymorphisms in gene encoding TRPV1-receptor involved in pain perception are unrelated to chronic pancreatitis

    NARCIS (Netherlands)

    van Esch, Aura A. J.; Lamberts, Mark P.; te Morsche, René H. M.; van Oijen, Martijn G. H.; Jansen, Jan B. M. J.; Drenth, Joost P. H.

    2009-01-01

    Background: The major clinical feature in chronic pancreatitis is pain, but the genetic basis of pancreatic pain in chronic pancreatitis is poorly understood. The transient receptor potential vanilloid receptor 1 (TRPV1) gene has been associated with pain perception, and genetic variations in TRPV1

  12. Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse.

    Science.gov (United States)

    Simon-Chazottes, Dominique; Tutois, Sylvie; Kuehn, Michael; Evans, Martin; Bourgade, Franck; Cook, Sue; Davisson, Muriel T; Guénet, Jean-Louis

    2006-05-01

    Positional cloning of two recessive mutations of the mouse that cause polysyndactyly (dan and mdig-Chr 2) confirmed that the gene encoding MEGF7/LRP4, a member of the low-density lipoprotein receptor family, plays an essential role in the process of digit differentiation. Pathologies observed in the mutant mice provide insight into understanding the function(s) of LRP4 as a negative regulator of the Wnt-beta-catenin signaling pathway and may help identify the genetic basis for common human disorders with similar phenotypes.

  13. Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells.

    Science.gov (United States)

    Chung, Stephanie Tsang Mui; Geerts, Dirk; Roseman, Kim; Renaud, Ashleigh; Connelly, Linda

    2017-02-01

    It is widely recognized that inflammation promotes breast cancer invasion and metastasis. Given the complex nature of the breast tumor inflammatory microenvironment, much remains to be understood of the molecular mechanisms that govern these effects. We have previously shown that osteoprotegerin knockdown in breast cancer cells resulted in reduced invasion and metastasis. Here we present novel insight into the role of osteoprotegerin in inflammation-driven tumor progression in breast cancer by investigating the link between osteoprotegerin, macrophages and the potent pro-inflammatory cytokine Interleukin-1beta. We used human breast cancer cell lines to investigate the effects of Interleukin-1beta treatment on osteoprotegerin secretion as measured by ELISA. We analyzed public datasets containing human breast cancer genome-wide mRNA expression data to reveal a significant and positive correlation between osteoprotegerin mRNA expression and the mRNA expression of Interleukin-1beta and of monocyte chemoattractant protein CC-chemokine ligand 2. Osteoprotegerin, Interleukin-1beta and CC-chemokine ligand 2 mRNA levels were also examined by qPCR on cDNA from normal and cancerous human breast tissue. We determined the effect of Interleukin-1beta-producing macrophages on osteoprotegerin expression by co-culturing breast cancer cells and differentiated THP-1 macrophages. Immunohistochemistry was performed on human breast tumor tissue microarrays to assess macrophage infiltration and osteoprotegerin expression. To demonstrate that osteoprotegerin mediated functional effects of Interleukin-1beta we performed cell invasion studies with control and OPG siRNA knockdown on Interleukin-1beta-treated breast cancer cells. We report that Interleukin-1beta induces osteoprotegerin secretion, independent of breast cancer subtype and basal osteoprotegerin levels. Co-culture of breast cancer cells with Interleukin-1beta-secreting macrophages resulted in a similar increase in osteoprotegerin

  14. Gene Encoding Duffy Antigen/Receptor for Chemokines Is Associated with Asthma and IgE in Three Populations

    Science.gov (United States)

    Vergara, Candelaria; Tsai, Yuhjung J.; Grant, Audrey V.; Rafaels, Nicholas; Gao, Li; Hand, Tracey; Stockton, Maria; Campbell, Monica; Mercado, Dilia; Faruque, Mezbah; Dunston, Georgia; Beaty, Terri H.; Oliveira, Ricardo Riccio; Ponte, Eduardo V.; Cruz, Alvaro A.; Carvalho, Edgar; Araujo, Maria Ilma; Watson, Harold; Schleimer, Robert P.; Caraballo, Luis; Nickel, Renate G.; Mathias, Rasika A.; Barnes, Kathleen C.

    2008-01-01

    Rationale: Asthma prevalence and severity are high among underserved minorities, including those of African descent. The Duffy antigen/receptor for chemokines is the receptor for Plasmodium vivax on erythrocytes and functions as a chemokine-clearing receptor. Unlike European populations, decreased expression of the receptor on erythrocytes is common among populations of African descent, and results from a functional T-46C polymorphism (rs2814778) in the promoter. This variant provides an evolutionary advantage in malaria-endemic regions, because Duffy antigen/receptor for chemokines-negative erythrocytes are more resistant to infection by P. vivax. Objectives: To determine the role of the rs2814778 polymorphism in asthma and atopy as measured by total serum IgE levels among four populations of African descent (African Caribbean, African American, Brazilian, and Colombian) and a European American population. Methods: Family-based association tests were performed in each of the five populations to test for association between the rs2814778 polymorphism and asthma or total IgE concentration. Measurements and Main Results: Asthma was significantly associated with the rs2814778 polymorphism in the African Caribbean, Colombian, and Brazilian families (P < 0.05). High total IgE levels were associated with this variant in African Caribbean and Colombian families (P < 0.05). The variant allele was not polymorphic among European Americans. Conclusions: Susceptibility to asthma and atopy among certain populations of African descent is influenced by a functional polymorphism in the gene encoding Duffy antigen/receptor for chemokines. This genetic variant, which confers resistance to malarial parasitic infection, may also partially explain ethnic differences in morbidity of asthma. PMID:18827265

  15. Interleukin-1β causes anxiety by interacting with the endocannabinoid system.

    Science.gov (United States)

    Rossi, Silvia; Sacchetti, Lucia; Napolitano, Francesco; De Chiara, Valentina; Motta, Caterina; Studer, Valeria; Musella, Alessandra; Barbieri, Francesca; Bari, Monica; Bernardi, Giorgio; Maccarrone, Mauro; Usiello, Alessandro; Centonze, Diego

    2012-10-03

    Interleukin-1β (IL-1β) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1β-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1β-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1β caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1β-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1β-CB1R coupling, and TRPV1-/- mice were indeed insensitive to the synaptic and behavioral effects of both IL-1β and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1β on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1-/- mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.

  16. Receptor expression and responsiveness of human peripheral blood mononuclear cells to a human cytomegalovirus encoded CC chemokine.

    Science.gov (United States)

    Zheng, Qi; Xu, Jun; Gao, Huihui; Tao, Ran; Li, Wei; Shang, Shiqiang; Gu, Weizhong

    2015-01-01

    Human cytomegalovirus is a ubiquitous pathogen that infects the majority of the world's population. After long period of time co-evolving with human being, this pathogen has developed several strategies to evade host immune surveillance. One of the major trick is encoding homologous to those of the host organism or stealing host cellular genes that have significant functions in immune system. To date, we have found several viral immune analogous which include G protein coupled receptor, class I major histocompatibility complex and chemokine. Chemokine is a small group of molecules which is defined by the presence of four cysteines in highly conserved region. The four kinds of chemokines (C, CC, CXC, and CX3C) are classified based on the arrangement of 1 or 2 N-terminal cysteine residues. UL128 protein is one of the analogous that encoded by human cytomegalovirus that has similar amino acid sequences to the human CC chemokine. It has been proved to be one of the essential particles that involved in human cytomegalovirus entry into epithelial/endothelial cells as well as macrophages. It is also the target of potent neutralizing antibodies in human cytomegalovirus-seropositive individuals. We had demonstrated the chemotactic trait of UL128 protein in our previous study. Recombinant UL128 in vitro has the ability to attract monocytes to the infection region and enhances peripheral blood mononuclear cell proliferation by activating the MAPK/ERK signaling pathway. However, the way that this viral encoded chemokine interacting with peripheral blood mononuclear cells and the detailed mechanism that involving the virus entry into host cells keeps unknown. Here we performed in vitro investigation into the effects of UL128 protein on peripheral blood mononuclear cell's activation and receptor binding, which may help us further understand the immunomodulatory function of UL128 protein as well as human cytomegalovirus diffusion mechanism. Copyright © 2015 Elsevier Editora Ltda

  17. The role of brain interleukin-1 in stress-enhanced fear learning.

    Science.gov (United States)

    Jones, Meghan E; Lebonville, Christina L; Barrus, Daniel; Lysle, Donald T

    2015-03-13

    Posttraumatic stress disorder (PTSD) has been shown to be associated with pro-inflammatory markers, including elevated plasma levels of interleukin-1β (IL-1β). However, the precise role of neuroinflammation and central immune signaling on the development of this debilitating psychological disorder is not known. Here, we used stress-enhanced fear learning (SEFL), an animal model of the disorder, to examine the role of central IL-1β in PTSD. The results show that the severe stressor in SEFL induces a time-dependent increase in IL-1β immunoreactivity and mRNA expression within the dentate gyrus of the dorsal hippocampus (DH). There was no increase in IL-1β in the basolateral amygdala or the perirhinal cortex. Moreover, blocking the action of IL-1β following the severe stressor with IL-1 receptor antagonist (10 μg, intracerebroventricular (i.c.v.), 24 and 48 h after the stressor) prevented the development of SEFL. To provide further support for the role of IL-1β in the development of SEFL, we show that systemic morphine, a treatment which is known to reduce both PTSD and SEFL, also reduces IL-1β expression in the DH induced by the severe stressor. These studies provide the first evidence that IL-1 is involved SEFL and suggest that IL-1 signaling in the brain may have a critical role in the development of PTSD.

  18. Caspase-11 Controls Interleukin-1β Release through Degradation of TRPC1

    Directory of Open Access Journals (Sweden)

    Bénédicte F. Py

    2014-03-01

    Full Text Available Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1β (IL-1β secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1 as a substrate of caspase-11. TRPC1 deficiency increases the secretion of IL-1β without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1−/− mice show higher IL-1β secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1.

  19. Differential Involvement of Amygdala and Cortical NMDA Receptors Activation upon Encoding in Odor Fear Memory

    Science.gov (United States)

    Hegoburu, Chloé; Parrot, Sandrine; Ferreira, Guilaume; Mouly, Anne-Marie

    2014-01-01

    Although the basolateral amygdala (BLA) plays a crucial role for the acquisition of fear memories, sensory cortices are involved in their long-term storage in rats. However, the time course of their respective involvement has received little investigation. Here we assessed the role of the glutamatergic N-methyl-D-aspartate (NMDA) receptors in the…

  20. Polymorphisms in the interleukin-1 (IL1) gene cluster are not associated with aggressive periodontitis in a large Caucasian population

    NARCIS (Netherlands)

    Fiebig, A.; Jepsen, S.; Loos, B.G.; Scholz, C.; Schäfer, C.; Rühling, A.; Nothnagel, M.; Eickholz, P.; van der Velden, U.; Schenck, K.; Schreiber, S.; Grössner-Schreiber, B.

    2008-01-01

    Polymorphisms in the interleukin-1 (IL1) gene have been suggested to influence transcription of IL1A (interleukin-1α) and IL1B (interleukin-1β) and thereby the pathophysiology of periodontitis. This case-control association study on 415 northern European Caucasian patients with aggressive

  1. Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome

    Directory of Open Access Journals (Sweden)

    Pierre Quartier

    2011-01-01

    Full Text Available Pierre QuartierUnité d'Immunologie-Hématologie et Rhumatologie pédiatriques, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, FranceAbstract: Cryopyrin-associated periodic syndrome (CAPS include a group of rare autoinflammatory disorders, the spectrum of which ranges from the mildest form, ie, familial cold autoinflammatory syndrome to more severe phenotypes, ie, Muckle-Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome, also known as neonatal-onset multisystem inflammatory disease. Three interleukin (IL-1 antagonists have been tested in adults and children with CAPS, ie, anakinra, a recombinant homolog of the human IL-1 receptor antagonist; rilonacept, a fusion protein comprising the extracellular domains of IL-1 receptor I and the IL-1 adaptor protein, IL-1RAcP, attached to a human immunoglobulin G molecule; and canakinumab, the anti-IL-1β monoclonal antibody. Following rapid clinical development, rilonacept and canakinumab were approved by both the US Food and Drug Administration and the European Medicines Agency for use in adults and children. This review describes how the study of CAPS has helped us to understand better the way the innate immune system works, the pathogenesis of autoinflammatory syndromes, and the key role of IL-1. It also reviews the effects of IL-1 blockade in CAPS and other disorders, in particular systemic juvenile idiopathic arthritis, adult-onset Still's disease, and gout. Finally, this review covers some issues addressed by very recent and ongoing work regarding treatment indications, from orphan diseases to common disorders, continuous versus intermittent treatment, the pharmacokinetics, pharmacodynamics, and optimal dosages of the different drugs, as well as the need for Phase IV trials, exhaustive registries, and long-term follow-up of several patient cohorts.Keywords: inflammation, interleukin-1, cytokines, treatment

  2. Academic Stress Influences Periodontal Health Condition and Interleukin-1 beta Level

    OpenAIRE

    Sandra O. Kuswandani; Sri LC Masulili; Nurtami Soedarsono; Yulianti Kemal

    2014-01-01

    Stress is a risk factor for periodontal disease, causing increase levels of interleukin-1 beta that involve in periodontal destruction. Objective: To analyze the relationship between academic stress in residency program students conditions and levels of interleukin-1 beta in gingival crevicular fluid. Methods: Thirty eight subjects filled the questionnaire of Graduate Dental Environtmental Stress (GDES), periodontal examination and samples of gingival crevicular fluid were tested for interleu...

  3. A novel human protease similar to the interleukin-1 beta converting enzyme induces apoptosis in transfected cells.

    Science.gov (United States)

    Faucheu, C; Diu, A; Chan, A W; Blanchet, A M; Miossec, C; Hervé, F; Collard-Dutilleul, V; Gu, Y; Aldape, R A; Lippke, J A

    1995-05-01

    We have identified a novel cDNA encoding a protein (named TX) with > 50% overall sequence identity with the interleukin-1 beta converting enzyme (ICE) and approximately 30% sequence identity with the ICE homologs NEDD-2/ICH-1L and CED-3. A computer homology model of TX was constructed based on the X-ray coordinates of the ICE crystal recently published. This model suggests that TX is a cysteine protease, with the P1 aspartic acid substrate specificity retained. Transfection experiments demonstrate that TX is a protease which is able to cleave itself and the p30 ICE precursor, but not to generate mature IL-1 beta from pro-IL-1 beta. In addition, this protein induces apoptosis in transfected COS cells. TX therefore delineates a new member of the growing Ice/ced-3 gene family coding for proteases with cytokine processing activity or involved in programmed cell death.

  4. Interleukin-1 gene cluster polymorphisms and gingival recessions after orthodontic treatment.

    Science.gov (United States)

    Bergandi, Loredana; Rubiano, Rachele; Brunazzo, Matteo; Aldieri, Elisabetta; Alfieri, Elisabetta; Dalmasso, Paola; Dal Masso, Paola; Cardaropoli, Giuseppe; Bracco, Pietro; Debernardi, Cesare; Ghigo, Dario

    2008-01-01

    Genetic polymorphisms in the interleukin-1 gene cluster have been associated with the severity of periodontal diseases featured by a variable degree of destruction of connective tissue and bone, such as periodontitis and periimplantitis. This study was aimed to investigate if a link exists between such interleukin-1 gene polymorphisms and the development of gingival recessions during orthodontic treatment in Italian children. We evaluated, in 74 young Italian patients of both sexes, the -889 C/T polymorphism of the interleukin-1alpha gene and the -511 C/T and +3954 C/T polymorphisms of interleukin-1alpha gene by polymerase chain reactions-restriction fragment length polymorphism method using NcoI, AvaI and TaqI as restriction enzymes. No association of interleukin-1 genotypes investigated and gingival recession occurring during orthodontic treatment were identified. In the population studied specific interleukin-1 genotypes (linked to a higher susceptibility to bone resorption in periodontal disease) there does not appear to be any association with the development of gingival recessions during orthodontic treatment.

  5. Academic Stress Influences Periodontal Health Condition and Interleukin-1 beta Level

    Directory of Open Access Journals (Sweden)

    Sandra O. Kuswandani

    2014-10-01

    Full Text Available Stress is a risk factor for periodontal disease, causing increase levels of interleukin-1 beta that involve in periodontal destruction. Objective: To analyze the relationship between academic stress in residency program students conditions and levels of interleukin-1 beta in gingival crevicular fluid. Methods: Thirty eight subjects filled the questionnaire of Graduate Dental Environtmental Stress (GDES, periodontal examination and samples of gingival crevicular fluid were tested for interleukin-1 beta with the Enzyme-linked Immunosorbent Assay (ELISA test. Results: There were significant differences between academic stress to periodontal tissue in oral hygiene (p=0.038, bleeding on probing index (p=0.02, but no significant differences in pocket depth and loss of attachment (p=0.972. There were significant differences between academic stress to levels of interleukin-1 beta (p=0.03, but no significant differences between levels of interleukin-1 beta to periodontal tissue in oral hygiene (p=0.465, bleeding on probing index (p=0.826, pocket depth (p=0.968, and loss of attachment (p=0.968. Conclusion: Academic stress influences the periodontal risk factor and level of interleukin-1 beta.

  6. Noradrenaline release in rodent tissues is inhibited by interleukin-1β but is not affected by urotensin II, MCH, NPW and NPFF.

    Science.gov (United States)

    Schulte, Kirsten; Kumar, Manush; Zajac, Jean-Marie; Schlicker, Eberhard

    2011-01-01

    We studied whether noradrenaline release is affected by interleukin-1β and the neuropeptides urotensin II, melanin-concentrating hormone (MCH), neuropeptide W (NPW) and neuropeptide FF (NPFF). Rodent tissues preincubated with [3H]noradrenaline were superfused, and the effect of peptides on the electrically-evoked tritium overflow ("noradrenaline release") was studied. In mouse brain cortex, interleukin-1β at 0.3 nM and the prostaglandin E2 analogue sulprostone at 3 nM inhibited noradrenaline release by about 40% the effect of interleukin-1β developed gradually, whereas the effect of sulprostone occurred promptly. Urotensin II at 0.001-1 μM did not affect noradrenaline release in rat kidney cortex, whereas 0.01 μM angiotensin II increased it (positive control). MCH at 0.01-1 μM did not alter noradrenaline release in the rat brain cortex, and NPW 1 μM did not affect noradrenaline release in the mouse hypothalamus or hippocampus. In each model, 0.1 μM sulprostone inhibited noradrenaline release (positive control). NPFF and the NPFF2 receptor agonist dNPA (1 μM) did not affect noradrenaline release in the mouse atria; the inhibitory effect of the δ opioid receptor agonist 1 μM DPDPE on noradrenaline release in this tissue was not altered by NPFF or dNPA at 0.32 μM but was counteracted by the δ opioid antagonist naltrindole at 0.001 μM. In conclusion, interleukin-1β inhibits noradrenaline release in the mouse cortex; the effect develops gradually, suggesting that it affects protein biosynthesis. Noradrenergic neurons in various tissues from rodents are devoid of presynaptic receptors for urotensin II, MCH, NPW and NPFF. Finally, an interaction between a δ opioid agonist and NPFF could not be detected.

  7. Cloning and characterization of tdhA, a locus encoding a TonB-dependent heme receptor from Haemophilus ducreyi.

    Science.gov (United States)

    Thomas, C E; Olsen, B; Elkins, C

    1998-09-01

    Haemophilus ducreyi is unable to synthesize heme and must acquire it from its only known host, humans. We cloned and sequenced a gene encoding an outer membrane receptor for heme. It was designated tdhA (for TonB-dependent heme receptor A) since it was related by sequence homology to the family of TonB-dependent receptors. TdhA was strikingly similar to open reading frame HI0113 from the genome of Haemophilus influenzae Rd and also shared homology with five other heme receptors, including HxuC, HemR, HmuR, ChuA, and ShuA, from gram-negative bacteria. An Escherichia coli hemA tonB mutant strongly expressing H. ducreyi tdhA grew on low levels of heme as a source of heme only when an intact H. ducreyi Ton system plasmid was present, formally demonstrating functional TonB dependence. tdhA was expressed poorly in vitro by H. ducreyi and only under conditions of heme limitation. A survey of H. ducreyi revealed that all tested strains but one synthesized small amounts of TdhA in vitro under heme-limiting conditions. Surprisingly, an isogenic mutant of tdhA as well as its parent, 35000, both required the same high levels of heme for growth (50 microgram/ml [77 microM] on agar medium). This result, together with previous findings, suggests that in vitro, the uptake of heme by H. ducreyi is mediated by a TonB- and TdhA-independent mechanism, possibly diffusion.

  8. Nucleic acid sequences encoding D1 and D1/D2 domains of human coxsackievirus and adenovirus receptor (CAR)

    Science.gov (United States)

    Freimuth, Paul I.

    2010-04-06

    The invention provides recombinant human CAR (coxsackievirus and adenovirus receptor) polypeptides which bind adenovirus. Specifically, polypeptides corresponding to adenovirus binding domain D1 and the entire extracellular domain of human CAR protein comprising D1 and D2 are provided. In another aspect, the invention provides nucleic acid sequences encoding these domains and expression vectors for producing the domains and bacterial cells containing such vectors. The invention also includes an isolated fusion protein comprised of the D1 polypeptide fused to a polypeptide which facilitates folding of D1 when expressed in bacteria. The functional D1 domain finds application in a therapeutic method for treating a patient infected with a CAR D1-binding virus, and also in a method for identifying an antiviral compound which interferes with viral attachment. The invention also provides a method for specifically targeting a cell for infection by a virus which binds to D1.

  9. Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro.

    Science.gov (United States)

    Lollinga, Wouter T; de Wit, Raymond H; Rahbar, Afsar; Vasse, Gwenda F; Davoudi, Belghis; Diepstra, Arjan; Riezebos-Brilman, Annelies; Harmsen, Martin C; Hillebrands, Jan-Luuk; Söderberg-Naucler, Cecilia; van Son, Willem J; Smit, Martine J; Sanders, Jan-Stephan; van den Born, Jacob

    2017-03-01

    Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling. Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro. Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller. In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

  10. Unusual varieties and duplication of Rig-I like receptors encoded in the marine mollusk, Crassostrea gigas

    Science.gov (United States)

    Tian, Z. H.; Jiao, C. Z.

    2017-07-01

    RIG-I like receptors (RLRs) play key roles in sensing non-self nucleic acids in cytoplasm and trigger antiviral innate immune response in vertebrates and human body. Here we carried out in silico analysis to identify and investigate the putative RLRs encoded in the genome of marine mollusk, Crassostrea gigas (cgRLRs), an invertebrate species. We found the unusual duplication and varieties on domain architecture of putative cgRLRs encoded in the genome of C. gigas. Three putative cgRLRs (accessions numbers are EKC24603, EKC31344.1 and EKC38304.1 on GenBank), have the similar domain architecture with that of human RIG-I or MDA5, and one protein (EKC34573.1) with that of human LGP2; The fifth putative cgRLRs (EKC38303.1) is somewhat similar with human RIG-I/MDA5 except that it has only one caspase activation and recruitment domain (CARD) in its N-terminal. Other nine proteins were identified to be partialy similar with RLRs while with the incomplete sequences, which maybe reflect the events of partial duplication of cgRLRs genes occurred in the oyster genome.

  11. Curcumin blocks interleukin-1 signaling in chondrosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Thomas Kalinski

    Full Text Available Interleukin (IL-1 signaling plays an important role in inflammatory processes, but also in malignant processes. The essential downstream event in IL-1 signaling is the activation of nuclear factor (NF-κB, which leads to the expression of several genes that are involved in cell proliferation, invasion, angiogenesis and metastasis, among them VEGF-A. As microenvironment-derived IL-1β is required for invasion and angiogenesis in malignant tumors, also in chondrosarcomas, we investigated IL-1β-induced signal transduction and VEGF-A expression in C3842 and SW1353 chondrosarcoma cells. We additionally performed in vitro angiogenesis assays and NF-κB-related gene expression analyses. Curcumin is a substance which inhibits IL-1 signaling very early by preventing the recruitment of IL-1 receptor associated kinase (IRAK to the IL-1 receptor. We demonstrate that IL-1 signaling and VEGF-A expression are blocked by Curcumin in chondrosarcoma cells. We further show that Curcumin blocks IL-1β-induced angiogenesis and NF-κB-related gene expression. We suppose that IL-1 blockade is an additional treatment option in chondrosarcoma, either by Curcumin, its derivatives or other IL-1 blocking agents.

  12. Influence of barometric pressure on interleukin-1 beta secretion.

    Science.gov (United States)

    Becker, W J; Cannon, J G

    2001-06-01

    Monocytes and macrophages are activated by various environmental challenges, including microorganisms, radiation, and pollutants. These cells release cytokines, such as interleukin (IL)-1 beta, that mediate physiological adaptations to stress. This study sought to define further the role of IL-1 beta in general adaptation to environmental stress by testing the hypothesis that high altitude (20,000 ft, 6,096 m) would stimulate IL-1 beta secretion from isolated human blood mononuclear cells. Cells from six young men (aged 22--26 yr) were divided into separate cultures incubated in either standard ambient conditions or in one of three test conditions, hypobaric hypoxia (simulating 20,000 ft), hypobaric normoxia (20,000 ft, O(2) supplemented), and normobaric hypoxia (10% O(2)). This design allowed differentiation between pressure-related vs. oxygen-related effects. Each subject made multiple blood donations in order that cells from all subjects were tested in all conditions. Contrary to the hypothesis, IL-1 beta secretion was not induced at simulated altitude in basal cell cultures. In lipopolysaccharide-stimulated cell cultures, exposure to altitude inhibited IL-1 beta secretion by approximately 40%, and the inhibition was due to the change in pressure (P = 0.039) rather than the change in oxygen. Secretion of other factors (IL-1 receptor antagonist and soluble IL-1 receptor type II) was not inhibited. Although these results are in opposition to the original hypothesis, they provide insight regarding adaptations necessary for hematopoiesis in response to high altitude and also provide a cellular rationale for the mountain sanatoriums of the 19th and early 20th centuries.

  13. Common variants of the genes encoding erythropoietin and its receptor modulate cognitive performance in schizophrenia

    DEFF Research Database (Denmark)

    Kästner, Anne; Grube, Sabrina; El-Kordi, Ahmed

    2012-01-01

    Erythropoietin (EPO) improves cognitive performance in clinical studies and rodent experiments. We hypothesized that an intrinsic role of EPO for cognition exists, with particular relevance in situations of cognitive decline, which is reflected by associations of EPO and EPO receptor (EPOR......) genotypes with cognitive functions. To prove this hypothesis, schizophrenic patients (N > 1000) were genotyped for 5' upstream-located gene variants, EPO SNP rs1617640 (T/G) and EPORSTR(GA)(n). Associations of these variants were obtained for cognitive processing speed, fine motor skills and short......-term memory readouts, with one particular combination of genotypes superior to all others (p 800), these associations were confirmed. A matching preclinical study with mice demonstrated cognitive processing speed and memory enhanced upon transgenic...

  14. Coordinated activation of distinct Ca2+ sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity

    Science.gov (United States)

    Tigaret, Cezar M.; Olivo, Valeria; Sadowski, Josef H.L.P.; Ashby, Michael C.; Mellor, Jack R.

    2016-01-01

    At glutamatergic synapses, induction of associative synaptic plasticity requires time-correlated presynaptic and postsynaptic spikes to activate postsynaptic NMDA receptors (NMDARs). The magnitudes of the ensuing Ca2+ transients within dendritic spines are thought to determine the amplitude and direction of synaptic change. In contrast, we show that at mature hippocampal Schaffer collateral synapses the magnitudes of Ca2+ transients during plasticity induction do not match this rule. Indeed, LTP induced by time-correlated pre- and postsynaptic spikes instead requires the sequential activation of NMDARs followed by voltage-sensitive Ca2+ channels within dendritic spines. Furthermore, LTP requires inhibition of SK channels by mGluR1, which removes a negative feedback loop that constitutively regulates NMDARs. Therefore, rather than being controlled simply by the magnitude of the postsynaptic calcium rise, LTP induction requires the coordinated activation of distinct sources of Ca2+ and mGluR1-dependent facilitation of NMDAR function. PMID:26758963

  15. Epigallocatechin-3-gallate suppresses the global interleukin-1beta-induced inflammatory response in human chondrocytes

    Science.gov (United States)

    2011-01-01

    Introduction Epigallocatechin-3-gallate (EGCG) is a bioactive polyphenol of green tea and exerts potent anti-inflammatory effects by inhibiting signaling events and gene expression. Interleukin-1beta (IL-1β) is the principal cytokine linked to cartilage degradation in osteoarthritis (OA). The objective of this study was to evaluate the global effect of EGCG on IL-1β-induced expression of proteins associated with OA pathogenesis in human chondrocytes. Methods Primary OA chondrocytes were pretreated with EGCG (10 to 100 uM) and then stimulated with IL-1β (5 ng/ml) for 24 hours. Culture supernatants were incubated with cytokine antibody arrays and immunoreactive proteins (80 proteins) were visualized by enhanced chemiluminiscence. Effect of EGCG on IL-1β-induced expression of 18 selected genes was verified by Real time-PCR and effect on IL-6, IL-8 and tumor necrosis factor-alpha (TNF-α) production was determined using specific ELISAs. Western immunoblotting was used to analyze the effect of EGCG on the interleukin-1 receptor-associated kinase 1 (IRAK-1) and TNF receptor-associated factor 6 (TRAF-6) proteins in IL-1β-stimulated chondrocytes. The role of nuclear factor kappa-B (NF-κB) and mitogen activated protein kinases (MAPKs) in the regulation of selected genes and the mechanism involved in EGCG mediated modulation of these genes was determined by using specific inhibitors for NF- κB (MG132) and MAPKs (p38-MAPK, SB202190; JNK-MAPK, SP600125, ERK-MAPK, PD98059). Results Out of 80 proteins present on the array, constitutive expression of 14% proteins was altered by EGCG treatment. No significant stimulatory effect was observed on the proteins associated with cartilage anabolic response. Stimulation with IL-1β enhanced the expression of 29 proteins. Expression of all 29 proteins up-regulated by IL-1β was found to be suppressed by EGCG. EGCG also inhibited the expression of the signaling intermediate TRAF-6 at 50 and 100 uM concentrations (P < 0.05). Our

  16. Systemic apomorphine alters HPA axis responses to interleukin-1 beta administration but not sound stress.

    Science.gov (United States)

    Buller, K M; Crane, J W; Spencer, S J; Day, T A

    2003-08-01

    Apomorphine is a dopamine receptor agonist that was recently licensed for the treatment of erectile dysfunction. However, although sexual activity can be stressful, there has been little investigation into whether treatments for erectile dysfunction affect stress responses. We have examined whether a single dose of apomorphine, sufficient to produce penile erections (50 microg/kg, i.a.), can alter basal or stress-induced plasma ACTH levels, or activity of central pathways thought to control the hypothalamic-pituitary-adrenal axis in rats. An immune challenge (interleukin-1 beta, 1 microg/kg, i.a.) was used as a physical stressor while sound stress (100 dB white noise, 30 min) was used as a psychological stressor. Intravascular administration of apomorphine had no effect on basal ACTH levels but did substantially increase the number of Fos-positive amygdala and nucleus tractus solitarius catecholamine cells. Administration of apomorphine prior to immune challenge augmented the normal ACTH response to this stressor at 90 min and there was a corresponding increase in the number of Fos-positive paraventricular nucleus corticotropin-releasing factor cells, paraventricular nucleus oxytocin cells and nucleus tractus solitarius catecholamine cells. However, apomorphine treatment did not alter ACTH or Fos responses to sound stress. These data suggest that erection-inducing levels of apomorphine interfere with hypothalamic-pituitary-adrenal axis inhibitory feedback mechanisms in response to a physical stressor, but have no effect on the response to a psychological stressor. Consequently, it is likely that apomorphine acts on a hypothalamic-pituitary-adrenal axis control pathway that is unique to physical stressors. A candidate for this site of action is the nucleus tractus solitarius catecholamine cell population and, in particular, A2 noradrenergic neurons.

  17. Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure.

    Directory of Open Access Journals (Sweden)

    Benjamin W Van Tassell

    Full Text Available Heart failure (HF is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1β (IL-1β is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects.We developed a model of IL-1β-induced left ventricular (LV dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001 and a 76% reduction in isoproterenol response (P<0.01 at 4 hours following a single dose of IL-1β 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra. This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7. The median peak oxygen consumption (VO(2 improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL · kg(-1 · min(-1 (P = 0.016 vs. baseline and median ventilator efficiency (V(E/VCO(2 slope improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline.These findings suggest that IL-1β activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1β blockade as a novel strategy for pharmacologic intervention.ClinicalTrials.gov NCT01300650.

  18. Mediation of glucose-induced anorexia by central nervous system interleukin 1 signaling.

    Science.gov (United States)

    Mizuno, Tooru M; Lew, Pei San; Spirkina, Alexandra; Xu, Yang

    2013-11-01

    Hypothalamic glucose sensing plays a critical role in the regulation of food intake and metabolism. Glucose injection, either centrally or peripherally suppresses food intake. However, the mechanism of glucose-induced feeding suppression is not fully understood. It has been demonstrated that hypothalamic interleukin 1 beta (IL-1β) mRNA levels are altered by metabolic states and IL-1 signaling participates in the regulation of food intake. Therefore, we hypothesized that hypothalamic IL-1 gene expression is regulated by glucose and glucose-induced feeding suppression is mediated via hypothalamic IL-1 signaling. To address this hypothesis, we examined the effect of glucose on IL-1α and IL-1β mRNA expression in the hypothalamus. We also examined the effect of intraperitoneal injection of glucose on food intake in wild-type and type I IL-1 receptor (IL-1RI)-deficient mice. Levels of IL-1α and IL-1β mRNA in the hypothalamus were increased in response to feeding and intraperitoneal injection of glucose, and were positively correlated with blood glucose levels in mice. Exposure of hypothalamic explants to high glucose (10 mM) media increased IL-1α and IL-1β mRNA levels compared to low glucose (1 mM) media. Intraperitoneal glucose administration reduced food intake in wild-type mice, while the feeding-suppressing effect of glucose was attenuated in IL-1RI-deficient mice. These findings support the role for hypothalamic IL-1 signaling in the mediation of the anorectic effect of glucose. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Interleukin 1 in oviductal tissues of viviparous, oviparous, and ovuliparous species of amphibians.

    Science.gov (United States)

    Jantra, Silke; Bigliardi, Elisa; Brizzi, Rossana; Ietta, Francesca; Bechi, Nicoletta; Paulesu, Luana

    2007-06-01

    In previous reports, we have shown that interleukin 1 (IL1), a cytokine associated with implantation in mice, is also expressed in reproductive tissues of viviparous squamate reptiles and cartilaginous fishes. In the present study, we investigated the expression of IL1B and its functional membrane receptor type I (IL1R1) in amphibians, a class of vertebrates that is characterized by different reproductive modes, including internal and external fertilization. In particular, we investigated the oviductal tissues of the aplacental viviparous Salamandra lanzai, the oviparous Triturus carnifex, and the ovuliparous Bufo bufo. In immunohistochemistry with anti-human IL1B and IL1R1 polyclonal antibodies we found that in S. lanzai, most cells in the uterine mucosa were immunoreactive for IL1B and IL1R1. In T. carnifex, IL1B and IL1R1 were present in ciliated luminal cells, and there was evidence of IL1B in glandular cells. In B. bufo, the expression of IL1B and IL1R1 was limited to the apical cytoplasm of the ciliated oviductal cells. Western blot analysis showed that a putative mature form of IL1B, similar to that seen in mammals, was present in the oviductal tissues of S. lanzai, whereas different forms, which probably correspond to an inactive pro-IL1B protein, were found in T. carnifex and B. bufo. A band that corresponded to the predicted 80-kDa human IL1R1 was found in S. lanzai and T. carnifex. Although the present study shows that IL1B and IL1R1 expression occurs in all reproductive modes, the differential expression patterns noted between ovuliparity and oviparity and viviparity may reflect the different roles of IL1 in the various reproductive modes.

  20. Constitutive Aberrant Endogenous Interleukin-1 Facilitates Inflammation and Growth in Human Melanoma

    Science.gov (United States)

    Qin, Yong; Ekmekcioglu, Suhendan; Liu, Ping; Duncan, Lyn M.; Lizée, Gregory; Poindexter, Nancy; Grimm, Elizabeth A.

    2011-01-01

    Interleukin-1-mediated inflammation is proposed to contribute to the development and progression of some cancers. IL-1 family member proteins are known to be expressed constitutively in many melanoma tumor cells, and we hypothesize that these support molecular pathways of inflammation and facilitate tumor growth. To investigate the expression of IL-1α and IL-1β in melanoma patients, and their association with disease progression, immunohistochemical staining was performed on tissues from 170 patients including benign nevi, primary melanomas, and metastatic melanomas. IL-1β levels were low (or zero) in benign nevi, and higher in primary and metastatic melanomas (Pmelanomas, with levels significantly higher in primary tumors (Pmelanoma samples were positive for IL-1α. In vitro studies with 7 human melanoma cell lines showed that 5 cell lines expressed IL-1α and IL-1β proteins and mRNA. We identified for the first time several important downstream signaling pathways affected by endogenous IL-1, including reactive oxygen and nitrogen species, COX-2, and phosphorylated IκB and SAPK/JNK; all of which were decreased by siRNA to IL-1s. Downregulation of IL-1α, IL-1β, or MyD88 substantially increased p21 and p53 levels. Treatment with IL-1 receptor type I neutralizing antibody or IL-1-pathway-specific siRNAs led to growth arrest in IL-1-positive melanoma cells. Furthermore, blocking the IL-1 pathway increased autophagy in IL-1-positive melanoma cells. These results indicate that the endogenous IL-1 system is functional in most human melanoma, and interrupting its signaling inhibits the growth of IL-1-positive melanoma cells. PMID:21954434

  1. A 5'-upstream short open reading frame encoded peptide regulates angiotensin type 1a receptor production and signalling via the β-arrestin pathway.

    Science.gov (United States)

    Yosten, Gina L C; Liu, Jun; Ji, Hong; Sandberg, Kathryn; Speth, Robert; Samson, Willis K

    2016-03-15

    AUG sequences and short open reading frames are commonly present in the 5'-leader sequence of G protein-coupled receptor mRNAs. The presence of these upstream AUG sequences has been demonstrated to inhibit downstream receptor translation efficiency and, most recently, receptor signal transduction. A seven amino acid peptide encoded by a short open reading frame in exon 2 of the angiotensin type 1a receptor has been shown to inhibit non-G protein-coupled signalling of angiotensin II, without altering the classical G protein-coupled pathway activated by the ligand. This finding may lead to the development of a new class of angiotensin receptor antagonists with activities biased for one, but not all, of the signalling cascades activated by angiotensin II, which could have therapeutic implications for the myriad hormones and neurotransmitters that signal through G protein-coupled receptors. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  2. A 5′‐upstream short open reading frame encoded peptide regulates angiotensin type 1a receptor production and signalling via the β‐arrestin pathway

    Science.gov (United States)

    Yosten, Gina L.C.; Liu, Jun; Ji, Hong; Sandberg, Kathryn; Speth, Robert

    2015-01-01

    Abstract AUG sequences and short open reading frames are commonly present in the 5′‐leader sequence of G protein‐coupled receptor mRNAs. The presence of these upstream AUG sequences has been demonstrated to inhibit downstream receptor translation efficiency and, most recently, receptor signal transduction. A seven amino acid peptide encoded by a short open reading frame in exon 2 of the angiotensin type 1a receptor has been shown to inhibit non‐G protein‐coupled signalling of angiotensin II, without altering the classical G protein‐coupled pathway activated by the ligand. This finding may lead to the development of a new class of angiotensin receptor antagonists with activities biased for one, but not all, of the signalling cascades activated by angiotensin II, which could have therapeutic implications for the myriad hormones and neurotransmitters that signal through G protein‐coupled receptors. PMID:26333095

  3. Coumestrol Counteracts Interleukin-1β-Induced Catabolic Effects by Suppressing Inflammation in Primary Rat Chondrocytes.

    Science.gov (United States)

    You, Jae-Seek; Cho, In-A; Kang, Kyeong-Rok; Oh, Ji-Su; Yu, Sang-Joun; Lee, Gyeong-Je; Seo, Yo-Seob; Kim, Su-Gwan; Kim, Chun Sung; Kim, Do Kyung; Im, Hee-Jeong; Kim, Jae-Sung

    2017-02-01

    In the present study, we investigated the anti-catabolic effects of coumestrol, a phytoestrogen derived from herbal plants, against interleukin-1β-induced cartilage degeneration in primary rat chondrocytes and articular cartilage. Coumestrol did not affect the viability of human normal oral keratinocytes and primary rat chondrocytes treated for 24 h and 21 days, respectively. Although coumestrol did not significantly increase the proteoglycan contents in long-term culture, it abolished the interleukin-1β-induced loss of proteoglycans in primary rat chondrocytes and knee articular cartilage. Furthermore, coumestrol suppressed the expression of matrix-degrading enzymes such as matrix metalloproteinase-13, -3, and -1 in primary rat chondrocytes stimulated with interleukin-1β. Moreover, the expression of catabolic factors such as nitric oxide synthase, cyclooxygenase-2, prostaglandin E 2 , and inflammatory cytokines in interleukin-1β-stimulated primary rat chondrocytes was suppressed by coumestrol. In summary, these results indicate that coumestrol counteracts the catabolic effects induced by interleukin-1β through the suppression of inflammation. Therefore, based on its biological activity and safety profile, coumestrol could be used as a potential anti-catabolic biomaterial for osteoarthritis.

  4. CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor

    DEFF Research Database (Denmark)

    Casarosa, Paola; Waldhoer, Maria; LiWang, Patricia J

    2005-01-01

    Human cytomegalovirus (HCMV) is the causative agent of life-threatening systemic diseases in immunocompromised patients as well as a risk factor for vascular pathologies, like atherosclerosis, in immunocompetent individuals. HCMV encodes a G-protein-coupled receptor (GPCR), referred to as US28...

  5. The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a Danish case-control sample

    DEFF Research Database (Denmark)

    Demontis, Ditte; Nyegaard, Mette; Christensen, Jane H

    2012-01-01

    OBJECTIVE: The MCHR1 gene encoding the melanin-concentrating hormone receptor 1 is located on chromosome 22q13.2 and has previously been associated with schizophrenia in a study of cases and controls from the Faroe Islands and Scotland. Herein we report an association between variations in the MCHR...

  6. Prognostic value of interleukin-1 beta levels after acute brain injury.

    Science.gov (United States)

    Taşçi, Alptekin; Okay, Onder; Gezici, Ali Riza; Ergün, Rüçhan; Ergüngör, Fikret

    2003-12-01

    Traumatic injury to central nervous system results in the production of inflammatory cytokines via intrinsic mechanisms by neurons, astrocytes and microglia, and extrinsic mechanisms by infiltrating macrophages, lymphocytes and other leukocytes. Interleukin-1 beta is the key mediator of the acute inflammatory host response. While this response is necessary for resolution of the pathologic event, the toxic nature of many of its products can cause significant tissue damage. We analyzed serum interleukin-1 beta levels by enzyme-linked immunosorbent assay in 48 patients with solitary head injury who were transported to our clinic immediately after trauma. We categorized the patients according to their initial Glasgow coma scores in three groups, and compared their serum interleukin-1 beta values both with their Glasgow coma initial and outcome scores. This study helped to provide quantitative data to estimate clinical impressions and prognosis after head injury.

  7. Interleukin 1 beta and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue.

    Science.gov (United States)

    Schäfer, M; Carter, L; Stein, C

    1994-01-01

    Local analgesic effects of exogenous opioid agonists are particularly prominent in painful inflammatory conditions and are mediated by opioid receptors on peripheral sensory nerves. The endogenous ligands of these receptors, opioid peptides, have been demonstrated in resident immune cells within inflamed tissue of animals and humans. Here we examine in vivo and in vitro whether interleukin 1 beta (IL-1) or corticotropin-releasing factor (CRF) is capable of releasing these endogenous opioids and inhibiting pain. When injected into inflamed rat paws (but not intravenously), IL-1 and CRF produce antinociception, which is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively, and by the immunosuppressant cyclosporine A. In vivo administration of antibodies against opioid peptides indicates that the effects of IL-1 and CRF are mediated by beta-endorphin and, in addition, by dynorphin A and [Met]enkephalin, respectively. Correspondingly, IL-1 effects are inhibited by mu-, delta-, and kappa-opioid antagonists, whereas CRF effects are attenuated by all except a kappa-antagonist. Finally, IL-1 and CRF produce acute release of immunoreactive beta-endorphin in cell suspensions freshly prepared from inflamed lymph nodes. This effect is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively. These findings suggest that IL-1 and CRF activate their receptors on immune cells to release opioids that subsequently occupy multiple opioid receptors on sensory nerves and result in antinociception. beta-Endorphin, mu- and delta-opioid receptors play a major role, but IL-1 and CRF appear to differentially release additional opioid peptides. PMID:7910403

  8. Interleukin-1β and interleukin-6 enhance thermal prolongation of the LCR in decerebrate piglets.

    Science.gov (United States)

    Xia, Luxi; Bartlett, Donald; Leiter, J C

    2016-08-01

    Thermal stress and prior upper respiratory tract infection are risk factors for the Sudden Infant Death Syndrome. The adverse effects of prior infection are likely mediated by interleukin-1β (IL-1β). Therefore, we examined the single and combined effects of IL-1β and elevated body temperature on the duration of the Laryngeal Chemoreflex (LCR) in decerebrate neonatal piglets ranging in age from post-natal day (P) 3 to P7. We examined the effects of intraperitoneal (I.P.) injections of 0.3mg/Kg IL-1β with or without I.P. 10mg/Kg indomethacin pretreatment on the duration of the LCR, and in the same animals we also examined the duration of the LCR when body temperature was elevated approximately 2°C. We found that IL-1β significantly increased the duration of the LCR even when body temperature was held constant. There was a significant multiplicative effect when elevated body temperature was combined with IL-1β treatment: prolongation of the LCR was significantly greater than the sum of independent thermal and IL-1β-induced prolongations of the LCR. The effects of IL-1β, but not elevated body temperature, were blocked by pretreatment with indomethacin alone. We also tested the interaction between IL-6 given directly into the nucleus of the solitary tract (NTS) bilaterally in 100ngm microinjections of 50μL and pretreatment with indomethacin. Here again, there was a multiplicative effect of IL-6 treatment and elevated body temperature, which significantly prolonged the LCR. The effect of IL-6 on the LCR, but not elevated body temperature, was blocked by pretreatment with indomethacin. We conclude that cytokines interact with elevated body temperature, probably through direct thermal effects on TRPV1 receptors expressed pre-synaptically in the NTS and through cytokine-dependent sensitization of the TRPV1 receptor. This sensitization is likely initiated by cyclo-oxygenase-2 dependent synthesis of prostaglandin E2, which is stimulated by elevated levels of IL-1

  9. Transfer of Her-2/neu specificity into cytokine-induced killer (CIK) cells with RNA encoding chimeric immune receptor (CIR).

    Science.gov (United States)

    Yoon, Sung Hee; Lee, Jin Myung; Woo, Sun-Je; Park, Min-Ji; Park, Jung-Sun; Kim, Hye-Sung; Park, Mi-Young; Sohn, Hyun-Jung; Kim, Tai-Gyu

    2009-11-01

    Efficient RNA transfer to dendritic cell and T cells by electroporation have been successfully applied for immunotherapy. Herein, RNA electroporation was used to transfer antigen-specific receptor (scFv) gene to cytokine-induced killer cells (CIK). CIK was generated from peripheral blood mononuclear cells with anti-CD3 antibody, interleukin-2, and interferon (IFN)-gamma for 14 days and showed typical characteristics of CIK expressing both CD3+ and CD56+ markers and NKG2D+. CIK could lyse K562 cells, but not SKOV3 and MCF7/Her-2/neu. After RNA encoding anti-Her-2/neu chimeric immune receptor (CIR) with signaling portion of CD28 and CD3zeta was electroporated to CIK, more than 95% of CIK expressed anti-Her-2/neu CIR (CIR-CIK). CIR-CIK was able to produce cytokines including IFN-gamma, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha, and show cytotoxicity specific to tumor cell lines expressing Her-2/neu, SKOV3, and MCF7/Her-2/neu. Adoptive transfer of CIR-CIK in SKOV3 xenograft nude mice model led to significant inhibition of tumor growth compared with transfer of mock-transduced CIK and showed higher inhibition than that of Herceptin, humanized monoclonal antibody specific for Her-2/neu. These results suggest that RNA transfer is the convenient and efficient strategy to introduce antigen-specificity into CIK and provide potential therapeutic value of CIR-CIK in the treatment of tumors.

  10. Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

    Energy Technology Data Exchange (ETDEWEB)

    Togi, Sumihito; Nakasuji, Misa; Muromoto, Ryuta; Ikeda, Osamu; Okabe, Kanako; Kitai, Yuichi; Kon, Shigeyuki [Department of Immunology, Graduate School of Pharmaceutical Sciences Hokkaido University, Sapporo 060-0812 (Japan); Oritani, Kenji [Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871 (Japan); Matsuda, Tadashi, E-mail: tmatsuda@pharm.hokudai.ac.jp [Department of Immunology, Graduate School of Pharmaceutical Sciences Hokkaido University, Sapporo 060-0812 (Japan)

    2015-07-31

    Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA), which interacts with cellular proteins, plays a central role in modification of viral and/or cellular gene expression. Here, we show that LANA associates with glucocorticoid receptor (GR), and that LANA enhances the transcriptional activity of GR. Co-immunoprecipitation revealed a physical interaction between LANA and GR in transiently transfected 293T and HeLa cells. In human B-lymphoma cells, LANA overexpression enhanced GR activity and cell growth suppression following glucocorticoid stimulation. Furthermore, confocal microscopy showed that activated GR was bound to LANA and accumulated in the nucleus, leading to an increase in binding of activated GR to the glucocorticoid response element of target genes. Taken together, KSHV-derived LANA acts as a transcriptional co-activator of GR. Our results might suggest a careful use of glucocorticoids in the treatment of patients with KSHV-related malignancies such as Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. - Highlights: • KSHV-LANA enhances the transcriptional activity of GR in 293T and HeLa cells. • KSHV-LANA physically associates with GR. • KSHV-LANA enhances GR activation and cell growth suppression in human B-lymphocytes. • KSHV-LANA influences the nuclear retention and DNA binding activity of GR.

  11. mRNA from NCB-20 cells encodes the N-methyl-D-aspartate/phencyclidine receptor: a Xenopus oocyte expression study.

    Science.gov (United States)

    Lerma, J; Kushner, L; Spray, D C; Bennett, M V; Zukin, R S

    1989-01-01

    The mouse neuroblastoma--Chinese hamster brain hybrid cell line NCB-20 is the only clonal cell line in which binding studies indicate the presence of phencyclidine (PCP) receptors. We report here that Xenopus oocytes injected with NCB-20 cell poly(A)+ RNA express N-methyl-D-aspartate (NMDA)-activated channels and that these channels include the PCP receptor site. In injected oocytes, NMDA application evoked a partially desensitizing inward current that was potentiated by glycine, blocked by the competitive antagonist D-2-amino-5-phosphonovaleric acid, blocked by Mg2+ and by Zn2+, and blocked in a use-dependent manner by the PCP receptor ligands PCP and MK-801. There was little or no response to kainate or quisqualate (agonists of the other excitatory amino acid receptors), to gamma-aminobutyric acid (an inhibitory transmitter), or to glycine (an inhibitory transmitter as well as an allosteric potentiator of NMDA channels). Thus, NMDA/PCP receptors expressed from NCB-20 cell mRNA exhibit properties similar to those of the neuronal receptors. The absence of expression of other excitatory amino acid receptors in this system makes it particularly useful for study of NMDA-evoked responses without interference from responses mediated by other receptors. Moreover, NCB-20 mRNA may be an appropriate starting material for cloning the cDNA(s) encoding the NMDA/PCP-receptor complex. PMID:2537982

  12. Repetitive in vivo treatment with human recombinant interleukin-1 beta modifies beta-cell function in normal rats

    DEFF Research Database (Denmark)

    Wogensen, L D; Reimers, J; Nerup, J

    1992-01-01

    changes in plasma insulin and in spite of increases in plasma glucagon and corticosterone. A lowering of blood glucose 2 h after interleukin-1 administration was reproduced with 40, but not 0.4 micrograms/kg of interleukin-1, and was also seen in interleukin-1 pre-treated rats. Two hours after the fifth...... injection of interleukin-1, intraperitoneal glucose tolerance was impaired with elevated plasma insulin and corticosterone levels and increased pancreatic insulin content, indicating a state of insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)...

  13. Effect of interleukin-1 on the biosynthesis of proinsulin and insulin in isolated rat pancreatic islets

    DEFF Research Database (Denmark)

    Hansen, Birgit Sehested; Linde, S; Spinas, G A

    1988-01-01

    Insulin dependent diabetes mellitus (IDDM) is often preceded or associated with lymphocytic infiltration in the islets of Langerhans (insulitis). We recently demonstrated that interleukin-1 (IL-1) produced by activated macrophages exerts a bimodal effect on insulin release and biosynthesis in iso...

  14. Variants in the interleukin-1 alpha and beta genes, and the risk for ...

    Indian Academy of Sciences (India)

    Elevated levels of interleukin-1 (IL-1) have been shown to amplify the inflammatory response against periodontopathogenic bacteria. In humans, polymorphisms in the IL1A and IL1B genes are the most well-studied genetic polymorphisms associated with periodontal disease (PD). In contrast to human, there is a lack of ...

  15. Global investigation of interleukin-1β signaling in primary β-cells using quantitative phosphoproteomics

    DEFF Research Database (Denmark)

    Engholm-Keller, Kasper; Størling, Joachim; Pociot, Flemming

    Novel Aspect: Global phosphoproteomic analysis of cytokine signaling in primary β-cells Introduction The insulin-producing β-cells of the pancreatic islets of Langerhans are targeted by aberrant immune system responses in diabetes mellitus involving cytokines, especially interleukin-1β (IL-1 β), ...

  16. Repeated intraperitoneal injections of interleukin 1 beta induce glucose intolerance in normal rats

    DEFF Research Database (Denmark)

    Wogensen, L; Reimers, J; Mandrup-Poulsen, T

    1991-01-01

    Previous in vitro findings suggest the involvement of interleukin 1 (IL-1) in the pathogenesis of insulin-dependent diabetes mellitus. The aims of the present study were to investigate the effects of single or repeated ip injections of recombinant IL-1 beta on blood glucose and glucose tolerance ...

  17. IgG autoantibodies against interleukin 1 alpha in sera of normal individuals

    DEFF Research Database (Denmark)

    Svenson, M; Poulsen, L K; Fomsgaard, A

    1989-01-01

    A pool of human sera from healthy blood donors was found to interfere competitively with the binding of 125I-labelled human recombinant interleukin 1 alpha (rIL-1 alpha) to the murine T-cell line EL4. The interference was reversible at the cellular level, and direct binding of the ligand to serum...

  18. Interleukin 1-induced down-regulation of antibody binding to CD4 molecules on human lymphocytes

    DEFF Research Database (Denmark)

    Tvede, N; Christensen, L D; Ødum, Niels

    1988-01-01

    Interleukin 1 (IL-1) is involved in the early activation of T lymphocytes. The CD4 antigen, described as a phenotypic marker of helper T cells, is also important in early T-cell activation by its ability to bind to MHC class II molecules on antigen-presenting cells, and to transmit positive (and...

  19. Variants in the interleukin-1 alpha and beta genes, and the risk for ...

    Indian Academy of Sciences (India)

    Elevated levels of interleukin-1 (IL-1) have been shown to amplify the inflammatory response against periodontopathogenic bacteria. In humans, polymorphisms in the 1 and 1 genes are the most well-studied genetic polymorphisms associated with periodontal disease (PD). In contrast to human, there is a lack of ...

  20. The influence of interleukin-1beta on gamma-glutamyl transpeptidase activity in rat hippocampus

    Czech Academy of Sciences Publication Activity Database

    Kaiser, M.; Mareš, Vladislav; Šťastný, František; Bubeníková-Valešová, V.; Lisá, Věra; Suchomel, P.; Balcar, V. J.

    2006-01-01

    Roč. 55, č. 4 (2006), s. 461-465 ISSN 0862-8408 R&D Projects: GA MZd(CZ) NF7626 Institutional research plan: CEZ:AV0Z50110509 Keywords : interleukin-1beta * gamma- glutamyltranspeptidase * hippocampus Subject RIV: ED - Physiology Impact factor: 2.093, year: 2006

  1. Induction of interleukin-1β mRNA after focal cerebral ischaemia in the rat

    NARCIS (Netherlands)

    Buttini, M.; Sauter, A.; Boddeke, H.W.G.M.

    1994-01-01

    The expression of interleukin-1β (IL-1β) mRNA in the brain in response to cerebral ischaemia in rats was examined using in situ hybridization histochemistry. Focal cerebral ischaemia was induced in spontaneously hypertensive rats by permanent occlusion of the left middle cerebral artery (MCAO).

  2. INDUCTION OF INTERLEUKIN-1-BETA MESSENGER-RNA AFTER FOCAL CEREBRAL-ISCHEMIA IN THE RAT

    NARCIS (Netherlands)

    BUTTINI, M; SAUTER, A; BODDEKE, HWGM

    The expression of interleukin-1beta (IL-1beta) mRNA in the brain in response to cerebral ischaemia in rats was examined using in situ hybridization histochemistry. Focal cerebral ischaemia was induced in spontaneously hypertensive rats by permanent occlusion of the left middle cerebral artery

  3. Molecular cloning and characterization of four genes encoding ethylene receptors associated with pineapple (Ananas comosus L. flowering

    Directory of Open Access Journals (Sweden)

    Yunhe eLi

    2016-05-01

    Full Text Available Exogenous ethylene, or ethephon, has been widely used to induce pineapple flowering, but the molecular mechanism behind ethephon induction is still unclear. In this study, we cloned four genes encoding ethylene receptors (designated AcERS1a, AcERS1b, AcETR2a and AcETR2b. The 5′ flanking sequences of these four genes were also cloned by self-formed adaptor PCR and SiteFinding-PCR, and a group of putative cis-acting elements was identified. Phylogenetic tree analysis indicated that AcERS1a, AcERS1b, AcETR2a and AcETR2b belonged to the plant ERS1s and ETR2/EIN4-like groups. Quantitative real-time PCR showed that AcETR2a and AcETR2b (subfamily 2 were more sensitive to ethylene treatment compared with AcERS1a and AcERS1b (subfamily 1. The relative expression of AcERS1b, AcETR2a and AcETR2b was significantly increased during the earlier period of pineapple inflorescence formation, especially at 1-9 days after ethylene treatment (DAET, whereas AcERS1a expression changed less than these three genes. In situ hybridization results showed that bract primordia (BP and flower primordia (FP appeared at 9 and 21 DAET, respectively, and flowers were formed at 37 DAET. AcERS1a, AcERS1b, AcETR2a and AcETR2b were mainly expressed in the shoot apex at 1-4 DAET; thereafter, with the appearance of BP and FP, higher expression of these genes was found in these new structures. Finally, at 37 DAET, the expression of these genes was mainly focused in the flower but was also low in other structures. These findings indicate that these four ethylene receptor genes, especially AcERS1b, AcETR2a and AcETR2b, play important roles during pineapple flowering induced by exogenous ethephon.

  4. Ocular toxoplasmosis: susceptibility in respect to the genes encoding the KIR receptors and their HLA class I ligands

    Science.gov (United States)

    Ayo, Christiane Maria; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Brandão de Mattos, Cinara de Cássia; Previato, Mariana; Barbosa, Amanda Pires; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; de Mattos, Luiz Carlos

    2016-01-01

    The objective of this study was to investigate the influence of the genes encoding the KIR receptors and their HLA ligands in the susceptibility of ocular toxoplasmosis. A total of 297 patients serologically-diagnosed with toxoplasmosis were selected and stratified according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping was performed by PCR-SSOP. Statistical analyses were conducted using the Chi-square test, and odds ratio with a 95% confidence interval was also calculated to evaluate the risk association. The activating KIR3DS1 gene was associated with increased susceptibility for ocular toxoplasmosis. The activating KIR together with their HLA ligands (KIR3DS1-Bw4-80Ile and KIR2DS1+/C2++ KIR3DS1+/Bw4-80Ile+) were associated with increased susceptibility for ocular toxoplasmosis and its clinical manifestations. KIR-HLA inhibitory pairs -KIR2DL3/2DL3-C1/C1 and KIR2DL3/2DL3-C1- were associated with decreased susceptibility for ocular toxoplasmosis and its clinical forms, while the KIR3DS1−/KIR3DL1+/Bw4-80Ile+ combination was associated as a protective factor against the development of ocular toxoplasmosis and, in particular, against recurrent manifestations. Our data demonstrate that activating and inhibitory KIR genes may influence the development of ocular toxoplasmosis. PMID:27827450

  5. Expression and functional analysis of genes encoding cytokinin receptor-like histidine kinase in maize (Zea mays L.).

    Science.gov (United States)

    Wang, Bo; Chen, Yanhong; Guo, Baojian; Kabir, Muhammad Rezaul; Yao, Yingyin; Peng, Huiru; Xie, Chaojie; Zhang, Yirong; Sun, Qixin; Ni, Zhongfu

    2014-08-01

    Cytokinin signaling is vital for plant growth and development which function via the two-component system (TCS). As one of the key component of TCS, transmembrane histidine kinases (HK) are encoded by a small gene family in plants. In this study, we focused on expression and functional analysis of cytokinin receptor-like HK genes (ZmHK) in maize. Firstly, bioinformatics analysis revealed that seven cloned ZmHK genes have different expression patterns during maize development. Secondly, ectopic expression by CaMV35S promoter in Arabidopsis further revealed that functional differentiation exists among these seven members. Among them, the ZmHK1a2-OX transgenic line has the lowest germination rate in the dark, ZmHK1-OX and ZmHK2a2-OX can delay leaf senescence, and seed size of ZmHK1-OX, ZmHK1a2-OX, ZmHK2-OX, ZmHK3b-OX and ZmHK2a2-OX was obviously reduced as compared to wild type. Additionally, ZmHK genes play opposite roles in shoot and root development; all ZmHK-OX transgenic lines display obvious shorter root length and reduced number of lateral roots, but enhanced shoot development compared with the wild type. Most notably, Arabidopsis response regulator ARR5 gene was up-regulated in ZmHK1-OX, ZmHK1a2-OX, ZmHK2-OX, ZmHK3b-OX and ZmHK2a2-OX as compared to wild type. Although the causal link between ZmHK genes and cytokinin signaling pathway is still an area to be further elucidated, these findings reflected that the diversification of ZmHK genes expression patterns and functions occurred in the course of maize evolution, indicating that some ZmHK genes might play different roles during maize development.

  6. A new splice variant of the major subunit of human asialoglycoprotein receptor encodes a secreted form in hepatocytes.

    Directory of Open Access Journals (Sweden)

    Jia Liu

    Full Text Available BACKGROUND: The human asialoglycoprotein receptor (ASGPR is composed of two polypeptides, designated H1 and H2. While variants of H2 have been known for decades, the existence of H1 variants has never been reported. PRINCIPAL FINDINGS: We identified two splice variants of ASGPR H1 transcripts, designated H1a and H1b, in human liver tissues and hepatoma cells. Molecular cloning of ASGPR H1 variants revealed that they differ by a 117 nucleotide segment corresponding to exon 2 in the ASGPR genomic sequence. Thus, ASGPR variant H1b transcript encodes a protein lacking the transmembrane domain. Using an H1b-specific antibody, H1b protein and a functional soluble ASGPR (sASGPR composed of H1b and H2 in human sera and in hepatoma cell culture supernatant were identified. The expression of ASGPR H1a and H1b in Hela cells demonstrated the different cellular loctions of H1a and H1b proteins at cellular membranes and in intracellular compartments, respectively. In vitro binding assays using fluorescence-labeled sASGPR or the substract ASOR revealed that the presence of sASGPR reduced the binding of ASOR to cells. However, ASOR itself was able to enhance the binding of sASGPR to cells expressing membrane-bound ASGPR. Further, H1b expression is reduced in liver tissues from patients with viral hepatitis. CONCLUSIONS: We conclude that two naturally occurring ASGPR H1 splice variants are produced in human hepatocytes. A hetero-oligomeric complex sASGPR consists of the secreted form of H1 and H2 and may bind to free substrates in circulation and carry them to liver tissue for uptake by ASGPR-expressing hepatocytes.

  7. Cloning of human and mouse EBI1, a lymphoid-specific G-protein-coupled receptor encoded on human chromosome 17q12-q21.2.

    Science.gov (United States)

    Schweickart, V L; Raport, C J; Godiska, R; Byers, M G; Eddy, R L; Shows, T B; Gray, P W

    1994-10-01

    A lymphoid-specific member of the G-protein-coupled receptor family has been identified by PCR with degenerate oligonucleotides. We have determined that this receptor, also reported as the Epstein-Barr-induced cDNA EBI1, is expressed in normal lymphoid tissues and in several B- and T-lymphocyte cell lines. While the function and the ligand for EBI1 remain unknown, its sequence and gene structure suggest that it is related to the receptors that recognize chemoattractants, such as interleukin-8, RANTES, C5a, and fMet-Leu-Phe. Like the chemoattractant receptors, EBI1 contains intervening sequences near its 5' end; however, EBI1 is unique in that both of its introns interrupt the coding region of the first extracellular domain. The gene is encoded on human chromosome 17q12-q21.2. None of the other G-protein-coupled receptors has been mapped to this region, but the C-C chemokine family has been mapped to 17q11-q21. The mouse EBI1 cDNA has also been isolated and encodes a protein with 86% identity to the human homolog.

  8. Central and peripheral interleukin-1β and interleukin-1 receptor I expression and their role in the acute stress response of common carp, Cyprinus carpio L

    NARCIS (Netherlands)

    Metz, J.R.; Huising, M.O.; Leon, K.; Verburg-van Kemenade, B.M.L.; Flik, G.

    2006-01-01

    In fish, the hypothalamus-pituitary-interrenal axis (HPI-axis), the equivalent of the hypothalamus-pituitary-adrenal axis (HPA-axis) in mammals, is activated during stress and leads to production and release of cortisol by the interregnal cells in the head kidney. In mammals, the cytokine

  9. Central and peripheral interleukin-1ß and interleukin-1 receptor I expression and their role in the acute stress response of common carp, Cyprinus carpio L.

    NARCIS (Netherlands)

    Metz, J.R.; Huising, M.O.; Leon, K.M.; Verburg-van Kemenade, B.M.L.; Flik, G.

    2006-01-01

    In fish, the hypothalamus-pituitary-interrenal axis (HPI-axis), the equivalent of the hypothalamus-pituitary-adrenal axis (HPA-axis) in mammals, is activated during stress and leads to production and release of cortisol by the interregnal cells in the head kidney. In mammals, the cytokine

  10. Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist

    DEFF Research Database (Denmark)

    2015-01-01

    2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453,411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746,171 total participants...... and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p = 1.8 × 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p...... observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about...

  11. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2009-01-01

    -to-insulin (PI/I) ratio but not stimulated C-peptide remained improved (by -0.07 [95% CI -0.14 to -0.02], P = 0.011) compared with values in placebo-treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels maintained the improved stimulated C......-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions in C-reactive protein (-3.2 mg/l [-6.2 to -1.1], P = 0.014) and in IL-6 (-1.4 ng/l [-2.6 to -0.3], P = 0.036) were maintained until the end of study. CONCLUSIONS: IL-1 blockade with anakinra induces improvement of the PI/I ratio and markers of systemic...

  12. Complete remission of severe idiopathic cold urticaria on interleukin-1 receptor antagonist (anakinra).

    NARCIS (Netherlands)

    Bodar, E.J.; Simon, A.; Visser, M. de; Meer, J.W.M. van der

    2009-01-01

    A 62-year-old patient had suffered from severe cold intolerance with an urticarial rash and oropharyngeal angio-oedema upon cold exposure since early childhood. This could be provoked by the ice cube test and by exposure in a cold room. Her family history was negative, and she did not carry any

  13. Complete remission of severe idiopathic cold urticaria on interleukin-1 receptor antagonist (anakinra)

    NARCIS (Netherlands)

    Bodar, E. J.; Simon, A.; de Visser, M.; van der Meer, J. W. M.

    2009-01-01

    A 62-year-old patient had suffered from severe cold intolerance with an urticarial rash and oropharyngeal angio-oedema upon cold exposure since early childhood. This could be provoked by the ice cube test and by exposure in a cold room. Her family history was negative, and she did not carry any

  14. Interleukin-1 receptor null mutant mice show decreased anxiety-like behavior and enhanced fear memory

    Science.gov (United States)

    Koo, Ja Wook; Duman, Ronald S.

    2013-01-01

    IL-1β is a proinflammatory cytokine that contributes to psychological stress responses and has been implicated in various psychiatric disorders most notably depression. Preclinical studies also demonstrate that IL-1β modulates anxiety- and fear-related behaviors, although these findings are difficult to assess because IL-1β infusions influence locomotor activity and nociception. Here we demonstrate that IL-1RI null mice exhibit a behavioral phenotype consistent with a decrease in anxiety-related behaviors. This includes significant effects in the elevated plus maze, light–dark, and novelty-induced hypophagia tests compared to wild-type mice, with no differences in locomotor activity. With regard to fear conditioning, IL-1RI null mice showed more freezing in auditory and contextual fear conditioning tests, and there was no effect on pain sensitivity. Taken together, the results indicate that the IL-1β/IL-1RI signaling pathway induces anxiety-related behaviors and impairs fear memory. PMID:19429130

  15. Interleukin-1 beta modulates endogenous thyroid hormone receptor alpha gene transcription in liver cells

    NARCIS (Netherlands)

    Kwakkel, J.; Wiersinga, W. M.; Boelen, A.

    2007-01-01

    One of the main characteristics of nonthyroidal illness (NTI) is a decrease in serum tri-iodothyronine, partly caused by a decrease in liver deiodinase type 1 (D1) mRNA and activity. Proinflammatory cytokines have been associated with NTI in view of their capability to decrease]:)I and thyroid

  16. In vivo effect of interleukin-1beta and interleukin-1RA on oocyte cytoplasmic maturation, ovulation, and early embryonic development in the mare

    Directory of Open Access Journals (Sweden)

    Gérard Nadine

    2005-06-01

    Full Text Available Abstract A growing body of evidence suggests that the interleukin-1 system is involved in periovulatory events. Previous work from our lab demonstrated that in the mare, interleukin-1beta (IL-1beta increases the ovulatory rate of metaphase II oocytes. The present study was conducted to analyze in vivo the effect of IL-1 on oocyte cytoplasmic maturation, ovulation and pregnancy rate. In the present work, IL-1beta (experiment 1, n = 13; experiment 2, n = 25 and interleukin-1RA (IL-1RA; experiment 1, n = 25 were injected intrafollicularly by using the transvaginal ultrasound-guided injection method. Injections were performed on cyclic mares when the diameter of the growing dominant follicle reached 30–34 mm. In experiment 1, mares were inseminated the day of the treatment and all the other day until ovulation. The time of ovulation was determined and a pregnancy diagnosis was performed 14 days after ovulation of the injected follicle. In experiment 2, the cumulus-oocyte complex from each injected follicle was collected by transvaginal ultrasound-guided aspiration 38 h after the intrafollicular injection. Oocyte nuclear stage and oocyte cytoplasmic maturation were assessed by analyzing chromatin configuration, cortical granules migration and mitochondria distribution under a confocal microscope. The results from experiment 1 confirm that an intrafollicular injection of 1 microgram IL-1beta induces ovulation in the mare whereas IL-1RA has no effect at the dose used in the present study. Furthemore, we demonstrated, that in our experimental conditions, IL-1beta and IL-1RA induced a decrease in embryo development. Experiment 2 leads us to observe that IL-1beta is unable to induce cortical granules migration and remodelling of mitochondria, that commonly occurs during oocyte maturation, whereas it acts on nuclear maturation. This result may explain the decrease in embryo development we observed after IL-1beta intrafollicular injection. In conclusion

  17. Interleukin-1beta induced changes in the protein expression of rat islets: a computerized database

    DEFF Research Database (Denmark)

    Andersen, H U; Fey, S J; Larsen, Peter Mose

    1997-01-01

    as well as the intracellular mechanisms of action of interleukin 1-mediated beta-cell cytotoxicity are unknown. However, previous studies have found an association of beta-cell destruction with alterations in protein synthesis. Thus, two-dimensional (2-D) gel electrophoresis of pancreatic islet proteins......% of %IOD was 45.7% in the NEPHGE gels. Addition of interleukin-1beta (IL-1beta) to the cultures resulted in statistically significant modulation or de novo synthesis of 105 proteins in the 10% gels. In conclusion, we present the first 10% and 15% acrylamide 2-D gel protein databases of neonatal rat islets...... may be an important tool facilitating studies of the molecular pathogenesis of insulin-dependent diabetes mellitus. 2-D gel electrophoresis of islet proteins may lead to (i) the determination of qualitative and quantitative changes in specific islet proteins induced by cytokines, (ii...

  18. The anti-interleukin-1 in type 1 diabetes action trial--background and rationale

    DEFF Research Database (Denmark)

    Pickersgill, Linda M S; Mandrup-Poulsen, Thomas R

    2009-01-01

    Type 1 diabetes (T1D) is caused by an inflammatory destruction of pancreatic beta-cells. Pro-inflammatory cytokines, in particular interleukin-1 (IL-1), have been suggested to be effector molecules based on the observations that pro-inflammatory cytokines cause beta-cell apoptosis in vitro...... and aggravate diabetes in vivo, and that inhibition of the action of these cytokines reduce diabetes incidence in animal models of type 1 diabetes and islet graft destruction. This review presents the rationale for and design of a recently launched double-blind, multicenter, randomized clinical trial...... that investigates the effect of interleukin-1 antagonism on beta-cell function in subjects with T1D of recent-onset....

  19. Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives.

    Science.gov (United States)

    Lopalco, Giuseppe; Cantarini, Luca; Vitale, Antonio; Iannone, Florenzo; Anelli, Maria Grazia; Andreozzi, Laura; Lapadula, Giovanni; Galeazzi, Mauro; Rigante, Donato

    2015-01-01

    A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet's disease, gout, Sjögren's syndrome, interstitial lung diseases, and Still's disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems.

  20. DNA-Encoded Flagellin Activates Toll-Like Receptor 5 (TLR5), Nod-like Receptor Family CARD Domain-Containing Protein 4 (NRLC4), and Acts as an Epidermal, Systemic, and Mucosal-Adjuvant

    Science.gov (United States)

    Nyström, Sanna; Bråve, Andreas; Falkeborn, Tina; Devito, Claudia; Rissiek, Björn; Johansson, Daniel X.; Schröder, Ulf; Uematsu, Satoshi; Akira, Shizuo; Hinkula, Jorma; Applequist, Steven E.

    2013-01-01

    Eliciting effective immune responses using non-living/replicating DNA vaccines is a significant challenge. We have previously shown that ballistic dermal plasmid DNA-encoded flagellin (FliC) promotes humoral as well as cellular immunity to co-delivered antigens. Here, we observe that a plasmid encoding secreted FliC (pFliC(-gly)) produces flagellin capable of activating two innate immune receptors known to detect flagellin; Toll-like Receptor 5 (TLR5) and Nod-like Receptor family CARD domain-containing protein 4 (NRLC4). To test the ability of pFliC(-gly) to act as an adjuvant we immunized mice with plasmid encoding secreted FliC (pFliC(-gly)) and plasmid encoding a model antigen (ovalbumin) by three different immunization routes representative of dermal, systemic, and mucosal tissues. By all three routes we observed increases in antigen-specific antibodies in serum as well as MHC Class I-dependent cellular immune responses when pFliC(-gly) adjuvant was added. Additionally, we were able to induce mucosal antibody responses and Class II-dependent cellular immune responses after mucosal vaccination with pFliC(-gly). Humoral immune responses elicited by heterologus prime-boost immunization with a plasmid encoding HIV-1 from gp160 followed by protein boosting could be enhanced by use of pFliC(-gly). We also observed enhancement of cross-clade reactive IgA as well as a broadening of B cell epitope reactivity. These observations indicate that plasmid-encoded secreted flagellin can activate multiple innate immune responses and function as an adjuvant to non-living/replicating DNA immunizations. Moreover, the capacity to elicit mucosal immune responses, in addition to dermal and systemic properties, demonstrates the potential of flagellin to be used with vaccines designed to be delivered by various routes. PMID:26344341

  1. Combined effects of interleukin-1? and cyclic stretching on metalloproteinase expression in corneal fibroblasts in vitro

    OpenAIRE

    Feng, Pengfei; Li, Xiaona; Chen, Weiyi; Liu, Chengxing; Rong, Shuo; Wang, Xiaojun; Du, Genlai

    2016-01-01

    Background Corneal tensile strain increases if the cornea becomes thin or if intraocular pressure increases. However, the effects of mechanical stress on extracellular matrix (ECM) remodelling in the corneal repair process and the corneal anomalies are unknown. Methods In this study, the combined effects of interleukin-1? (IL-1?) on matrix metalloproteinases (MMPs) in corneal fibroblasts under cyclic stretching were investigated in vitro. Cultured rabbit corneal fibroblasts were subjected to ...

  2. Enzymatic activity of two caspases related to interleukin-1beta-converting enzyme.

    Science.gov (United States)

    Fassy, F; Krebs, O; Rey, H; Komara, B; Gillard, C; Capdevila, C; Yea, C; Faucheu, C; Blanchet, A M; Miossec, C; Diu-Hercend, A

    1998-04-01

    Interleukin-1beta-converting enzyme is a member of a family of human cysteine proteases with specificity for aspartic acid, which have been named caspases. Within this family of enzymes, transcript X (TX) and transcript Y (TY) (caspases 4 and 5, respectively) are very similar to ICE (caspase 1) and form the ICE subfamily. Given the high degree of conservation in the sequences of these proteases (more than 50% amino acid identity in the mature enzymes), it was of interest to examine whether they shared similar substrate specificities. The three enzymes, ICE, TX and TY, were therefore expressed in baculovirus-infected insect cells, as 30-kDa proteins lacking the propeptide. Automaturation into p20 and p10 subunits occurred within the cells. Active ICE, TX and TY were collected in the cell culture supernatants. In addition, their production induced the activation of an endogenous 32-kDa putative cysteine protease (CPP32) like caspase. T7-tagged ICE, TX and TY were purified by immunoaffinity and tested for their catalytic efficiency on YVAD-containing synthetic substrates and on the ICE natural substrate, pro-interleukin-1beta. TX cleaved the same synthetic substrates as ICE (Km of 90 microM and k(cat) of 0.4 s(-1) for Suc-YVAD-NH-Mec, where Suc represents succinyl and NH-Mec represents amino-4-methylcoumarin) and could cleave pro-interleukin-1beta into the same peptides as ICE but less efficiently. On the other hand, TY showed very little efficacy on the different ICE substrates (Km of 860 microM for Suc-YVAD-NH-Mec). These results show that the ICE/TX/TY subfamily has functional heterogeneity and that ICE remains the preferred enzyme for pro-interleukin-1beta cleavage.

  3. The pharmacokinetics, distribution and degradation of human recombinant interleukin 1 beta in normal rats

    DEFF Research Database (Denmark)

    Reimers, J; Wogensen, L D; Welinder, B

    1991-01-01

    Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half-lives of distribut......Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half......-lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from...

  4. Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro

    NARCIS (Netherlands)

    Lollinga, Wouter T; de Wit, Raymond H; Rahbar, Afsar; Vasse, Gwenda F; Davoudi, Belghis; Diepstra, Arjan; Riezebos-Brilman, Annelies; Harmsen, Martin C; Hillebrands, Jan-Luuk; Söderberg-Naucler, Cecilia; van Son, Willem J; Smit, Martine J; Sanders, Jan-Stephan; van den Born, Jacob

    BACKGROUND: Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G

  5. The decoy Fcγ receptor encoded by the cytomegalovirus UL119-UL118 gene has differential affinity to IgG proteins expressing different GM allotypes.

    Science.gov (United States)

    Pandey, Janardan P; Namboodiri, Aryan M; Radwan, Faisal F; Nietert, Paul J

    2015-08-01

    Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been implicated in many diseases. However, there is significant divergence between HCMV seroprevalence and the prevalence of HCMV-associated diseases, implying the presence of host genetic factors that might modulate immunity to this virus. HCMV deploys many sophisticated strategies to evade host immunosurveillance. One strategy involves encoding for proteins that have functional properties of the Fcγ receptor (FcγR). The aim of the present investigation was to determine whether the UL119-UL118-encoded recombinant FcγR ectodomain binds differentially to genetically disparate IgG1 proteins. Results show that mean absorbance values for binding of HCMV UL119-UL118-encoded Fcγ receptor to the immunoglobulin GM (γ marker) 1,17-expressing IgG1 were significantly higher than to the IgG1 expressing the allelic GM 3 allotype (0.225 vs. 0.151; p=0.039). These findings suggest possible mechanisms underlying the maintenance of immunoglobulin GM gene polymorphism and its putative role in the etiology of HCMV-associated diseases. Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  6. TNF-α potentiates uric acid-induced interleukin-1β (IL-1β) secretion in human neutrophils.

    Science.gov (United States)

    Yokose, Kohei; Sato, Shuzo; Asano, Tomoyuki; Yashiro, Makiko; Kobayashi, Hiroko; Watanabe, Hiroshi; Suzuki, Eiji; Sato, Chikako; Kozuru, Hideko; Yatsuhashi, Hiroshi; Migita, Kiyoshi

    2017-09-14

    Monosodium urate (MSU) has been shown to promote interleukin-1β (IL-1β) secretion in human monocytes, but the priming signals for NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway remains elusive. In this study, we investigated the role of Tumor necrosis factor-alpha (TNF-α) on MSU-mediated IL-1β induction in human neutrophils. Human neutrophils were stimulated with MSU, in the presence or absence of TNF-α priming. The cellular supernatants were analyzed for IL-1β, IL-18, and caspase-1 by enzyme-linked immunosorbent assay (ELISA) methods. Pro-IL-1β mRNA expressions in human neutrophils were analyzed by real-time PCR method. TNF-α stimulation induced pro-IL-1β mRNA expression; however, MSU stimulation did not induce pro-IL-1β mRNA expression in human neutrophils. TNF-α alone or MSU stimulation did not result in efficient IL-1β secretion in human neutrophils, whereas in TNF-α-primed neutrophils, MSU stimulation resulted in a marked IL-1β and IL-18 secretion. TNF-α-primed neutrophils secreted cleaved caspase-1 (p20), in response to MSU stimulation. Our data demonstrate that priming of human neutrophils with TNF-α promotes uric acid-mediated IL-1β secretion in the absence of microbial stimulation. These findings provide insights into the neutrophils-mediated inflammatory processes in gouty arthritis.

  7. Potential role of interleukin-1 at the peri-ovulation stage in a species of placental viviparous reptile, the three-toed skink, Chalcides chalcides (squamata: scincidae)

    Science.gov (United States)

    Romagnoli, Roberta; Cateni, Chiara; Guarino, Fabio M; Bigliardi, Elisa; Paulesu, Luana Ricci

    2003-01-01

    We recently showed that interleukin-1 (IL-1) is secreted by the placenta of a species of squamate reptile, the three-toed skink, Chalcides chalcides. In this study, we used immunohistochemical techniques to investigate the expression of IL-1 (in the two isoforms, IL-1α and IL-1β) and its specific membrane receptor IL-1 RtI in uterine oviduct during the peri-implantation period. We found that both IL-1 and its receptor were expressed in uterine tissues before and after ovulation (in the pre-ovulatory stage, even before the yolk had formed in the ovary). However, while IL-1α was mostly localized in the uterine mesenchyme tissue, IL-1β and IL-1RtI were present in the uterine epithelium. Our data provide a further comparison between the reproduction of mammals and squamate reptiles. PMID:14585105

  8. Potential role of interleukin-1 at the peri-ovulation stage in a species of placental viviparous reptile, the three-toed skink, Chalcides chalcides (squamata: scincidae

    Directory of Open Access Journals (Sweden)

    Bigliardi Elisa

    2003-09-01

    Full Text Available Abstract We recently showed that interleukin-1 (IL-1 is secreted by the placenta of a species of squamate reptile, the three-toed skink, Chalcides chalcides. In this study, we used immunohistochemical techniques to investigate the expression of IL-1 (in the two isoforms, IL-1α and IL-1β and its specific membrane receptor IL-1 RtI in uterine oviduct during the peri-implantation period. We found that both IL-1 and its receptor were expressed in uterine tissues before and after ovulation (in the pre-ovulatory stage, even before the yolk had formed in the ovary. However, while IL-1α was mostly localized in the uterine mesenchyme tissue, IL-1β and IL-1RtI were present in the uterine epithelium. Our data provide a further comparison between the reproduction of mammals and squamate reptiles.

  9. Inhibition of IRE1 signaling affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells

    Directory of Open Access Journals (Sweden)

    Minchenko D.O.

    2016-07-01

    Full Text Available Objective. The aim of the present investigation was to examine the effect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1, which is a central mediator of the unfolded protein response on the expression of genes encoding glucocorticoid receptor (NR3C1 and some related proteins (SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, NNT and their hypoxic regulation in U87 glioma cells for evaluation of their possible significance in the control of the glioma growth.

  10. DMPD: The interrelated role of fibronectin and interleukin-1 in biomaterial-modulatedmacrophage function. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available latedmacrophage function. Schmidt DR, Kao WJ. Biomaterials. 2007 Jan;28(3):371-82. Epub 2006 Sep 15. (.png) ...and interleukin-1 in biomaterial-modulatedmacrophage function. Authors Schmidt DR, Kao WJ. Publication Biomaterial

  11. Enhanced susceptibility to subcutaneous abscess formation and persistent infection around catheters is associated with sustained interleukin-1beta levels

    NARCIS (Netherlands)

    Boelens, J. J.; Zaat, S. A.; Murk, J. L.; Weening, J. J.; van der Poll, T.; Dankert, J.

    2000-01-01

    A persistent Staphylococcus epidermidis infection in mice around a subcutaneous polyvinylpyrrolidone-grafted silicon elastomer catheter (SEpvp) but not around a conventional silicon elastomer catheter was observed. With SEpvp pericatheter tissue, protracted and exaggerated interleukin-1beta

  12. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly).

    Science.gov (United States)

    Hoffmann, Katrin; Dreger, Christine K; Olins, Ada L; Olins, Donald E; Shultz, Leonard D; Lucke, Barbara; Karl, Hartmut; Kaps, Reinhard; Müller, Dietmar; Vayá, Amparo; Aznar, Justo; Ware, Russell E; Sotelo Cruz, Norberto; Lindner, Tom H; Herrmann, Harald; Reis, André; Sperling, Karl

    2002-08-01

    Pelger-Huët anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape.

  13. Interleukin-1 exerts distinct actions on different cell types of the brain in vitro

    Directory of Open Access Journals (Sweden)

    Ying An

    2011-01-01

    Full Text Available Ying An, Qun Chen, Ning QuanDepartment of Oral Biology, Ohio State University, Columbus, OH, USAAbstract: Interleukin-1 (IL-1 is a critical neuroinflammatory mediator in the central nervous system (CNS. In this study, we investigated the effect of IL-1 on inducing inflammation-related gene expression in three astrocyte, two microglial, and one brain endothelial cell line. Interleukin-1 beta (IL-1β is found to be produced by the two microglial cell lines constitutively, but these cells do not respond to IL-1β stimulation. The three astrocyte cell lines responded to IL-1ß stimulation by expressing MCP-1, CXCL-1, and VCAM-1, but different subtypes of astrocytes exhibited different expression profiles after IL-1β stimulation. The brain endothelial cells showed strongest response to IL-1β by producing MCP-1, CXCL-1, VCAM-1, ICAM-1, IL-6, and COX-2 mRNA. The induction of endothelial COX-2 mRNA is shown to be mediated by p38 MAPK pathway, whereas the induction of other genes is mediated by the NF-κB pathway. These results demonstrate that IL-1 exerts distinct cell type-specific action in CNS cells and suggest that IL-1-mediated neuroinflammation is the result of the summation of multiple responses from different cell types in the CNS to IL-1.Keywords: astrocyte, microglia, endothelial cells, signal transduction pathways, gene expression 

  14. Interleukin-1 as a Common Denominator from Autoinflammatory to Autoimmune Disorders: Premises, Perils, and Perspectives

    Directory of Open Access Journals (Sweden)

    Giuseppe Lopalco

    2015-01-01

    Full Text Available A complex web of dynamic relationships between innate and adaptive immunity is now evident for many autoinflammatory and autoimmune disorders, the first deriving from abnormal activation of innate immune system without any conventional danger triggers and the latter from self-/non-self-discrimination loss of tolerance, and systemic inflammation. Due to clinical and pathophysiologic similarities giving a crucial role to the multifunctional cytokine interleukin-1, the concept of autoinflammation has been expanded to include nonhereditary collagen-like diseases, idiopathic inflammatory diseases, and metabolic diseases. As more patients are reported to have clinical features of autoinflammation and autoimmunity, the boundary between these two pathologic ends is becoming blurred. An overview of monogenic autoinflammatory disorders, PFAPA syndrome, rheumatoid arthritis, type 2 diabetes mellitus, uveitis, pericarditis, Behçet’s disease, gout, Sjögren’s syndrome, interstitial lung diseases, and Still’s disease is presented to highlight the fundamental points that interleukin-1 displays in the cryptic interplay between innate and adaptive immune systems.

  15. Modern and Convensional Wound Dressing to Interleukin 1 and Interleukin 6 in Diabetic wound

    Directory of Open Access Journals (Sweden)

    Werna Nontji

    2015-04-01

    Full Text Available Introduction:Holistic wound care is one of the ways to prevent gangrene and amputation, modern wound dressing is more effective than convensional with increasing transforming growth factor and cytokine, especially interleukin. This study aims to identify the effectiveness of Modern and Convensional Wound Dressing to Interleukin 1 (IL-1 and Interleukin 6 (IL-6 in Diabetic wound. Method:A Quasi eksperimental pre-post with control group design was used. The intervention given was modern wound dressing and Control group by convensional wound dressing, This study was conducted in Makassar with 32 samples (16 in intervention group and 16 in control group. Result: The result of Pooled T- test showed that p = 0.00 (p < 0.05, it means that there was signifi cant correlation between modern wound dressing to IL-6 and IL-1 than Convensional wound dressing. Discussion: Process of wound healing was produced growth factor and cytokine (IL-1 and IL-6, it will stimulated by wound dressing, modern wound dressing (Calcium alginat can absorb wound drainage, non oklusive, non adhesif, and autolytic debridement. Keywords: Modern wound dressing, Interleukin 1 (IL-1, Interleukin 6 (IL-6

  16. Identification of a cysteine protease closely related to interleukin-1 beta-converting enzyme.

    Science.gov (United States)

    Faucheu, C; Blanchet, A M; Collard-Dutilleul, V; Lalanne, J L; Diu-Hercend, A

    1996-02-15

    The present study describes the identification and molecular cloning of a new member of the interleukin-1 beta-converting enzyme (ICE) family denoted transcript Y (TY). TY is very closely related to both ICE (51% amino acid identity) and a protein named transcript X (TX) (75% amino acid identity) that we recently identified [Faucheu, C., Diu, A., Chan, A.W.E., Blanchet, A.-M., Miossec, C., Hervé, F.,Collard-Dutilleul, V., Gu, Y., Aldape, R., Lippke, J., Rocher, C., Su, M.S.-S., Livingston, D.J., Hercend, T. & Lalanne, J.-L. (1995) EMBO J. 14, 1914-1922]. The amino acids that are implicated in both the ICE catalytic site and in the PI aspartate-binding pocket are conserved in TY. Within the ICE gene family, TY belongs to a subfamily of proteins closely related to the prototype ICE protein. Using transfection experiments into mammalian cells, we demonstrate that TY has protease activity on its own precursor and that this activity is dependent on the presence of a cysteine residue at position 245. However, despite the close similarity between TY and ICE active sites, TY fails to process the interleukin-1 beta precursor. In addition, as already observed for ICE and TX, TY is able to induce apoptosis when overexpressed in COS cells. TY therefore represents a new member of the growing family of apoptosis-inducing ICE-related cysteine proteases.

  17. Identification and characterization of Aeromonas hydrophila genes encoding the outer membrane receptor of ferrioxamine B and an AraC-type transcriptional regulator.

    Science.gov (United States)

    Funahashi, Tatsuya; Tanabe, Tomotaka; Maki, Jun; Miyamoto, Katsushiro; Tsujibo, Hiroshi; Yamamoto, Shigeo

    2014-01-01

    We found that, under iron-limiting conditions, Aeromonas hydrophila ATCC 7966(T) could utilize the xenosiderophore desferrioxamine B (DFOB) for growth by inducing the expression of its own outer membrane receptor. Two consecutive genes, desR and desA, were selected as candidates involved in DFOB utilization. The presence of the ferric-uptake regulator boxes in their promoters suggested that these genes are under iron-dependent regulation. Mutation of desA, a gene that encodes the outer membrane receptor of ferrioxamine B, disrupted the growth of the amonabactin-deficient mutant in the presence of DFOB. β-Galactosidase reporter assays and reverse transcriptase-quantitative PCR demonstrated that desR, a gene that encodes an AraC-like regulator homolog is required for the induction of desA transcription in the presence of DFOB and under iron-limiting conditions. The functions of desA and desR were analyzed using complementation experiments. Our data provided evidence that DesA is powered primarily by the TonB2 system.

  18. Site-specific epitope tagging of G protein-coupled receptors by bioorthogonal modification of a genetically encoded unnatural amino acid.

    Science.gov (United States)

    Naganathan, Saranga; Ye, Shixin; Sakmar, Thomas P; Huber, Thomas

    2013-02-12

    We developed a general strategy for labeling expressed membrane proteins with a peptide epitope tag and detecting the tagged proteins in native cellular membranes. First, we genetically encoded the unnatural amino acid p-azido-L-phenylalanine (azF) at various specific sites in a G protein-coupled receptor (GPCR), C-C chemokine receptor 5 (CCR5). The reactive azido moiety facilitates Staudinger ligation to a triarylphosphine-conjugated FLAG peptide. We then developed a whole-cell-based enzyme-linked immunosorbent assay approach to detect the modified azF-CCR5 using anti-FLAG mAb. We optimized conditions to achieve labeling and detection of low-abundance GPCRs in live cells. We also performed an accessibility screen to identify azF positions on CCR5 amenable to labeling. Finally, we demonstrate a preparative strategy for obtaining pure bioorthogonally modified GPCRs suitable for single-molecule detection fluorescence experiments. This peptide epitope tagging strategy, which employs genetic encoding and bioorthogonal labeling of azF in live cells, should be useful for studying biogenesis of polytopic membrane proteins and GPCR signaling mechanisms.

  19. Olfaction in the Queensland fruit fly, Bactrocera tryoni. II: Response spectra and temporal encoding characteristics of the carbon dioxide receptors.

    Science.gov (United States)

    Hull, C D; Cribb, B W

    2001-05-01

    Single-unit electrophysiology was used to record the nerve impulses from the carbon dioxide receptors of female Queensland fruit flies, Bactroera tryoni. The receptors responded to stimulation in a phasic-tonic manner and also had a period of inhibition of the nerve impulses after the end of stimulation. at high stimulus intensities. The cell responding to carbon dioxide was presented with a range of environmental odorants and found to respond to methyl butyrate and 2-butanone. The coding characteristics of the carbon dioxide cell and the ability to detect other odorants are discussed, with particular reference to the known behavior of the fly.

  20. The "thrifty" gene encoding Ahsg/Fetuin-A meets the insulin receptor: Insights into the mechanism of insulin resistance.

    Science.gov (United States)

    Goustin, Anton-Scott; Abou-Samra, Abdul B

    2011-06-01

    Ahsg (fetuin-A) is a 55-59kDa phosphorylated glycoprotein synthesized in the adult predominantly by hepatocytes, from which it enters the circulation. When dysregulated, this glycoprotein operates to influence the clinical sequelae of insulin resistance-type 2 diabetes and cardiovascular disease. The pathological sequelae likely arise from two separable molecular "faces" of Ahsg-one acting at the level of the insulin receptor and a second face influencing ectopic biomineralization in the intima. A detailed understanding of these two functional faces of Ahsg is not yet clear for lack of structural studies. Ahsg has a physiological role in the biomineralization of bone, which when dysregulated can lead to ectopic calcification of soft tissues in the vasculature. Ahsg has a second physiological function in regulating how insulin signals through its receptor, a transmembrane tyrosine kinase. Dysregulation of this "face" of Ahsg results in morbid sequelae such as impaired glucose disposal and fatty liver. Ahsg binds to tandem fibronectin type 3 (Fn3) domains present in the 194 amino acid residue extracellular portion of the β-subunit of the insulin receptor, distant from the high-affinity pocket formed by two complementing α-subunits where insulin binds. Only two proteins are known to bind directly to the insulin receptor ectodomain - insulin and Ahsg - the former turns on the receptor's intrinsic tyrosine kinase (TK) activity, and the latter shuts it down. Recent X-ray crystallographic studies of the ectodomain of the insulin receptor now sharpen our understanding of the receptor's extracellular α-subunit and linked β-subunit. Ahsg genotype and its circulating level have been correlated with body morphometrics (obese versus lean and visceral adiposity) in epidemiological studies enrolling thousands of patients. Epidemiological studies from the clinic reveal high levels of circulating Ahsg in insulin resistance and diabetes. This review endeavors to explain how one

  1. Interleukin-1β Promotes Ovarian Tumorigenesis through a p53/NF-κB-Mediated Inflammatory Response in Stromal Fibroblasts

    Directory of Open Access Journals (Sweden)

    Isaiah Gregory Schauer

    2013-04-01

    Full Text Available Cancer has long been considered a disease that mimics an “unhealed wound,” with oncogene-induced secretory activation signals from epithelial cancer cells facilitating stromal fibroblast, endothelial, and inflammatory cell participation in tumor progression. However, the underlying mechanisms that orchestrate cooperative interaction between malignant epithelium and the stroma remain largely unknown. Here, we identified interleukin-1β (IL-1β as a stromal-acting chemokine secreted by ovarian cancer cells, which suppresses p53 protein expression in cancer-associated fibroblasts (CAFs. Elevated expression of IL-1β and cognate receptor IL-1R1 in ovarian cancer epithelial cells and CAFs independently predicted reduced overall patient survival, as did repressed nuclear p53 in ovarian CAFs. Knockdown of p53 expression in ovarian fibroblasts significantly enhanced the expression and secretion of chemokines IL-8, growth regulated oncogene-alpha (GRO-α, IL-6, IL-1β, and vascular endothelial growth factor (VEGF, significantly increased in vivo mouse xenograft ovarian cancer tumor growth, and was entirely dependent on interaction with, and transcriptional up-regulation of, nuclear factor-kappaB (NF-κB p65. Our results have uncovered a previously unrecognized circuit whereby epithelial cancer cells use IL-1β as a communication factor instructing stromal fibroblasts through p53 to generate a protumorigenic inflammatory microenvironment. Attenuation of p53 protein expression in stromal fibroblasts generates critical protumorigenic functionality, reminiscent of the role that oncogenic p53 mutations play in cancer cells. These findings implicate CAFs as an important target for blocking inflammation in the tumor microenvironment and reducing tumor growth.

  2. Octacalcium phosphate crystals induce inflammation in vivo through interleukin-1 but independent of the NLRP3 inflammasome in mice.

    Science.gov (United States)

    Narayan, Sharmal; Pazar, Borbala; Pazar, Borbola; Ea, Hang-Korng; Kolly, Laeticia; Bagnoud, Nathaliane; Chobaz, Véronique; Lioté, Frédéric; Vogl, Thomas; Holzinger, Dirk; Kai-Lik So, Alexander; Busso, Nathalie

    2011-02-01

    To determine the mechanisms involved in inflammatory responses to octacalcium phosphate (OCP) crystals in vivo. OCP crystal-induced inflammation was monitored using a peritoneal model of inflammation in mice with different deficiencies affecting interleukin-1 (IL-1) secretion (IL-1α(-/-) , IL-1β(-/-) , ASC(-/-) , and NLRP3(-/-) mice) or in mice pretreated with IL-1 inhibitors (anakinra [recombinant IL-1 receptor antagonist] and anti-IL-1β). The production of IL-1α, IL-1β, and myeloid-related protein 8 (MRP-8)-MRP-14 complex was determined by enzyme-linked immunosorbent assay. Peritoneal neutrophil recruitment and cell viability were determined by flow cytometry. Depletion of mast cells or resident macrophages was performed by pretreatment with compound 48/80 or clodronate liposomes, respectively. OCP crystals induced peritoneal inflammation, as demonstrated by neutrophil recruitment and up-modulation of IL-1α, IL-1β, and MRP-8-MRP-14 complex, to levels comparable with those induced by monosodium urate monohydrate crystals. This OCP crystal-induced inflammation was both IL-1α- and IL-1β-dependent, as shown by the inhibitory effects of anakinra and anti-IL-1β antibody treatment. Accordingly, OCP crystal stimulation resulted in milder inflammation in IL-1α(-/-) and IL-1β(-/-) mice. Interestingly, ASC(-/-) and NLRP3(-/-) mice did not show any alteration in their inflammation status in response to OCP crystals. Depletion of the resident macrophage population resulted in a significant decrease in crystal-induced neutrophil infiltration and proinflammatory cytokine production in vivo, whereas mast cell depletion had no effect. Finally, OCP crystals induced apoptosis/necrosis of peritoneal cells in vivo. These data indicate that macrophages, rather than mast cells, are important for initiating and driving OCP crystal-induced inflammation. Additionally, OCP crystals induce IL-1-dependent peritoneal inflammation without requiring the NLRP3 inflammasome. Copyright

  3. Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial).

    Science.gov (United States)

    Van Tassell, Benjamin W; Canada, Justin; Carbone, Salvatore; Trankle, Cory; Buckley, Leo; Oddi Erdle, Claudia; Abouzaki, Nayef A; Dixon, Dave; Kadariya, Dinesh; Christopher, Sanah; Schatz, Aaron; Regan, Jessica; Viscusi, Michele; Del Buono, Marco; Melchior, Ryan; Mankad, Pranav; Lu, Juan; Sculthorpe, Robin; Biondi-Zoccai, Giuseppe; Lesnefsky, Edward; Arena, Ross; Abbate, Antonio

    2017-11-01

    An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of IL-1 (interleukin-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. We randomly assigned 60 patients with reduced left ventricular ejection fraction (2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (Vo2 [mL/kg per minute]) and ventilatory efficiency (the VE/Vco2 slope). Treatment with anakinra did not affect peak Vo2 or VE/Vco2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak Vo2 from 14.5 (10.5-16.6) mL/kg per minute to 16.1 (13.2-18.6) mL/kg per minute (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between-groups differences, however, were not statistically significant. The incidence of death or rehospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12-week, anakinra 2-week, and placebo groups, respectively (log-rank test P=0.10). No change in peak Vo2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak Vo2 and rehospitalization for HF. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936909. © 2017 American Heart Association, Inc.

  4. Interleukin-1β promotes ovarian tumorigenesis through a p53/NF-κB-mediated inflammatory response in stromal fibroblasts.

    Science.gov (United States)

    Schauer, Isaiah Gregory; Zhang, Jing; Xing, Zhen; Guo, Xiaoqing; Mercado-Uribe, Imelda; Sood, Anil K; Huang, Peng; Liu, Jinsong

    2013-04-01

    Cancer has long been considered a disease that mimics an "unhealed wound," with oncogene-induced secretory activation signals from epithelial cancer cells facilitating stromal fibroblast, endothelial, and inflammatory cell participation in tumor progression. However, the underlying mechanisms that orchestrate cooperative interaction between malignant epithelium and the stroma remain largely unknown. Here, we identified interleukin-1β (IL-1β) as a stromal-acting chemokine secreted by ovarian cancer cells, which suppresses p53 protein expression in cancer-associated fibroblasts (CAFs). Elevated expression of IL-1β and cognate receptor IL-1R1 in ovarian cancer epithelial cells and CAFs independently predicted reduced overall patient survival, as did repressed nuclear p53 in ovarian CAFs. Knockdown of p53 expression in ovarian fibroblasts significantly enhanced the expression and secretion of chemokines IL-8, growth regulated oncogene-alpha (GRO-α), IL-6, IL-1β, and vascular endothelial growth factor (VEGF), significantly increased in vivo mouse xenograft ovarian cancer tumor growth, and was entirely dependent on interaction with, and transcriptional up-regulation of, nuclear factor-kappaB (NF-κB) p65. Our results have uncovered a previously unrecognized circuit whereby epithelial cancer cells use IL-1β as a communication factor instructing stromal fibroblasts through p53 to generate a protumorigenic inflammatory microenvironment. Attenuation of p53 protein expression in stromal fibroblasts generates critical protumorigenic functionality, reminiscent of the role that oncogenic p53 mutations play in cancer cells. These findings implicate CAFs as an important target for blocking inflammation in the tumor microenvironment and reducing tumor growth.

  5. Interleukin-1beta and TNF-alpha: reliable targets for protective therapies in Parkinson´s Disease?

    Directory of Open Access Journals (Sweden)

    María Celeste Leal

    2013-04-01

    Full Text Available Neuroinflammation has received increased attention as a target for putative neuroprotective therapies in Parkinson´s Disease (PD. Two prototypic pro-inflammatory cytokines Interleukin-1beta (IL-1 and Tumor necrosis factor-alpha (TNF have been implicated as main effectors of the functional consequences of neuroinflammation on neurodegeneration in PD models. In this review, we describe that the functional interaction between these cytokines in the brain differs from the periphery (e.g. their expression is not induced by each other and present data showing predominantly a toxic effect of these cytokines when expressed at high doses and for a sustained period of time in the substantia nigra pars compacta (SN. In addition, we highlight opposite evidence showing protective effects of these two main cytokines when conditions of duration, amount of expression or state of activation of the target or neighboring cells are changed. Furthermore, we discuss these results in the frame of previous disappointing results from anti-TNF clinical trials against Multiple Sclerosis, another neurodegenerative disease with a clear neuroinflammatory component. In conclusion, we hypothesize that the available evidence suggests that the duration and dose of IL-1 or TNF expression is crucial to predict their functional effect on the SN. Since these parameters are not amenable for measurement in the SN of PD patients, we call for an in-depth analysis to identify downstream mediators that could be common to the toxic (and not the protective effects of these cytokines in the SN. This strategy could spare the possible neuroprotective effect of these cytokines operative in the patient at the time of treatment, increasing the probability of efficacy in a clinical setting. Alternatively, receptor-specific agonists or antagonists could also provide a way to circumvent undesired effects of general anti-inflammatory or specific anti IL-1 or TNF therapies against PD.

  6. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework

    DEFF Research Database (Denmark)

    Nikota, Jake; Banville, Allyson; Goodwin, Laura Rose

    2017-01-01

    Background: The accumulation of MWCNTs in the lung environment leads to inflammation and the development of disease similar to pulmonary fibrosis in rodents. Adverse Outcome Pathways (AOPs) are a framework for defining and organizing the key events that comprise the biological changes leading...... to undesirable events. A putative AOP has been developed describing MWCNT-induced pulmonary fibrosis; inflammation and the subsequent healing response induced by inflammatory mechanisms have been implicated in disease progression. The objective of the present study was to address a key data gap in this AOP......: empirical data supporting the essentiality of pulmonary inflammation as a key event prior to fibrosis. Specifically, Interleukin-1 Receptor1 (IL-1R1) and Signal Transducer and Activator of Transcription 6 (STAT6) knock-out (KO) mice were employed to target inflammation and the subsequent healing response...

  7. Sequence analysis of HindIII Q2 fragment of capripoxvirus reveals a putative gene encoding a G-protein-coupled chemokine receptor homologue.

    Science.gov (United States)

    Cao, J X; Gershon, P D; Black, D N

    1995-05-10

    The DNA sequence of the HindIII Q2 fragment near the left terminus of the capripoxvirus (KS-1 strain) genome was determined. The sequence contains two complete open reading frames (ORFs) and a part of a third. Analysis of the deduced amino acid sequence of one of these ORFs, Q2/3L, revealed that this gene has the capacity to encode a protein which is related to members of the G-protein coupled chemokine receptor subfamily, the swinepoxvirus K2R and the human cytomegalovirus US28 ORFs. It has the key structural characteristics of the G-protein-coupled receptor superfamily, e.g., seven hydrophobic regions, predicted to span the cell membrane, and the cysteine residues in the first and second extracellular loops that are implicated in formation of a disulfide bond. Southern blot analysis showed that all three species of the Capripoxvirus genus, i.e., sheep pox, goat pox, and lumpy skin disease of cattle, contain copies of this putative G-protein-coupled chemokine receptor homologue.

  8. Directional specificity and encoding of muscle forces and loads by stick insect tibial campaniform sensilla, including receptors with round cuticular caps.

    Science.gov (United States)

    Zill, Sasha N; Chaudhry, Sumaiya; Büschges, Ansgar; Schmitz, Josef

    2013-11-01

    In many systems, loads are detected as the resistance to muscle contractions. We studied responses to loads and muscle forces in stick insect tibial campaniform sensilla, including a subgroup of receptors (Group 6B) with unusual round cuticular caps in oval-shaped collars. Loads were applied in different directions and muscle contractions were emulated by applying forces to the tibial flexor muscle tendon (apodeme). All sensilla 1) were maximally sensitive to loads applied in the plane of joint movement and 2) encoded muscle forces but did not discharge to unresisted movements. Identification of 6B sensilla by stimulation of cuticular caps demonstrated that receptor responses were correlated with their morphology. Sensilla with small cuticular collars produced small extracellular potentials, had low thresholds and strong tonic sensitivities that saturated at moderate levels. These receptors could effectively signal sustained loads. The largest spikes, derived from sensilla with large cuticular collars, had strong dynamic sensitivities and signaled a wide range of muscle forces and loads. Tibial sensilla are apparently tuned to produce no responses to inertial forces, as occur in the swing phase of walking. This conclusion is supported by tests in which animals 'stepped' on a compliant surface and sensory discharges only occurred in stance. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase

    Energy Technology Data Exchange (ETDEWEB)

    O' Bryan, J.P.; Frye, R.A.; Cogswell, P.C.; Neubauer, A.; Kitch, B.; Prokop, C.; Earp, H.S.; Liu, E.T. (Univ. of North Carolina, Chapel Hill (United States)); Espinosa, R. III; Le Beau, M.M. (Univ. of Chicago, IL (United States))

    1991-10-01

    Using a sensitive transfection-tumorigenicity assay, the authors have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antophosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type II and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.

  10. Interleukin-1 beta converting enzyme requires oligomerization for activity of processed forms in vivo.

    Science.gov (United States)

    Gu, Y; Wu, J; Faucheu, C; Lalanne, J L; Diu, A; Livingston, D J; Su, M S

    1995-05-01

    Interleukin-1 beta converting enzyme (ICE) is composed of 10' (p10) and 20 kDa (p20) subunits, which are derived from a common 45 kDa precursor. Recent crystallographic studies have shown that ICE exists as a tetramer (p20/p10)2 in the crystal lattice. We provide evidence that the p10 and p20 subunits of ICE associate as oligomers in transfected COS cells. Using intragenic complementation, we show that the activity of a p10/p10 interface mutant defective in autoprocessing can be restored by co-expression with active site ICE mutants. Different active site mutants can also complement each other by oligomerization to form active ICE. These studies indicate that ICE precursor polypeptides may associate in different quaternary structures and that oligomerization is required for autoprocessing. Furthermore, integenic complementation of active site mutants of ICE and an ICE homolog restores autoprocessing activity, suggesting that hetero-oligomerization occurs between ICE homologs.

  11. A critical role for interleukin-1β in the progression of autoimmune diseases.

    Science.gov (United States)

    Zhao, Ruijuan; Zhou, Hongyan; Su, Shao Bo

    2013-11-01

    Interleukin-1β (IL-1β) belongs to IL-1 family and is a potent pro-inflammatory cytokine. It is known to be also involved in a variety of cellular activities, including cell proliferation, differentiation and apoptosis. In addition to its pathophysiologic role in host protection, IL-1β promotes the progression of a number of autoimmune diseases. Most of such diseases can be controlled by anti-IL-1β treatment. This review discusses the contribution of IL-1β to the course of autoimmune diseases, such as rheumatic diseases, uveitis, autoimmune thyroid diseases (AITD), insulin-dependent diabetes mellitus (IDDM), autoimmune inner ear disease (AIED), multiple sclerosis (MS), myocarditis, hepatitis and kidney diseases. The critical involvement of IL-1β in the pathogenesis of autoimmune diseases provides targets for developing therapeutic treatment. © 2013. Published by Elsevier B.V. All rights reserved.

  12. The Therapeutic Role of Interleukin-1 Inhibition in Idiopathic Recurrent Pericarditis: Current Evidence and Future Challenges

    Science.gov (United States)

    Lazaros, George; Antonatou, Katerina; Vassilopoulos, Dimitrios

    2017-01-01

    Recurrent pericarditis is a common complication of acute pericarditis (15–30%) for which, in most cases, no underlying etiology is found [idiopathic recurrent pericarditis (IRP)]. IRP is currently viewed as an autoinflammatory disease with characteristic recurrent episodes of sterile inflammation. According to the most recent Guidelines, the initial treatment regimen consists of a combination of aspirin or non-steroidal anti-inflammatory drugs with colchicine followed by the addition of corticosteroids in resistant or intolerant cases. Despite this treatment approach, a number of patients either do not respond or cannot tolerate the above therapies. For this refractory group, small case series and a recent randomized controlled trial have shown that interleukin-1 inhibition with anakinra is a rapidly acting, highly efficient, steroid-sparing, and safe therapeutic intervention. In this perspective, we discuss the available clinical evidence and our own clinical experience as well as the future prospects of this novel therapeutic approach for patients with IRP. PMID:28660191

  13. Ovarian Epithelial-Stromal Interactions: Role of Interleukins 1 and 6

    Directory of Open Access Journals (Sweden)

    Kamisha T. Woolery

    2011-01-01

    Full Text Available Ovarian epithelial cancer is the most lethal gynecologic malignancy. The high mortality is attributed to the fact that most cases typically present in late stage when ovarian cancer (OC has already spread beyond the ovary. Ovarian epithelial cancer cells are shed into intraperitoneal ascites and easily disseminate throughout the peritoneal cavity with preferential metastasis to the omentum, peritoneum, and local organs. Understanding how ovarian epithelial cells interact with and modulate their microenvironment can provide insight into the molecular mechanism(s involved with malignant transformation and progression which may eventually identify novel diagnostic, prognostic, and therapeutic targets. The objective of this paper is to provide a brief consideration of ovarian surface epithelial-stromal interactions in regard to normal physiological function and tumor progression as influenced by two potentially key interleukins, interleukins-1 (IL-1 and -6 (IL-6, present in the microenvironment. Lastly, we will consider the clinical implications of IL-1 and IL-6 for OC patients.

  14. Involvement of Cyclic AMP Receptor Protein in Regulation of the rmf Gene Encoding the Ribosome Modulation Factor in Escherichia coli

    OpenAIRE

    Shimada, Tomohiro; Yoshida, Hideji; Ishihama, Akira

    2013-01-01

    The decrease in overall translation in stationary-phase Escherichia coli is accompanied with the formation of functionally inactive 100S ribosomes mediated by the ribosome modulation factor (RMF). At present, however, little is known regarding the regulation of stationary-phase-coupled RMF expression. In the course of a systematic screening of regulation targets of DNA-binding transcription factors from E. coli, we realized that CRP (cyclic AMP [cAMP] receptor protein), the global regulator f...

  15. Interleukin 1-beta analysis in chronically inflamed and healthy human dental pulp

    Directory of Open Access Journals (Sweden)

    Šubarić Ljiljana

    2017-01-01

    Full Text Available Background/Aim. Proinflammatory cytokines can act like endogenous pyrogen interleukin 1 (IL-1, interleukin 6 (IL-6 and tumour necrosis factor alpha (TNF α which regulate the synthesis of secondary mediators and other proinflammatory cytokines through macrophages and mesenchymal cells. They stimulate acute-phase proteins and attract inflammatory cells. The aim of this study was to determine interleukin 1-β (IL-1 β concentrations in chronically inflamed and healthy dental pulps. Methods. A total of 41 pulps (19 from patients with pulpitis chronic causa and 22 from patients with pulpatis chronic aperta, divided into two groups, were obtained from teeth with chronic pulp inflammation. The control group consisted of 12 teeth with healthy pulp. After extirpation, pulp samples were immediately placed in sterile Eppendorf tubes and frozen. After that, homogenisation was performed by a Teflon® pestle in ice-cold phosphate buffer solution at pH 7.4 whose volume was adjusted according to the weight of tissue. The supernatant was then frozen at -70°C until the performance of appropriate biochemical analyses. Cytokine IL-1 β value was determined by a commercial enzyme- linked immunosorbent assay (ELISA test. We applied the high sensitivity system technique, which may register low levels of cytokines, ranging from 0.125 to 8.0 pg/mL for IL-1 β. Results. By comparing the mean value of IL-1β, in the pulps we can see a statistically significant difference (p < 0.01 among them. The highest value of IL-1 β was in the subjects with pulpitis chronica clausa and it was 6.21 ± 2.70 pg/mL. Conclusion. Proinflammatory cytokine IL-1 β is present in detectable quantities in the pulp tissue of all vital pulps. Its highest concentrations were found in the sample group with pulpitis chronica clausa.

  16. A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB and neuropeptide receptors NPY1R, NPY5R

    Directory of Open Access Journals (Sweden)

    Steinberg-Epstein Robin

    2004-04-01

    Full Text Available Abstract Background Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes. Case presentation We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33. Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R. Conclusions The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate

  17. Interleukin-1 and TRAF6-dependent activation of TAK1 in the absence of TAB2 and TAB3.

    Science.gov (United States)

    Zhang, Jiazhen; Macartney, Thomas; Peggie, Mark; Cohen, Philip

    2017-06-26

    Interleukin-1 (IL-1) signaling induces the formation of Lys63-linked ubiquitin (K63-Ub) chains, which are thought to activate the 'master' protein kinase TGFβ-activated kinase 1 (TAK1) by interacting with its TAK1-binding 2 (TAB2) and TAB3 subunits. Here, we report that IL-1β can also activate the TAB1-TAK1 heterodimer present in TAB2/TAB3 double knockout (DKO) IL-1 receptor-expressing cells. The IL-1β-dependent activation of the TAB1-TAK1 heterodimer in TAB2/3 DKO cells is required for the expression and E3 ligase activity of tumor necrosis factor receptor-associated factor 6 (TRAF6) and is reduced by the small interfering RNA (siRNA) knockdown of ubiquitin conjugating 13 (Ubc13), an E2-conjugating enzyme that directs the formation of K63-Ub chains. IL-1β signaling was restored to TAB1/2/3 triple KO cells by the re-expression of either TAB1 or TAB2, but not by an ubiquitin binding-defective mutant of TAB2. We conclude that IL-1β can induce the activation of TAK1 in two ways, only one of which requires the binding of K63-Ub chains to TAB2/3. The early IL-1β-stimulated, TAK1-dependent activation of p38α mitogen-activated protein (MAP) kinase and the canonical IκB kinase (IKK) complex, as well as the NF-κB-dependent transcription of immediate early genes, was similar in TAB2/3 DKO cells and TAB2/3-expressing cells. However, in contrast with TAB2/3-expressing cells, IL-1β signaling was transient in TAB2/3 DKO cells, and the activation of c-Jun N-terminal kinase 1 (JNK1), JNK2 and p38γ was greatly reduced at all times. These observations indicate a role for TAB2/3 in directing the TAK1-dependent activation of MAP kinase kinases that switch on JNK1/2 and p38γ MAP kinases. These observations and the transient activation of the TAB1-TAK1 heterodimer may explain why IL-1β-dependent IL-8 mRNA formation was abolished in TAB2/3 DKO cells. © 2017 The Author(s).

  18. Phospholipase C-{delta}{sub 1} regulates interleukin-1{beta} and tumor necrosis factor-{alpha} mRNA expression

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Eric; Jakinovich, Paul; Bae, Aekyung [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States); Rebecchi, Mario, E-mail: Mario.rebecchi@SBUmed.org [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States)

    2012-10-01

    Phospholipase C-{delta}{sub 1} (PLC{delta}{sub 1}) is a widely expressed highly active PLC isoform, modulated by Ca{sup 2+} that appears to operate downstream from receptor signaling and has been linked to regulation of cytokine production. Here we investigated whether PLC{delta}{sub 1} modulated expression of the pro-inflammatory cytokines interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) in rat C6 glioma cells. Expression of PLC{delta}{sub 1} was specifically suppressed by small interfering RNA (siRNA) and the effects on cytokine mRNA expression, stimulated by the Toll-like receptor (TLR) agonist, lipopolysaccharide (LPS), were examined. Real-time polymerase chain reaction (RT-PCR) results showed that PLC{delta}{sub 1} knockdown enhanced expression IL-1{beta} and tumor necrosis factor-{alpha} (TNF-{alpha}) mRNA by at least 100 fold after 4 h of LPS stimulation compared to control siRNA treatment. PLC{delta}{sub 1} knock down caused persistently high Nf{kappa}b levels at 4 h of LPS stimulation compared to control siRNA-treated cells. PLC{delta}{sub 1} knockdown was also associated with elevated nuclear levels of c-Jun after 30 min of LPS stimulation, but did not affect LPS-stimulated p38 or p42/44 MAPK phosphorylation, normally associated with TLR activation of cytokine gene expression; rather, enhanced protein kinase C (PKC) phosphorylation of cellular proteins was observed in the absence of LPS stimulation. An inhibitor of PKC, bisindolylmaleimide II (BIM), reversed phosphorylation, prevented elevation of nuclear c-Jun levels, and inhibited LPS-induced increases of IL-1{beta} and TNF-{alpha} mRNA's induced by PLC{delta}{sub 1} knockdown. Our results show that loss of PLC{delta}{sub 1} enhances PKC/c-Jun signaling and up-modulates pro-inflammatory cytokine gene transcription in concert with the TLR-stimulated p38MAPK/Nf{kappa}b pathway. Our findings are consistent with the idea that PLC{delta}{sub 1} is a

  19. Interleukin 1 beta induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases

    DEFF Research Database (Denmark)

    Reimers, J I; Bjerre, U; Mandrup-Poulsen, T

    1994-01-01

    Substantial in vitro evidence suggests that nitric oxide may be a major mediator of interleukin 1 (IL-1) induced pancreatic beta-cell inhibition and destruction in the initial events leading to insulin-dependent diabetes mellitus. Using NG-nitro-L-arginine methyl ester, an inhibitor of both......, glucagon, corticosterone and leukocyte- and differential-counts in normal rats injected once daily for 5 days with interleukin 1 beta (IL-1 beta) (0.8 microgram/rat = 4.0 micrograms/kg). Inhibition of both the constitutive and the inducible forms of nitric oxide synthase prevented IL-1 beta-induced fever...

  20. The role of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide and interleukin-1 stimulated enterocyte prostanoid formation

    Directory of Open Access Journals (Sweden)

    W. E. Longo

    1998-01-01

    Full Text Available Lipopolysaccharide is an inflammatory agent and interleukin-1 is a cytokine. Their pro-inflammatory effects may be mediated by prostanoids produced by inducible cyclooxygenase-2. The aim of this study was to determine the prostanoids produced by lipopolysaccharide and interleukin-1 stimulated enterocytes through the cyclooxygenase-1 and 2 pathways. Cultured enterocytes were stimulated with lipopolysaccharide or interleukin-1 β with and without cyclooxygenase inhibitors. Low concentrations of indomethacin and valerylsalicylic acid (VSA were evaluated as cyclooxygenase-1 inhibitors and their effects compared with the effects of a specific cyclooxygenase-2 inhibitor, SC-58125. Prostaglandin E2 , 6-keto prostaglandin F1α , prostaglandin D2 and leukotriene B4 levels were determined by radio immunoassay. Immunoblot analysis using isoformspecific antibodies showed that the inducible cyclooxygenase enzyme (COX-2 was expressed by 4 h in LPS and IL-1β treated cells while the constitutive COX-1 remained unaltered in its expression. Interleukin-1β and lipopolysaccharide stimulated the formation of all prostanoids compared with untreated cells, but failed to stimulate leukotriene B4. Indomethacin at 20 μ M concentration, and VSA inhibited lipopolysaccharide and interleukin 1β stimulated prostaglandin E2 , but not 6-keto prostaglandin F1α formation. SC-58125 inhibited lipopolysaccharide and interleukin-1β stimulated 6-keto prostaglandin F1α but not prostaglandin E2 release. The specific cyclooxygenase-2 inhibitor also inhibited lipopolysaccharide produced prostaglandin D2 but not interleukin-1β stimulated prostaglandin D2 While SC-58125 inhibited basal 6-keto prostaglandin-F1α formation it significantly increased basal prostaglandin E2 and prostaglandin D2 formation. As SC-58125 inhibited lipopolysaccharide and interleukin-1β induced 6-keto prostaglandin F1α production but not prostaglandin E2 production, it suggests that these agents stimulate

  1. A first genotyping assay of French cattle breeds based on a new allele of the extension gene encoding the melanocortin-1 receptor (Mc1r

    Directory of Open Access Journals (Sweden)

    Julien Raymond

    2000-09-01

    Full Text Available Abstract The seven transmembrane domain melanocortin-1 receptor (Mc1r encoded by the coat color extension gene (E plays a key role in the signaling pathway of melanin synthesis. Upon the binding of agonist (melanocortin hormone, α-MSH or antagonist (Agouti protein ligands, the melanosomal synthesis of eumelanin and/or phaeomelanin pigments is stimulated or inhibited, respectively. Different alleles of the extension gene were cloned from unrelated animals belonging to French cattle breeds and sequenced. The wild type E allele was mainly present in Normande cattle, the dominant ED allele in animals with black color (i.e. Holstein, whereas the recessive e allele was identified in homozygous animals exhibiting a more or less strong red coat color (Blonde d'Aquitaine, Charolaise, Limousine and Salers. A new allele, named E1, was found in either homozygous (E1/E1 or heterozygous (E1/E individuals in Aubrac and Gasconne breeds. This allele displayed a 4 amino acid duplication (12 nucleotides located within the third cytoplasmic loop of the receptor, a region known to interact with G proteins. A first genotyping assay of the main French cattle breeds is described based on these four extension alleles.

  2. Lymphatic Reprogramming by Kaposi Sarcoma Herpes Virus Promotes the Oncogenic Activity of the Virus-Encoded G-protein Coupled Receptor

    Science.gov (United States)

    Aguilar, Berenice; Choi, Inho; Choi, Dongwon; Chung, Hee Kyoung; Lee, Sunju; Yoo, Jaehyuk; Lee, Yong Suk; Maeng, Yong Sun; Lee, Ha Neul; Park, Eunkyung; Kim, Kyu Eui; Kim, Nam Yoon; Baik, Jae Myung; Jung, Jae U.; Koh, Chester J.; Hong, Young-Kwon

    2012-01-01

    Kaposi sarcoma (KS), the most common cancer in HIV-positive individuals, is caused by endothelial transformation mediated by the KS herpes virus (KSHV)-encoded G-protein coupled receptor (vGPCR). Infection of blood vascular endothelial cells (BECs) by KSHV reactivates an otherwise silenced embryonic program of lymphatic differentiation. Thus, KS tumors express numerous lymphatic endothelial cell (LEC)-signature genes. A key unanswered question is how lymphatic reprogramming by the virus promotes tumorigenesis leading to KS formation. In this study, we present evidence that this process creates an environment needed to license the oncogenic activity of vGPCR. We found that the G-protein regulator RGS4 is an inhibitor of vGPCR that is expressed in BECs, but not in LECs. RGS4 was downregulated by the master regulator of LEC differentiation PROX1, which is upregulated by KSHV and directs KSHV-induced lymphatic reprogramming. Moreover, we found that KSHV upregulates the nuclear receptor LRH1, which physically interacts with PROX1 and synergizes with it to mediate repression of RGS4 expression. Mechanistic investigations revealed that RGS4 reduced vGPCR-enhanced cell proliferation, migration, VEGF expression and Akt activation and to suppress tumor formation induced by vGPCR. Our findings resolve long-standing questions about the pathological impact of KSHV-induced reprogramming of host cell identity, and they offer biological and mechanistic insights supporting the hypothesis that a lymphatic microenvironment is more favorable for KS tumorigenesis. PMID:22942256

  3. The human herpes virus 8-encoded chemokine receptor is required for angioproliferation in a murine model of Kaposi's sarcoma

    DEFF Research Database (Denmark)

    Jensen, Kristian K; Manfra, Denise J; Grisotto, Marcos G

    2005-01-01

    active G protein-coupled receptor known as vGPCR that binds CXC chemokines with high affinity. In this study, we show that conditional transgenic expression of vGPCR by cells of endothelial origin triggers an angiogenic program in vivo, leading to development of an angioproliferative disease...... that resembles KS. This angiogenic program consists partly in the expression of the angiogenic factors placental growth factor, platelet-derived growth factor B, and inducible NO synthase by the vGPCR-expressing cells. Finally, we show that continued vGPCR expression is essential for progression of the KS......-like phenotype and that down-regulation of vGPCR expression results in reduced expression of angiogenic factors and regression of the lesions. Together, these findings implicate vGPCR as a key element in KS pathogenesis and suggest that strategies to block its function may represent a novel approach...

  4. Polymorphisms in the gene encoding bovine interleukin-10 receptor alpha are associated with Mycobacterium avium ssp. paratuberculosis infection status

    Directory of Open Access Journals (Sweden)

    Kelton David F

    2010-04-01

    Full Text Available Abstract Background Johne's disease is a chronic inflammatory bowel disease (IBD of ruminants caused by Mycobacterium avium ssp. paratuberculosis (MAP. Since this pathogen has been implicated in the pathogenesis of human IBDs, the goal of this study was to assess whether single nucleotide polymorphism (SNPs in several well-known candidate genes for human IBD are associated with susceptibility to MAP infection in dairy cattle. Methods The bovine candidate genes, interleukin-10 (IL10, IL10 receptor alpha/beta (IL10RA/B, transforming growth factor beta 1 (TGFB1, TGFB receptor class I/II (TGFBR1/2, and natural resistance-associated macrophage protein 1 (SLC11A1 were sequenced for SNP discovery using pooled DNA samples, and the identified SNPs were genotyped in a case-control association study comprised of 242 MAP negative and 204 MAP positive Holstein dairy cattle. Logistic regression was used to determine the association of SNPs and reconstructed haplotypes with MAP infection status. Results A total of 13 SNPs were identified. Four SNPs in IL10RA (984G > A, 1098C > T, 1269T > C, and 1302A > G were tightly linked, and showed a strong additive and dominance relationship with MAP infection status. Haplotypes AGC and AAT, containing the SNPs IL10RA 633C > A, 984G > A and 1185C > T, were associated with an elevated and reduced likelihood of positive diagnosis by serum ELISA, respectively. Conclusions SNPs in IL10RA are associated with MAP infection status in dairy cattle. The functional significance of these SNPs warrants further investigation.

  5. NLRP3 inflammasome mediates interleukin-1β production in immune cells in response to Acinetobacter baumannii and contributes to pulmonary inflammation in mice.

    Science.gov (United States)

    Kang, Min-Jung; Jo, Sung-Gang; Kim, Dong-Jae; Park, Jong-Hwan

    2017-04-01

    Acinetobacter baumannii is a multi-drug resistant, Gram-negative bacteria and infection with this organism is one of the major causes of mortality in intensive care units. Inflammasomes are multiprotein oligomers that include caspase-1, and their activation is required for maturation of interleukin-1β (IL-1β). Inflammasome signalling is involved in host defences against various microbial infections, but the precise mechanism by which A. baumannii activates inflammasomes and the roles of relevant signals in host defence against pulmonary A. baumannii infection are unknown. Our results showed that NLRP3, ASC and caspase-1, but not NLRC4, are required for A. baumannii-induced production of IL-1β in macrophages. An inhibitor assay revealed that various pathways, including P2X7R, K + efflux, reactive oxygen species production and release of cathepsins, are involved in IL-1β production in macrophages in response to A. baumannii. Interleukin-1β production in bronchoalveolar lavage (BAL) fluid was impaired in NLRP3-deficient and caspase-1/11-deficient mice infected with A. baumannii, compared with that in wild-type (WT) mice. However, the bacterial loads in BAL fluid and lungs were comparable between WT and NLRP3-deficient or caspase-1/11-deficient mice. The severity of lung pathology was reduced in NLRP3- deficient, caspase-1/11- deficient and IL-1-receptor-deficient mice, although the recruitment of immune cells and production of inflammatory cytokines and chemokines were not altered in these mice. These findings indicate that A. baumannii leads to the activation of NLRP3 inflammasome, which mediates IL-1β production and lung pathology. © 2016 John Wiley & Sons Ltd.

  6. Calcium-dependent, interleukin 1-converting enzyme inhibitor-insensitive degradation of lamin B1 and DNA fragmentation in isolated thymocyte nuclei.

    Science.gov (United States)

    McConkey, D J

    1996-09-13

    Recent work suggests that the proteolytic degradation of the nuclear lamins is a common event in apoptosis, although the nature of the proteases involved is still not clear. Our previous work showed that the degradation of lamin B1 in glucocorticoid-treated thymocytes occurs via a Ca2+-sensitive mechanism and that exogenous Ca2+ promotes lamin degradation in isolated thymocyte nuclei from untreated cells. Here we demonstrate that peptide-based inhibitors of the interleukin 1beta-converting enzyme family of cysteine proteases (Tyr-Val-Ala-Asp fluoromethyl ketone) and of the nuclear scaffold multicatalytic proteinase (Ala-Pro-Phe chloromethyl ketone) block the degradation of lamin B1 to a 21-kDa fragment in thymocytes treated with glucocorticoid, the Ca2+-mobilizing agent thapsigargin, or antibodies to the T cell receptor. However, among a panel of inhibitors specific for several different proteases implicated in apoptosis, only tosylphenylalanyl chloromethyl ketone and the nuclear scaffold protease inhibitor block lamin degradation, histone H1 cleavage, and DNA fragmentation in isolated thymocyte nuclei incubated with Ca2+. Overexpression of human BCL-2 in nuclei by stable transfection resulted in an inhibition of Ca2+-stimulated lamin degradation and DNA fragmentation, suggesting that endogenous nuclear BCL-2 regulates activation of the nuclear scaffold protease. The results demonstrate the existence of an alternative pathway of lamin degradation and DNA fragmentation mediated by a resident Ca2+-stimulated nuclear protease that is not directly dependent upon activation of the interleukin 1beta-converting enzyme family of cell death regulators.

  7. Different effects of continuous infusion of interleukin-1 and interleukin-6 on the hypothalamic-hypophysial-thyroid axis

    NARCIS (Netherlands)

    G.A.C. van Haasteren (Goedele); M.J. van der Meer; A.R.M.M. Hermus (Ad); E. Linkels; W. Klootwijk (Willem); E. Kaptein (Ellen); H. van Toor (Hans); C.G. Sweep; T.J. Visser (Theo); W.J. de Greef

    1994-01-01

    textabstractThe cytokines interleukin-1 (IL-1) and IL-6 are thought to be important mediators in the suppression of thyroid function during nonthyroidal illness. In this study we compared the effects of IL-1 and IL-6 infusion on the hypothalamus-pituitary-thyroid

  8. Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome

    NARCIS (Netherlands)

    Frenkel, Joost; Rijkers, Ger T.; Mandey, Saskia H. L.; Buurman, Sandra W. M.; Houten, Sander M.; Wanders, Ronald J. A.; Waterham, Hans R.; Kuis, Wietse

    2002-01-01

    OBJECTIVE: To investigate whether the increased interleukin-1beta (IL-1beta) secretion in hyperimmunoglobulinemia D and periodic fever syndrome is due to the accumulation of mevalonate kinase (MK), the substrate of the deficient enzyme, or the lack of its products, the isoprenoid compounds. METHODS:

  9. Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans

    DEFF Research Database (Denmark)

    Spinas, G A; Hansen, B S; Linde, S

    1987-01-01

    Human crude and recombinant interleukin 1 (IL-1) was found to dose- and time-dependently affect the biosynthesis of (pro)insulin in isolated rat islets of Langerhans. Incubation of rat islets with either 0.5 U/ml or 5 U/ml of crude IL-1 for 1 h had no detectable effect on (pro)insulin biosynthesis...

  10. Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis.

    NARCIS (Netherlands)

    Rudolphi, K.; Gerwin, N.; Verzijl, N.; Kraan, P.M. van der; Berg, W.B. van den

    2003-01-01

    OBJECTIVE: To study the effect of pralnacasan, the orally bioavailable pro-drug of a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE), RU 36384/VRT-18858, on joint damage in two mouse models of knee osteoarthritis (OA). DESIGN: In a collagenase-induced OA model, pralnacasan

  11. Involvement of cyclic AMP receptor protein in regulation of the rmf gene encoding the ribosome modulation factor in Escherichia coli.

    Science.gov (United States)

    Shimada, Tomohiro; Yoshida, Hideji; Ishihama, Akira

    2013-05-01

    The decrease in overall translation in stationary-phase Escherichia coli is accompanied with the formation of functionally inactive 100S ribosomes mediated by the ribosome modulation factor (RMF). At present, however, little is known regarding the regulation of stationary-phase-coupled RMF expression. In the course of a systematic screening of regulation targets of DNA-binding transcription factors from E. coli, we realized that CRP (cyclic AMP [cAMP] receptor protein), the global regulator for carbon source utilization, participates in regulation of some ribosomal protein genes, including the rmf gene. In this study, we carried out detailed analysis of the regulation of the RMF gene by cAMP-CRP. The cAMP-dependent binding of CRP to the rmf gene promoter was confirmed by gel shift and DNase I footprinting assays. By using a reporter assay system, the expression level of RMF was found to decrease in the crp knockout mutant, indicating the involvement of CRP as an activator of the rmf promoter. In good agreement with the reduction of rmf promoter activity, we observed decreases in RMF production and 100S ribosome dimerization in the absence of CRP. Taken together, we propose that CRP regulates transcription activation of the rmf gene for formation of 100S ribosome dimers. Physiological roles of CRP involvement in RMF production are discussed.

  12. Prenatal expression of interleukin 1beta and interleukin 6 in the rat pituitary gland.

    Science.gov (United States)

    Moro, J A; Carretero, J; Alonso, M I; Martín, C; Gato, A; Mano, A de la

    2008-12-01

    It is known that interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) are expressed post-natally in normal and tumoral cells in the anterior pituitary, and that they play a role in both the liberation of different hormones and in the growth, proliferation and tumor formation of the pituitary gland. However, their expression and role during embryonic and fetal development remain unknown. We have performed an immunocytochemistry study of prenatal expression and distribution of IL-1beta and IL-6 in isolated embryonic rat Rathke's pouch prior to birth, more specifically between 13.5 and 19.5 days p.c. Western-blot analysis carried out on 19.5-day p.c. embryos showed positive immunolabelling for IL-1beta and IL-6. These interleukins were initially expressed simultaneously in the rostral and ventral portions of Rathke's pouch in 15.5-day p.c. embryos, and this expression progressed caudodorsally in later developmental stages, extending to most of the hypophysis before birth. The number of cells expressing these interleukins increased throughout this period: 48.22% of anterior pituitary cells expressed IL-6 in 19.5-day embryos, whilst IL-1beta was positive in 39.8% of the cells. Moreover, we have demonstrated that some adenohypophyseal cells co-express both interleukins. Such findings represent the first step towards an understanding of the physiological role of these interleukins in anterior pituitary development.

  13. Whole-body irradiation transiently diminishes the adrenocorticotropin response to recombinant human interleukin-1{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Perlstein, R.S.; Mehta, N.R.; Neta, R.; Whitnall, M.H. [Armed Forces Radiobiology Research Institute, Bethesda, MD (United States); Mougey, E.H. [Walter Reed Army Institute of Research, Washington, DC (United States)

    1995-03-01

    Recombinant human interleukin-1{alpha} (rhIL-1{alpha}) has significant potential as a radioprotector and/or treatment for radiation-induced hematopoietic injury. Both IL-1 and whole-body ionizing irradiation acutely stimulate the hypothalamic-pituitary-adrenal axis. We therefore assessed the interaction of whole-body irradiation and rhIL-1{alpha} in altering the functioning of the axis in mice. Specifically, we determined the adrenocorticotropin (ACTH) and corticosterone responses to rhIL-1{alpha} administered just before and hours to days after whole-body or sham irradiation. Our results indicate that whole-body irradiation does not potentiate the rhIL-1{alpha}-induced increase in ACTH levels at the doses used. In fact, the rhIL-1{alpha}-induced increase in plasma ACTH is transiently impaired when the cytokine is administered 5 h after, but not 1 h before, exposure to whole-body irradiation. The ACTH response may be inhibited by elevated corticosterone levels after whole-body irradiation, or by other radiation-induced effects on the pituitary gland and hypothalamus. 36 refs., 3 figs.

  14. Association of interleukin-1beta polymorphism with recurrent aphthous stomatitis in Brazilian individuals.

    Science.gov (United States)

    Guimarães, A L S; de Sá, A R; Victória, J M N; Correia-Silva, J F; Pessoa, P S; Diniz, M G; Gomez, R S

    2006-11-01

    Recurrent aphthous stomatitis (RAS) is characterized by recurrent episodes of oral ulceration in an otherwise healthy individual. Some reports in the literature indicate that RAS may have immunological, psychological, genetic and microbiological bases. The purpose of the present study was to investigate the possible association between interleukin-1beta (IL-1beta) +3954 (C/T) genetic polymorphism and RAS in a sample of Brazilian patients. Sixty-two consecutive subjects affected by minor and major forms of RAS and 62 healthy volunteers were genotyped at IL-1beta (+3954). The chi-squared test was used for statistical analysis. A significant increase in the high production of IL-1beta genotype CT was observed in the group with RAS (P = 0.01). After stratifying RAS patients according to the mean number of lesions per episode, a significant difference was only observed between patients with >or=3 lesions in each episode and control. There is an increased frequency of polymorphism associated with high IL-1beta production in RAS patients.

  15. Unusual interleukin-1 and -6 expression in fetal cartilage is associated with placental abnormalities.

    Directory of Open Access Journals (Sweden)

    Robert Klepacz

    2010-06-01

    Full Text Available Unusual expression of interleukin-1alpha, -1beta and -6 was previously found in the epiphyseal cartilage of rat fetuses prenatally exposed to various non-steroidal anti-inflammatory drugs (NSAID, i.e., ibuprofen, piroxicam, tolmetin and selective cyclooxygenase-2 inhibitor (DFU. The aim of the present study was to evaluate the role of placenta in such phenomenon. Morphology of the organ, thickness of basal and labyrinth layer, immunoexpression of COX isoenzymes were examined, and confronted with maternal biochemical data and fetal developmental parameters. Higher maternal urea level, as well as lower placental weight and labyrinth thickness were found in the group of fetuses who revealed expression of genes coded the selected interleukins, when compared with the xenobiotic-exposed pups without the selected genes expression and untreated control. A significant correlation between placental weight and maternal total protein or urea level was revealed. Histological changes like inflammatory infiltration and calcification were observed sporadically. Location and intensity of COX-1 staining was similar in all cases. However, more intense COX-2 staining for majority of cells of the basal zone and in dispersed giant cells of the labyrinth was found in inflamed organs. It could be concluded that abnormal expression of the selected interleukins is associated with low placental weight and decrease of its thickness, especially labyrinth zone, as well as with high maternal urea level.

  16. Carboxymethyl-chitosan protects rabbit chondrocytes from interleukin-1beta-induced apoptosis.

    Science.gov (United States)

    Chen, Qing; Liu, Shi-Qing; Du, Yu-Ming; Peng, Hao; Sun, Li-Ping

    2006-07-10

    Chondrocyte apoptosis is important in pathogenesis of osteoarthritis. Chitosan is a non-toxic, biodegradable and biocompatible glycosaminoglycan. In this study, the effects of carboxymethyl-chitosan (CM-chitosan), a soluble derivative of chitosan, on chondrocyte apoptosis were investigated. Primary rabbit chondrocytes were cultured and induced to apoptosis by 10 ng/ml interleukin-1beta (IL-1beta). After treatment with various concentrations of CM-chitosan (50, 100, 200 microg/ml), the apoptotic rate, mitochondrial function, nitric oxide production, and the levels of inducible nitric oxide synthase (iNOS) mRNA and reactive oxygen species in IL-1beta-induced chondrocytes were examined. The results showed that CM-chitosan could inhibit chondrocyte apoptosis in a dose-dependent manner. Furthermore, it could partly restore the levels of mitochondrial membrane potential and ATP, decrease nitric oxide production by down-regulation of iNOS mRNA expression, and scavenge reactive oxygen species in chondrocytes induced by IL-1beta. The results suggested that the inhibitory effects of CM-chitosan on IL-1beta-induced chondrocyte apoptosis were possibly due to the protection of mitochondrial function, the decline in the levels of nitric oxide and reactive oxygen species.

  17. Interleukin-1beta and serotonin transporter gene polymorphisms in burning mouth syndrome patients.

    Science.gov (United States)

    Guimarães, André Luiz Sena; de Sá, Alessandra Rosa; Victoria, Júnia Maria Netto; de Fátima Correia-Silva, Jeane; Gomez, Marcus Vinícius; Gomez, Ricardo Santiago

    2006-09-01

    Burning mouth syndrome (BMS) is a chronic pain syndrome that encompasses all forms of burning sensations in the oral cavity when the oral mucosa is clinically normal. Neural, psychologic, and cytokine factors may be implicated in the pathogenesis of BMS. There are no studies of genetic factors associated with psychologic behavior and cytokine pain sensitivity in BMS patients. The purpose of the present study was to investigate a possible association between functional genetic polymorphisms, +3,954 (C/T) interleukin-1beta, and the polymorphic site on promoter region of the serotonin transporter gene (5-HTTLPR) in a sample of Brazilian patients. Thirty patients affected by BMS and 31 healthy volunteers were genotyped for 5-HTTLPR and IL-1beta gene. The chi-squared test was used for statistical analysis. There was no statistical difference in 5-HTTLPR genotypes between the case and control groups (P = .60), however a significant increase was observed in the IL-1beta high production genotype CT in BMS subjects (P = .005). In conclusion, the present study shows association between BMS and IL-1beta high producer genotype. This article shows evidence that genetic polymorphisms associated with IL-1beta high production genotype are implicated on the pathogenesis of BMS. The modulation of IL1beta production may be an interesting tool in BMS management.

  18. The pharmacokinetics, distribution and degradation of human recombinant interleukin 1 beta in normal rats

    DEFF Research Database (Denmark)

    Wogensen, L D; Welinder, B; Hejnaes, K R

    1991-01-01

    -lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from...... the circulation with a T1/2 alpha of 2.9 min and a T1/2 beta of 41.1 min. The central and peripheral volume of distribution was 20.7 and 19.1 ml/rat, respectively, and the metabolic clearance rate was 16.9 ml/min/kg. The kidney and liver showed the highest accumulation of tracer, and autoradiography demonstrated...... that 125I-rIL-1 beta was localized to the proximal tubules in the kidney and to the hepatocytes in the liver. Furthermore, grains were localized to the islets of Langerhans in the pancreas. Tracer-bound proteins corresponding to intact 125I-rIL-1 beta were found in the circulation after i...

  19. Macrophage recruitment, but not interleukin 1 beta activation, enhances noise-induced hearing damage.

    Science.gov (United States)

    Mizushima, Yu; Fujimoto, Chisato; Kashio, Akinori; Kondo, Kenji; Yamasoba, Tatsuya

    2017-11-18

    It has been suggested that macrophages or inflammatory monocytes participate in the pathology of noise-induced hearing loss (NIHL), but it is unclear how extensively these cells contribute to the development of temporary and/or permanent NIHL. To address this question, we used clodronate liposomes to deplete macrophages and monocytes. After clodronate liposome injection, mice were exposed to 4-kHz octave band noise at 121 dB for 4 h. Compared to vehicle-injected controls, clodronate-treated mice exhibited significantly reduced permanent threshold shifts at 4 and 8 kHz and significantly smaller outer hair cell losses in the lower-apical cochlear turn. Following noise exposure, the stria vascularis had significantly more cells expressing the macrophage-specific protein F4/80, and this effect was significantly suppressed by clodronate treatment. These F4/80-positive cells expressed interleukin 1 beta (IL-1β), which noise exposure activated. However, IL-1β deficient mice did not exhibit significant resistance to intense noise when compared to wild-type mice. These findings suggest that macrophages that enter the cochlea after noise exposure are involved in NIHL, whereas IL-1β inhibition does not reverse this cochlear damage. Therefore, macrophages may be a promising therapeutic target in human sensorineural hearing losses such as NIHL. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Interleukin-1 hyperproduction by in vitro activated peripheral macrophages from cerebellar mutant mice.

    Science.gov (United States)

    Kopmels, B; Wollman, E E; Guastavino, J M; Delhaye-Bouchaud, N; Fradelizi, D; Mariani, J

    1990-12-01

    Several mutations in mice produce complex patterns of neuronal degeneration of the cerebellum and of its afferent pathways. In the staggerer (sg/sg) mutant, atrophy of the lymphoid organs and immunological abnormalities have been described. To search for a possible link between the neurological and the immune disorders in this mutant, we studied the production by its peripheral macrophages of interleukin-1 (IL-1), which roles in both immune and nervous systems are well established. Suspensions of peritoneal and/or spleen macrophages from mutants and their appropriate controls were stimulated in vitro by lipopolysaccharide. Northern and dot blots, performed with murine IL-1 cDNA probes, revealed a clear-cut hyperexpression of IL-1 mRNA in staggerer macrophages. An IL-1 bioassay using the IL-1-responsive D10.G4 cell line also revealed a sixfold increase of IL-1 activity in the macrophage supernatants of staggerer mutant mice. The hyperproduction was found in 3-week to 1-year-old staggerer and also in heterozygous (+/sg) mice. A similar phenomenon existed in cerebellar mutants lurcher, Purkinje cell degeneration (pcd), and to a lesser extent reeler and wobbler, but was absent in the neurological mutants weaver, jimpy, and motor end plate disease (medH). These observations establish that in several point mutations in mice, central nervous degeneration is associated with dysregulation of IL-1 production by peripheral macrophages.

  1. Functional imaging of interleukin 1 beta expression in inflammatory process using bioluminescence imaging in transgenic mice

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    Liu Zhihui

    2008-08-01

    Full Text Available Abstract Background Interleukin 1 beta (IL-1β plays an important role in a number of chronic and acute inflammatory diseases. To understand the role of IL-1β in disease processes and develop an in vivo screening system for anti-inflammatory drugs, a transgenic mouse line was generated which incorporated the transgene firefly luciferase gene driven by a 4.5-kb fragment of the human IL-1β gene promoter. Luciferase gene expression was monitored in live mice under anesthesia using bioluminescence imaging in a number of inflammatory disease models. Results In a LPS-induced sepsis model, dramatic increase in luciferase activity was observed in the mice. This transgene induction was time dependent and correlated with an increase of endogenous IL-1β mRNA and pro-IL-1β protein levels in the mice. In a zymosan-induced arthritis model and an oxazolone-induced skin hypersensitivity reaction model, luciferase expression was locally induced in the zymosan injected knee joint and in the ear with oxazolone application, respectively. Dexamethasone suppressed the expression of luciferase gene both in the acute sepsis model and in the acute arthritis model. Conclusion Our data suggest that the transgenic mice model could be used to study transcriptional regulation of the IL-1β gene expression in the inflammatory process and evaluation the effect of anti-inflammatory drug in vivo.

  2. CASE OF USING THE INHIBITOR OF INTERLEUKIN 1 CANACINUMAB IN PATIENTS WITH AUTO INFLAMMATORY DISEASES

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    S. O. Salugina

    2015-01-01

    Full Text Available Interleukin 1 (IL 1 is the main mediator for many auto inflammatory diseases (AID. Cryopyrin-associated periodic syndromes (CAPS became the first diseases, for which the efficacy of IL 1 inhibitors was shown with a high degree of evidence. Canacinumb (totally human monoclonal antibodies to IL 1 is registered in Russia since 2011 for treating CAPS. At the moment research is being conducted to evaluate the efficacy and tolerance to IL 1 inhibitors in patients with other AIDs. The accumulated experience and scarce randomizedcontrolled studies demonstrate a successful usage of IL 1 inhibitors in colchicine-resistant patients with family Mediterranean fever with the cupping of inflammation attacks, reducing the acute phase activity and also in patients with other monogenic (TRAPS, HIDS and others and multifactorial pathologies (systemic juvenile arthritis, Stilk disease in adults, gout etc.. Using the IL 1 inhibitors, especially canacinumab, in patients with different AIDs has shown good tolerance and a high efficacy in all patients with no correlation to the age, according to Russian and world research. Thus, canacinumab, thanks to its therapeutic abilities, has broad perspectives in terms of lightening the disease course, improving survival, life quality and the overall prognosis. 

  3. Influence of supragingival biofilm control and smoking habit on Interleukin-1β concentration

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    Sabrina Carvalho GOMES

    2015-01-01

    Full Text Available This investigation compared gingival crevicular fluid (GCF interleukin-1β (IL-1β concentrations in periodontitis patients subjected to a strict supragingival biofilm control (Supra for 6 months. Never-smokers (23 and smokers (n = 20; 19.6 ± 11.8 cigarettes/day moderate-to-severe chronic periodontitis patients underwent a 6 months period of supragingival control with weekly recall visits. Periodontal probing depth (PPD, bleeding on probing (BOP and GCF samples (from different PPD category sites: 3-5 mm and 6–10 mm were obtained at the baseline, 30, and 180 days. IL-1β was assessed by enzyme-linked immunosorbent assay. Generalized estimating equations were used to fit prediction models of IL-1β changes, considering the dependence between the examinations, and using only data from experimental sites. Overall IL-1β concentrations decreased from 3.2 pg/µL to 1.9 pg/µL. Higher baseline IL-1β concentrations were associated with higher baseline PPD values in both groups. There were no differences in IL-1β concentrations between never-smokers and smokers over time for any PPD category. Higher baseline PPD values and the presence of BOP on day 180 were significantly associated with higher IL-1β concentrations. A strict Supra regimen reduced IL-1β concentrations over time in periodontitis patients. The benefits observed for smokers underline the importance of oral hygiene measures, even considering the presence of this important risk factor.

  4. Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells

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    Wu, K.K.; Sanduja, R.; Tsai, A.L.; Ferhanoglu, B.; Loose-Mitchell, D.S. (Univ. of Texas Medical School, Houston (United States))

    1991-03-15

    Prostaglandin H (PGH) synthase is a key enzyme in the biosynthesis of prostaglandins, thromboxane, and prostacyclin. In cultured human umbilical vein endothelial cells, interleukin 1 (IL-1) is known to induce the synthesis of this enzyme, thereby raising the level of PGH synthase protein severalfold over the basal level. Pretreatment with aspirin at low concentrations inhibited more than 60% of the enzyme mass and also the cyclooxygenase activity in IL-1-induced cells with only minimal effects on the basal level of the synthase enzyme in cells without IL-1. Sodium salicylate exhibited a similar inhibitory action whereas indomethacin had no apparent effect. Similarly low levels of aspirin inhibited the increased L-({sup 35}S)methionine incorporation into PGH synthase that was induced by IL0-1 and also suppressed expression of the 2.7-kilobase PGH synthase mRNA. These results suggest that in cultured endothelial cells a potent inhibition of eicosanoid biosynthetic capacity can be effected by aspirin or salicylate at the level of PGH synthase gene expression. The aspirin effect may well be due to degradation of salicylate.

  5. The role of inflammation and interleukin-1 in acute cerebrovascular disease

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    Galea J

    2013-08-01

    Full Text Available James Galea,1 David Brough21Manchester Academic Health Sciences Center, Brain Injury Research Group, Clinical Sciences Building, Salford Royal Foundation Trust, Salford, UK; 2Faculty of Life Sciences, University of Manchester, AV Hill Building, Manchester, UKAbstract: Acute cerebrovascular disease can affect people at all stages of life, from neonates to the elderly, with devastating consequences. It is responsible for up to 10% of deaths worldwide, is a major cause of disability, and represents an area of real unmet clinical need. Acute cerebrovascular disease is multifactorial with many mechanisms contributing to a complex pathophysiology. One of the major processes worsening disease severity and outcome is inflammation. Pro-inflammatory cytokines of the interleukin (IL-1 family are now known to drive damaging inflammatory processes in the brain. The aim of this review is to discuss the recent literature describing the role of IL-1 in acute cerebrovascular disease and to provide an update on our current understanding of the mechanisms of IL-1 production. We also discuss the recent literature where the effects of IL-1 have been targeted in animal models, thus reviewing potential future strategies that may limit the devastating effects of acute cerebrovascular disease.Keywords: cerebral ischemia, stroke, inflammation, microglia, interleukin-1, caspase-1

  6. Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes.

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    Yue Wang

    Full Text Available The blood-brain barrier (BBB is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β, a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.

  7. Piperine Suppresses Pyroptosis and Interleukin-1β Release upon ATP Triggering and Bacterial Infection.

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    Liang, Yi-Dan; Bai, Wen-Jing; Li, Chen-Guang; Xu, Li-Hui; Wei, Hong-Xia; Pan, Hao; He, Xian-Hui; Ouyang, Dong-Yun

    2016-01-01

    Piperine is a phytochemical present in black pepper (Piper nigrum Linn) and other related herbs, possessing a wide array of pharmacological activities including anti-inflammatory effects. Previously, we demonstrated that piperine has therapeutic effects on bacterial sepsis in mice, but the underlying mechanism has not been fully elucidated. In this study, we aimed to investigate the influences of piperine on pyroptosis in murine macrophages. The results showed that piperine dose-dependently inhibited ATP-induced pyroptosis, thereby suppressing interleukin-1β (IL-1β) or high mobility group box-1 protein (HMGB1) release in LPS-primed bone marrow-derived macrophages and J774A.1 cells. Accompanying this, ATP-induced AMP-activated protein kinase (AMPK) activation was greatly suppressed by piperine, whereas AMPK agonist metformin counteracted piperine's inhibitory effects on pyroptosis. Moreover, piperine administration greatly reduced both peritoneal and serum IL-1β levels in the mouse model intraperitoneally infected with Escherichia coli, suggestive of suppressing systemic inflammation and pyroptosis. Our data indicated that piperine could protect macrophages from pyroptosis and reduced IL-1β and HMGB1 release by suppressing ATP-induced AMPK activation, suggesting that piperine may become a potential therapeutic agent against bacterial sepsis.

  8. Piperine suppresses pyroptosis and interleukin-1β release upon ATP triggering and bacterial infection

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    Yi-Dan Liang

    2016-10-01

    Full Text Available Piperine is a phytochemical present in black pepper (Piper nigrum Linn and other related herbs, possessing a wide array of pharmacological activities including anti-inflammatory effects. Previously, we demonstrated that piperine has therapeutic effects on bacterial sepsis in mice, but the underlying mechanism has not been fully elucidated. In this study, we aimed to investigate the influences of piperine on pyroptosis in murine macrophages. The results showed that piperine dose-dependently inhibited ATP-induced pyroptosis, thereby suppressing interleukin-1β (IL-1β or high mobility group box-1 protein (HMGB1 release in LPS-primed bone marrow-derived macrophages (BMDMs and J774A.1 cells. Accompanying this, ATP-induced AMP-activated protein kinase (AMPK activation was greatly suppressed by piperine, whereas AMPK agonist metformin counteracted piperine’s inhibitory effects on pyroptosis. Moreover, piperine administration greatly reduced both peritoneal and serum IL-1β levels in the mouse model intraperitoneally infected with Escherichia coli, suggestive of suppressing systemic inflammation and pyroptosis. Our data indicated that piperine could protect macrophages from pyroptosis and reduced IL-1β and HMGB1 release by suppressing ATP-induced AMPK activation, suggesting that piperine may become a potential therapeutic agent against bacterial sepsis.

  9. Proteome of monocyte priming by lipopolysaccharide, including changes in interleukin-1beta and leukocyte elastase inhibitor

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    Beranova-Giorgianni Sarka

    2008-05-01

    Full Text Available Abstract Background Monocytes can be primed in vitro by lipopolysaccharide (LPS for release of cytokines, for enhanced killing of cancer cells, and for enhanced release of microbicidal oxygen radicals like superoxide and peroxide. We investigated the proteins involved in regulating priming, using 2D gel proteomics. Results Monocytes from 4 normal donors were cultured for 16 h in chemically defined medium in Teflon bags ± LPS and ± 4-(2-aminoethyl-benzenesulfonyl fluoride (AEBSF, a serine protease inhibitor. LPS-primed monocytes released inflammatory cytokines, and produced increased amounts of superoxide. AEBSF blocked priming for enhanced superoxide, but did not affect cytokine release, showing that AEBSF was not toxic. After staining large-format 2D gels with Sypro ruby, we compared the monocyte proteome under the four conditions for each donor. We found 30 protein spots that differed significantly in response to LPS or AEBSF, and these proteins were identified by ion trap mass spectrometry. Conclusion We identified 19 separate proteins that changed in response to LPS or AEBSF, including ATP synthase, coagulation factor XIII, ferritin, coronin, HN ribonuclear proteins, integrin alpha IIb, pyruvate kinase, ras suppressor protein, superoxide dismutase, transketolase, tropomyosin, vimentin, and others. Interestingly, in response to LPS, precursor proteins for interleukin-1β appeared; and in response to AEBSF, there was an increase in elastase inhibitor. The increase in elastase inhibitor provides support for our hypothesis that priming requires an endogenous serine protease.

  10. Interleukin-1 beta, interleukin-6 and TGF-beta in follicular tissue of impacted third molars.

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    Mesgarzadeh, Ali Hossein; Abolfathi, Ali Akbar; Dastgiri, Saeed; Shaaker, Maghsod; Vatankhah, Amir Mansour; Solehakahnamoiee, Shiva; Darabi, Masoud

    2011-06-01

    The clinical evaluation and management of impacted third molars remain challenging. The aim of the present study was to investigate possible associations between follicular tissue cytokines and radiographic manifestations of impacted third molar. The population included 72 patients who underwent surgical extraction of impacted third molars. All these patients underwent a preliminary panoramic radiograph. Levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and transforming growth factor beta (TGF-β) in tissue extracts were determined using ELISA. There were no significant differences between bony and tissue impaction as regards IL-1β, IL-6 and TGF-β levels. Moreover, the same results were obtained as far as the amount of pericoronal space and the presence or absence of a history of pericoronitis are concerned. These results suggest that radiographic findings or a history of pericoronitis are not associated with levels of expression of pro-inflammatory cytokines in patients undergoing surgical removal of impacted third molars. However, further studies are needed to address the possibility of variability during disease progression.

  11. Regulation of the Expression of the Vibrio parahaemolyticus peuA Gene Encoding an Alternative Ferric Enterobactin Receptor

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    Tanabe, Tomotaka; Kato, Ayaka; Shiuchi, Keiichi; Miyamoto, Katsushiro; Tsujibo, Hiroshi; Maki, Jun; Yamamoto, Shigeo; Funahashi, Tatsuya

    2014-01-01

    A pvsB-vctA-irgA triple deletion mutant of Vibrio parahaemolyticus can utilize enterobactin under iron-limiting conditions by inducing a previously undescribed receptor, PeuA (VPA0150), in response to extracellular alkaline pH and enterobactin. In silico analyses revealed the existence of a two-component regulatory system operon, peuRS, immediately upstream of peuA, which constitutes an operon with the TonB2 system genes. Both the peuRS and peuA-tonB2 operons were found to be upregulated under iron-limiting conditions in a ferric uptake regulator (Fur)-dependent manner. The involvement of peuA and peuRS in enterobactin utilization was analyzed by complementation experiments using deletion mutants. Primer extension analysis indicated that, under iron-limiting conditions, the transcription of peuA was initiated from the +1 site at pH 7.0 and from both the +1 and +39 sites at pH 8.0 in the presence of enterobactin. The +39 transcript was absent from the peuRS deletion mutant. Secondary structure prediction of their 5′-untranslated regions suggested that translation initiation is blocked in the +1 transcript, but not in the +39 transcript. Consistent with this, in vitro translation analysis demonstrated that production of PeuA was determined only by the +39 transcript. These studies establish a novel gene regulation mechanism in which the two-component regulatory system PeuRS enhances expression of the alternative +39 transcript that possesses non-inhibitory structure, allowing the peuA expression to be regulated at the translation stage. PMID:25148374

  12. Chromosomal localization and genomic organization of genes encoding guanylyl cyclase receptors expressed in olfactory sensory neurons and retina

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    Yang, Ruey-Bing; Fuelle, H.J.; Garbers, D.L. [Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)

    1996-02-01

    We recently cloned three membrane guanylyl cyclases, designated GC-D, CG-E, and GC-F, from rat olfactory tissue and eye. Amino acid sequence homology suggests that they may compose a new gene subfamily of guanylyl cyclase receptors specifically expressed in sensory tissues. Their chromosomal localization was determined by mouse interspecific backcross analysis. The GC-D, CG-E, and GC-F genes (Gucy2d, Gucy2e, and Gucy2f) are dispersed through the mouse genome in that they map to chromosomes 7, 11, and X, respectively. Close proximity of the mouse GC-D gene to Omp (olfactory marker protein) and Hbb (hemoglobin {beta}-chain complex) suggests that the human homolog gene maps to 11p15.4 or 11q13.4-q14.1. The human GC-F gene was localized to the long arm of chromosome Xq22 by fluorescence in situ hybridization. The genomic organization of the mouse GC-E, and GC-F genomic clones contain identical exon-intron boundaries within their extracellular and cytoplasmic domains, demonstrating the conservation of the gene structures. With respect to human genetic diseases, GC-E mapped to mouse chromosome 11 within a syntenic region on human chromosome 17p13 that has been linked with loci for autosomal dominant retinitis pigmentosa and Leber congenital amaurosis. No apparent disease loci have been yet linked to the locations of the GC-D or GC-F genes. 39 refs., 3 figs., 2 tabs.

  13. Cerebrospinal fluid markers of neuroinflammation in delirium: A role for interleukin-1β in delirium after hip fracture

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    Cape, Eleanor; Hall, Roanna J; van Munster, Barbara C; de Vries, Annick; Howie, Sarah EM; Pearson, Andrew; Middleton, Scott D; Gillies, Fiona; Armstrong, Ian R; White, Tim O; Cunningham, Colm; de Rooij, Sophia E; MacLullich, Alasdair MJ

    2014-01-01

    Objective Exaggerated central nervous system (CNS) inflammatory responses to peripheral stressors may be implicated in delirium. This study hypothesised that the IL-1β family is involved in delirium, predicting increased levels of interleukin-1β (IL-1β) and decreased IL-1 receptor antagonist (IL-1ra) in the cerebrospinal fluid (CSF) of elderly patients with acute hip fracture. We also hypothesised that Glial Fibrillary Acidic Protein (GFAP) and interferon-γ (IFN-γ) would be increased, and insulin-like growth factor 1 (IGF-1) would be decreased. Methods Participants with acute hip fracture aged > 60 (N = 43) were assessed for delirium before and 3–4 days after surgery. CSF samples were taken at induction of spinal anaesthesia. Enzyme-linked immunosorbent assays (ELISA) were used for protein concentrations. Results Prevalent delirium was diagnosed in eight patients and incident delirium in 17 patients. CSF IL-1β was higher in patients with incident delirium compared to never delirium (incident delirium 1.74 pg/ml (1.02–1.74) vs. prevalent 0.84 pg/ml (0.49–1.57) vs. never 0.66 pg/ml (0–1.02), Kruskal–Wallis p = 0.03). CSF:serum IL-1β ratios were higher in delirious than non-delirious patients. CSF IL-1ra was higher in prevalent delirium compared to incident delirium (prevalent delirium 70.75 pg/ml (65.63–73.01) vs. incident 31.06 pg/ml (28.12–35.15) vs. never 33.98 pg/ml (28.71–43.28), Kruskal–Wallis p = 0.04). GFAP was not increased in delirium. IFN-γ and IGF-1 were below the detection limit in CSF. Conclusion This study provides novel evidence of CNS inflammation involving the IL-1β family in delirium and suggests a rise in CSF IL-1β early in delirium pathogenesis. Future larger CSF studies should examine the role of CNS inflammation in delirium and its sequelae. PMID:25124807

  14. Cartilage stem/progenitor cells are activated in osteoarthritis via interleukin-1β/nerve growth factor signaling.

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    Jiang, Yangzi; Hu, Changchang; Yu, Shuting; Yan, Junwei; Peng, Hsuan; Ouyang, Hong Wei; Tuan, Rocky S

    2015-11-17

    Interleukin-1β (IL-1β) and nerve growth factor (NGF) are key regulators in the pathogenesis of inflammatory arthritis; specifically, IL-1β is involved in tissue degeneration and NGF is involved in joint pain. However, the cellular and molecular interactions between IL-1β and NGF in articular cartilage are not known. Cartilage stem/progenitor cells (CSPCs) have recently been identified in osteoarthritic (OA) cartilage on the basis of their migratory properties. Here we hypothesize that IL-1β/NGF signaling is involved in OA cartilage degeneration by targeting CSPCs. NGF and NGF receptor (NGFR: TrkA and p75NTR) expression in healthy and OA human articular cartilage and isolated chondrocytes was determined by immunostaining, qRT-PCR, flow cytometry and western blot. Articular cartilage derived stem/progenitor cells were collected and identified by stem/progenitor cell characteristics. 3D-cultured CSPC pellets and cartilage explants were treated with NGF and NGF neutralizing antibody, and extracellular matrix changes were examined by sulfated glycosaminoglycan (GAG) release and MMP expression and activity. Expression of NGF, TrkA and p75NTR was found to be elevated in human OA cartilage. Cellular changes upon IL-1β and/or NGF treatment were then examined. NGF mRNA and NGFR proteins levels were upregulated in cultured chondrocytes exposed to IL-1β. NGF was chemotactic for cells isolated from OA cartilage. Cells isolated on the basis of their chemotactic migration towards NGF demonstrated stem/progenitor cell characteristics, including colony-forming ability, multi-lineage differentiation potential, and stem cell surface markers. The effects of NGF perturbation in cartilage explants and 3D-cultured CSPCs were next analyzed. NGF treatment resulted in extracellular matrix catabolism indicated by increased sGAG release and MMP expression and activity; conversely, treatment with NGF neutralizing antibody inhibited increased MMP levels, and enhanced tissue inhibitor of

  15. Interleukin-1β increases neuronal death in the hippocampal dentate gyrus associated with status epilepticus in the developing rat.

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    Rincón-López, C; Tlapa-Pale, A; Medel-Matus, J-S; Martínez-Quiroz, J; Rodríguez-Landa, J F; López-Meraz, M-L

    Interleukin-1β (IL-1β) increases necrotic neuronal cell death in the CA1 area after induced status epilepticus (SE) in developing rats. However, it remains uncertain whether IL-1β has a similar effect on the hippocampal dentate gyrus (DG). In this study, we analysed the effects of IL-1β on 14-day-old Wistar rats experiencing DG neuronal death induced by SE. SE was induced with lithium-pilocarpine. Six hours after SE onset, a group of pups was injected with IL-1β (at 0, 0.3, 3, 30, or 300ng/μL) in the right ventricle; another group was injected with IL-1β receptor (IL-1R1) antagonist (IL-1Ra, at 30ng/μL) of IL-1RI antagonist (IL-1Ra) alone, and additional group with 30ng/μL of IL-1Ra plus 3ng/μL of IL-1β. Twenty-four hours after SE onset, neuronal cell death in the dentate gyrus of the dorsal hippocampus was assessed using haematoxylin-eosin staining. Dead cells showed eosinophilic cytoplasm and condensed and fragmented nuclei. We observed an increased number of eosinophilic cells in the hippocampal DG ipsilateral to the site of injection of 3ng/μL and 300ng/μL of IL-1β in comparison with the vehicle group. A similar effect was observed in the hippocampal DG contralateral to the site of injection of 3ng/μL of IL-1β. Administration of both of IL-1β and IL-1Ra failed to prevent an increase in the number of eosinophilic cells. Our data suggest that IL-1β increases apoptotic neuronal cell death caused by SE in the hippocampal GD, which is a mechanism independent of IL-1RI activation. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  16. The effect of clozapine on mRNA expression for genes encoding G protein-coupled receptors and the protein components of clathrin-mediated endocytosis

    Science.gov (United States)

    Hu, Ying; Weymer, Jon F.; Rizig, Mie; McQuillin, Andrew; Hunt, Stephen P.; Gurling, Hugh M.D.

    2013-01-01

    Objectives Clathrin-mediated endocytosis (CME) is an intracellular trafficking mechanism for packaging cargo, including G protein-coupled receptors (GPCRs), into clathrin-coated vesicles (CCVs). The antipsychotic chlorpromazine inhibits CCV assembly of adaptor protein AP2 whereas clozapine increases serotonin2A receptor internalization. We hypothesized that clozapine alters the expression of CME genes modulating vesicle turnover and GPCR internalization. Materials and methods SH-SY5Y human neuroblastoma cells were incubated with clozapine (1–20 µmol/l) for 24–72 h. GPCR and CME-related gene mRNA expression was measured using RT-PCR. We quantified changes in the same genes using expression data from a microarray study of mice brains after 12 weeks of treatment with 12 mg/kg/day clozapine. Results The expression of genes encoding adaptor and clathrin assembly proteins, AP2A2, AP2B1, AP180, CLINT1, HIP1, ITSN2, and PICALM, increased relative to the control in SH-SY5Y cells incubated with 5–10 µmol/l clozapine for 24–72 h. The microarray study showed significantly altered expression of the above CME-related genes, with a marked 641-fold and 17-fold increase in AP180 and the serotonin1A GPCR, respectively. The expression of three serotonergic receptor and lysophosphatidic acid receptor 2 (EDG4) GPCR genes was upregulated in SH-SY5Y cells incubated with 5 µmol/l clozapine for 24 h. EDG4 expression was also increased with 10–20 µmol/l clozapine treatment at 48–72 h. Clozapine significantly decreased the expression of β-arrestin, involved in GPCR desensitization, both in vitro and vivo. Conclusion The changes we report in CME and GPCR mRNAs implicate CCV-mediated internalization of GPCRs and the serotonergic system in clozapine’s mechanism of action, which may be useful in the design of more effective and less toxic antipsychotic therapies. PMID:23811784

  17. Expression levels of genes encoding melanin concentrating hormone (MCH) and MCH receptor change in taste aversion, but MCH injections do not alleviate aversive responses.

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    Mitra, Anaya; Klockars, Anica; Gosnell, Blake A; Le Grevès, Madeleine; Olszewski, Pawel K; Levine, Allen S; Schiöth, Helgi B

    2012-01-01

    Melanin concentrating hormone (MCH) stimulates feeding driven by energy needs and reward and modifies anxiety behavior. Orexigenic peptides of similar characteristics, including nociceptin/orphanin FQ, Agouti-related protein and opioids, increase consumption also by reducing avoidance of potentially tainted food in animals displaying a conditioned taste aversion (CTA). Herein, using real-time PCR, we assessed whether expression levels of genes encoding MCH and its receptor, MCHR1, were affected in CTA in the rat. We also investigated whether injecting MCH intracerebroventricularly (ICV) during the acquisition and retrieval of LiCl-induced CTA, would alleviate aversive responses. MCHR1 gene was upregulated in the hypothalamus and brain stem of aversive animals, MCH mRNA was significantly higher in the hypothalamus, whereas a strong trend suggesting upregulation of MCH and MCHR1 genes was detected in the amygdala. Despite these expression changes associated with aversion, MCH injected prior to the induction of CTA with LiCl as well as later, during the CTA retrieval upon subsequent presentations of the aversive tastant, did not reduce the magnitude of CTA. We conclude that MCH and its receptor form an orexigenic system whose expression is affected in CTA. This altered MCH expression may contribute to tastant-targeted hypophagia in CTA. However, changing the MCH tone in the brain by exogenous peptide was insufficient to prevent the onset or facilitate extinction of LiCl-induced CTA. This designates MCH as one of many accessory molecules associated with shaping an aversive response, but not a critical one for LiCl-dependent CTA to occur. Published by Elsevier Inc.

  18. Molecular cloning and characterization of two novel genes from hexaploid wheat that encode double PR-1 domains coupled with a receptor-like protein kinase.

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    Lu, Shunwen; Faris, Justin D; Edwards, Michael C

    2017-04-01

    Hexaploid wheat (Triticum aestivum L.) contains at least 23 TaPr-1 genes encoding the group 1 pathogenesis-related (PR-1) proteins as identified in our previous work. Here, we report the cloning and characterization of TaPr-1-rk1 and TaPr-1-rk2, two novel genes closely related to the wheat PR-1 family. The two TaPr-1-rk genes are located on homoeologous chromosomes 3D and 3A, respectively, and each contains a large open reading frame (7385 or 6060 bp) that is interrupted by seven introns and subjected to alternative splicing (AS) with five or six isoforms of mRNA transcripts. The deduced full-length TaPR-1-RK1 and TaPR-1-RK2 proteins (95% identity) contain two repeat PR-1 domains, the second of which is fused via a transmembrane helix to a serine/threonine kinase catalytic (STKc) domain characteristic of receptor-like protein kinases. Phylogenetic analysis indicated that the two PR-1 domains of the TaPR-1-RK proteins form sister clades with their homologues identified in other monocot plants and are well separated from stand-alone PR-1 proteins, whereas the STKc domains may have originated from cysteine-rich receptor-like kinases (CRKs). Reverse-transcriptase-PCR analysis revealed that the TaPr-1-rk genes are predominantly expressed in wheat leaves and their expression levels are elevated in response to pathogen attack, such as infection by barley stripe mosaic virus (BSMV), and also to stress conditions, most obviously, to soil salinity. This is the first report of PR-1-CRK hybrid proteins in wheat. The data may shed new insights into the function/evolutionary origin of the PR-1 family and the STKc-mediated defense/stress response pathways in plants.

  19. Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia

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    Alyssa Carey

    2017-03-01

    Full Text Available Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML. Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1 elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

  20. Role of tumor necrosis factor-α and interleukin-1β in anorexia induction following oral exposure to the trichothecene deoxynivalenol (vomitoxin) in the mouse.

    Science.gov (United States)

    Wu, Wenda; Zhang, Haibin

    2014-01-01

    The trichothecene deoxynivalenol (DON), a foodborne mycotoxin found in grain-based foods, has been associated with human and animal food poisoning. Although induction of anorexia has been described as a hallmark of DON-induced toxicity in many animal species, the mechanistic basis for this adverse effect is not fully understood. The purpose of this research was to determine the role of two proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in DON-induced anorexia. In a nocturnal mouse food consumption model, DON-induced anorectic response occurred at 1 hr and lasted up to 6 hr. Similar anorectic effects were observed following acute administration of exogenous TNF-α and IL-1β. Oral exposure to DON at 5 mg/kg bw stimulated splenic and hepatic mRNA and plasma protein elevations of TNF-α and IL-1β that corresponded to anorexia induction. Pretreatment with the TNF-α receptor (TNFR) antagonist R-7050 dose-dependently attenuated both TNF-α- and DON-induced anorexia. While, the type 1 IL-1 receptor (IL-1R1) antagonist IL-1RA dose-dependently attenuated both IL-1β- and DON-induced anorexia. Taken together, the results suggest that both TNF-α and IL-1β play contributory role in anorexia induction following oral exposure to DON.

  1. Requirement for protein kinase R in interleukin-1alpha-stimulated effects in cartilage.

    Science.gov (United States)

    Tam, Christine L; Hofbauer, Maria; Towle, Christine A

    2007-12-03

    Interleukin-1 (IL-1) has pleiotropic effects in cartilage. The interferon-induced, double stranded RNA-activated protein kinase PKR that phosphorylates eukaryotic initiation factor 2 (eIF2) alpha has been implicated in cytokine effects in chondrocytes. A compound was recently identified that potently suppresses PKR autophosphorylation (IC50 approximately 200 etaM) and partially restores PKR-inhibited translation in a cell-free system with significant effect in the nanomolar range. The objectives of this study were to exploit this potent PKR inhibitor to assess whether PKR kinase activity is required for catabolic and proinflammatory effects of IL-1alpha in cartilage and to determine whether IL-1alpha causes an increase in eIF2alpha phosphorylation that is antagonized by the PKR inhibitor. Cartilage explants were incubated with the PKR inhibitor and IL-1alpha. Culture media were assessed for sulfated glycosaminoglycan as an indicator of proteoglycan degradation and for prostaglandin E(2). Cartilage extracts were analyzed by Western blot for cyclooxygenase-2 and phosphorylated signaling molecules. Nanomolar concentrations of the PKR inhibitor suppressed proteoglycan degradation and cyclooxygenase-2 accumulation in IL-1alpha-activated cartilage. The PKR inhibitor stimulated or inhibited PGE(2) production with a biphasic dose response relationship. IL-1alpha increased the phosphorylation of both PKR and eIF2alpha, and nanomolar concentrations of PKR inhibitor suppressed the IL-1alpha-induced changes in phosphorylation. The results strongly support PKR involvement in pathways activated by IL-1alpha in chondrocytes.

  2. Interleukin 1 beta promoter polymorphism is associated with keratoconus in a Japanese population.

    Science.gov (United States)

    Mikami, Takenori; Meguro, Akira; Teshigawara, Takeshi; Takeuchi, Masaki; Uemoto, Riyo; Kawagoe, Tatsukata; Nomura, Eiichi; Asukata, Yuri; Ishioka, Misaki; Iwasaki, Miki; Fukagawa, Kazumi; Konomi, Kenji; Shimazaki, Jun; Nishida, Teruo; Mizuki, Nobuhisa

    2013-01-01

    Polymorphisms in the interleukin 1 alpha (IL1A) and IL1B gene regions were previously associated with keratoconus in a Korean population. In the present study, we investigated whether the IL1A and IL1B polymorphisms are associated with keratoconus in a Japanese population. A total of 169 Japanese patients with keratoconus and 390 Japanese healthy controls were recruited. We genotyped one IL1A single nucleotide polymorphism (SNP; rs2071376) and two IL1B SNPs (rs1143627 and rs16944) to compare the frequencies of alleles, genotypes, and haplotypes between cases and controls. Statistically significant association was observed for rs1143627 (-31 T>C) in the IL1B promoter region; the T allele of rs1143627 was associated with an increased risk of keratoconus (p=0.014, corrected p value [pc]=0.043, odds ratio=1.38). The C allele of rs16944 (-511 C>T) in the IL1B promoter region had a 1.33-fold increased risk of keratoconus, although this increase did not reach statistical significance (p=0.033, pc=0.098). The TT genotype of rs1143627 was weakly associated with an increased risk of keratoconus (p=0.033, pc=0.099, odds ratio=1.52). However, no significant differences were found in the allele and genotype frequencies between the cases and controls for rs2071376 in IL1A. Regarding haplotypic diversity, the haplotype created by the T allele of rs1143627 and C allele of rs16944 was associated with a 1.72-fold increased risk of keratoconus (p=4.0×10(-5), pc=1.6×10(-4)). Our results replicate associations reported recently in a Korean population. Thus, IL1B may play an important role in the development of keratoconus through genetic polymorphisms.

  3. Regulatory effect of caspase-11 on interleukin-1β in the fungal keratitis.

    Science.gov (United States)

    Zhu, Keke; Mu, Hongmei; Pi, Baimu

    2016-11-01

    Caused by fungus, fungal keratitis is a kind of infections corneal disease with high rate of blindness, which patients are mainly farmers in developing countries. Interleukin, as important proinflammatory cytokines, involve in immune defense process against fungal infection of cornea. The expression of interleukin in the pathogenesis of fungal keratitis, especially the main source of its cells, is not clear and the cell signaling pathways which regulate the synthesis and modification of interleukin is still unknown. Caspase-11 was obtained and cultured. And the ELISA and Western-blot methods were used to explore the regulatory effect of Caspse-11 on Interleukin-1β in the fungal keratitis. neutrophils were the main cell lineage of IL-1β to take part in the innate anti-fungi immunity in the cornea; IL-1β generation induced by fungal infection might not be through the pre-excitation in the classical signal pathway; TLR4/TRIF pathway was not involved in pro-IL-1β generation; while Dectin-1/syk pathway was involved in IL-1β generation in the fungal keratitis; Caspase-l participated in the modification of IL-1β to change from the precursor into the mature body; but NLRP3 inflammasome and ASC inflammasome were not involved in IL-1β generation; Caspase-11 was involved in IL-1β generation through regulating the modified process of Caspase-l to turning from precursor into mature body. TLR4/TRIF pathway and NLRP3 inflammasome and ASC inflammasome are not involved in the pro-IL-1β generation, while Caspase-l, Caspase-11 and Dectin-1/syk pathway are involved in the IL-1β generation.

  4. Divergent effects of brain interleukin-1ß in mediating fever, lethargy, anorexia and conditioned fear memory.

    Science.gov (United States)

    Baartman, Tamzyn L; Swanepoel, Tanya; Barrientos, Ruth M; Laburn, Helen P; Mitchell, Duncan; Harden, Lois M

    2017-05-01

    The influence of brain interleukin-1 (IL-1ß) on memory processes includes both detrimental and beneficial effects. To further explore the dynamics of brain IL-1ß in mediating learning and memory during acute sickness, we injected species-homologous rat IL-1ß (100ng/5μl) or vehicle (0.1% bovine serum albumin, 5μl) directly into the cisterna magna (i.c.m.) of male Sprague-Dawley rats. We measured, in parallel, body temperature, food intake, body mass, cage activity, as well as learning and memory using contextual fear conditioning. To investigate the effects of IL-1ß on learning and memory processes we used: (1) a retrograde experiment that involved injecting rats i.c.m. with IL-1ß immediately after training in the novel context, and (2) an anterograde experiment that involved injecting rats i.c.m. with IL-1ß two hours before training in the novel context. In addition, hypothalamic and hippocampal concentrations of IL-1β were measured at several time points following injection. Administration of IL-1ß induced fever, lethargy and anorexia for∼two-to-three days and increased the concentration of IL-1ß in the hippocampus and hypothalamus for at least eight hours. Training in the context immediately before IL-1ß administration (retrograde experiment), did not impair contextual and auditory fear memory. However, when training in the context occurred concurrently with elevated hippocampal IL-1ß levels, two hours after IL-1ß administration (anterograde experiment), contextual, but not auditory, fear memory was impaired. Our results show that there are instances where memory consolidation can occur concurrently with elevated levels of IL-1ß in the hippocampus, fever, anorexia and lethargy during acute short-term sickness. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1β-treated hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Yoshigai, Emi [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan); Ritsumeikan Global Innovation Research Organization (R-GIRO), Kusatsu, Shiga (Japan); Machida, Toru [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan); Okuyama, Tetsuya [Ritsumeikan Global Innovation Research Organization (R-GIRO), Kusatsu, Shiga (Japan); Mori, Masatoshi; Murase, Hiromitsu; Yamanishi, Ryota [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan); Okumura, Tadayoshi [Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga (Japan); Department of Surgery, Kansai Medical University, Hirakata, Osaka (Japan); Ikeya, Yukinobu [Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga (Japan); Nishino, Hoyoku [Ritsumeikan Global Innovation Research Organization (R-GIRO), Kusatsu, Shiga (Japan); Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto (Japan); Nishizawa, Mikio, E-mail: nishizaw@sk.ritsumei.ac.jp [Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga (Japan)

    2013-09-13

    Highlights: •Nobiletin is a polymethoxylated flavone that is abundant in citrus peels. •Nobiletin is a major constituent of the Citrus unshiu peel extract. •Nobiletin suppresses induction of NO and reduces iNOS expression in hepatocytes. •Nobiletin reduces the iNOS promoter activity and the DNA-binding activity of NF-κB. -- Abstract: Background: Nobiletin is a polymethoxylated flavone that is abundant in the peels of citrus fruits, such as Citrus unshiu (Satsuma mandarin) and Citrus sinensis. The dried peels of C. unshiu (chinpi) have been included in several formulae of Japanese Kampo medicines. Nobiletin may suppress the induction of inducible nitric oxide synthase (iNOS), which synthesizes the inflammatory mediator nitric oxide (NO) in hepatocytes. Methods: A C. unshiu peel (CUP) extract was prepared. Primary cultured rat hepatocytes were treated with the CUP extract or nobiletin in the presence of interleukin 1β (IL-1β), which induces iNOS expression. NO production and iNOS gene expression were analyzed. Results: High-performance liquid chromatography analyses revealed that the nobiletin content in the CUP extract was 0.14%. Nobiletin dose-dependently reduced the NO levels and decreased iNOS expression at the protein, mRNA and antisense transcript levels. Flavone, which does not contain any methoxy groups, also suppressed iNOS induction. Nobiletin reduced the transcriptional activity of iNOS promoter-luciferase constructs and the DNA-binding activity of nuclear factor κB (NF-κB) in the nuclei. Conclusions: The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.

  6. Isoflurane induces learning impairment that is mediated by interleukin 1β in rodents.

    Directory of Open Access Journals (Sweden)

    Lin Cao

    Full Text Available Postoperative cognitive decline is a clinical syndrome. Volatile anesthetics are commonly used during surgery. It is conceivable that volatile anesthetics may contribute to postoperative cognitive decline. Isoflurane can impair cognitive functions of animals under certain conditions. However, the mechanisms for this impairment are not clear. Here, male 18-month old Fisher 344 rats or 10-week old mice were exposed to 1.2 or 1.4% isoflurane for 2 h. Our studies showed that isoflurane impaired the cognitive functions of the rats in Barnes maze. Isoflurane-exposed rats had reduced freezing behavior during the training sessions in the fear conditioning test. This isoflurane effect was attenuated by lidocaine, a local anesthetic with anti-inflammatory property. Rats that had training sessions and were exposed to isoflurane 30 min later had freezing behavior similar to that of control animals. Isoflurane increased the expression of interleukin 1β (IL-1β, interleukin-6 and activated caspase 3 in the hippocampus of the 18-month old rats. IL-1β positive staining was co-localized with that of NeuN, a neuronal marker. The increase of IL-1β and activated caspase 3 but not interleukin-6 was attenuated by lidocaine. Isoflurane also impaired the cognitive functions of 10-week old C57BL/6J mice and increased IL-1β in their hippocampi. However, isoflurane did not affect the cognitive functions of IL-1β deficient mice. Our results suggest that isoflurane impairs the learning but may not affect the recall of the aged rats. IL-1β may play an important role in this isoflurane effect.

  7. Interleukin 1 genetic tests provide no support for reduction of preventive dental care.

    Science.gov (United States)

    Diehl, Scott R; Kuo, Fengshen; Hart, Thomas C

    2015-03-01

    It has been proposed that the PST and PerioPredict genetic tests that are based on polymorphisms in interleukin 1 (IL-1) genes identify a subset of patients who experience fewer tooth extractions if provided with 2 annual preventive visits. Economic analyses indicate rationing preventive care to only "high-risk" genotypes, smokers, patients with diabetes, or combinations of these risk factors would reduce the cost of dental care by $4.8 billion annually in the United States. Data presented in the study that claimed clinical utility for the PST and PerioPredict tests were obtained for reanalysis using logistic regression to assess whether the PST genetic test, smoking, diabetes, or number of preventive visits were risk factors for tooth extraction during a span of 16 years. Consistency of risk classification by the PST (version 1) and PerioPredict (version 2) genetic tests was evaluated in different ethnic groups from the 1000 Genomes database. Multivariate analyses revealed association of tooth extraction with diabetes (P preventive visits (P = .004), but no support for the PST genetic test (P = .96) nor indication that the benefit of 2 preventive visits was affected by this genetic test (P = .58). Classification of risk was highly inconsistent between the PST (version 1) and PerioPredict (version 2) genetic tests. Two annual preventive visits were supported as beneficial for all patients, and there was no evidence that the IL-1 PST genetic test has any effect on tooth extraction risk or influences the benefits of 2 annual preventive visits. Neither IL-1 PST nor PerioPredict genetic tests are useful for rationing preventive dental care. Further research is needed to identify genetic biomarkers with robust clinical validity and clinical utility to effectively personalize the practice of dentistry. Copyright © 2015 American Dental Association. Published by Elsevier Inc. All rights reserved.

  8. Serum tumor necrosis factor and interleukin 1 in leprosy and during lepra reactions.

    Science.gov (United States)

    Parida, S K; Grau, G E; Zaheer, S A; Mukherjee, R

    1992-04-01

    Tumor necrosis factor--alpha (TNF), one of the mediators of septic shock, has a role in the immunopathological complications of several infections. However, its role in leprosy is yet unclear. In this study, serum TNF and IL-1 levels in 64 patients spread over the spectrum of leprosy [lepromatous leprosy (LL), 30; borderline lepromatous, 12; borderline borderline, 8; and borderline tuberculoid-tuberculoid leprosy, 14] were measured at the time of admission. Elevated levels of TNF ranging from 15 to 4500 pg/ml were detected in lepromatous leprosy cases (399 +/- 189) and low levels ranging from 15 to 160 pg/ml were detected in the tuberculoid form of leprosy. Patients undergoing type 1 and type 2 lepra reactions also exhibited high TNF levels of 15-2100 pg/ml. Of the 14 clinically healthy individuals studied, 3 showed TNF levels of 15, 50, and 58 pg/ml. Interleukin 1-beta (IL-1) levels were found to be significantly higher in LL cases (70-5000 pg/ml) (328 +/- 184) in comparison to other groups or normal controls (9 +/- 3). The coefficient of correlation between TNF and IL-1 levels was statistically significant in LL and reaction cases (r = 0.96, P less than 0.001). These patients were followed up as outpatients for a period of 1 year. It was observed that 4 out of 8 patients with TNF levels greater than 100 pg/ml went into lepra reactions between 2 and 6 months after entry into the study, whereas only 5 out of 56 with less than 100 pg/ml went into mild lepra reactions (chi 2 = 9.7, P less than 0.01). Determination of TNF and IL-1 levels thus seems to have a prognostic significance in terms of lepra reaction in patients.

  9. Vitamin D induces interleukin-1β expression: paracrine macrophage epithelial signaling controls M. tuberculosis infection.

    Directory of Open Access Journals (Sweden)

    Mark Verway

    Full Text Available Although vitamin D deficiency is a common feature among patients presenting with active tuberculosis, the full scope of vitamin D action during Mycobacterium tuberculosis (Mtb infection is poorly understood. As macrophages are the primary site of Mtb infection and are sites of vitamin D signaling, we have used these cells to understand the molecular mechanisms underlying modulation of the immune response by the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D. We found that the virulent Mtb strain H37Rv elicits a broad host transcriptional response. Transcriptome profiling also revealed that the profile of target genes regulated by 1,25D is substantially altered by infection, and that 1,25D generally boosts infection-stimulated cytokine/chemokine responses. We further focused on the role of 1,25D- and infection-induced interleukin 1β (IL-1β expression in response to infection. 1,25D enhanced IL-1β expression via a direct transcriptional mechanism. Secretion of IL-1β from infected cells required the NLRP3/caspase-1 inflammasome. The impact of IL-1β production was investigated in a novel model wherein infected macrophages were co-cultured with primary human small airway epithelial cells. Co-culture significantly prolonged survival of infected macrophages, and 1,25D/infection-induced IL-1β secretion from macrophages reduced mycobacterial burden by stimulating the anti-mycobacterial capacity of co-cultured lung epithelial cells. These effects were independent of 1,25D-stimulated autophagy in macrophages but dependent upon epithelial IL1R1 signaling and IL-1β-driven epithelial production of the antimicrobial peptide DEFB4/HBD2. These data provide evidence that the anti-microbial actions of vitamin D extend beyond the macrophage by modulating paracrine signaling, reinforcing its role in innate immune regulation in humans.

  10. Possible association between Interleukin-1beta gene and schizophrenia in a Japanese population

    Directory of Open Access Journals (Sweden)

    Sasayama Daimei

    2011-08-01

    Full Text Available Abstract Background Several lines of evidence have implicated the pro-inflammatory cytokine interleukin-1beta (IL-1β in the etiology of schizophrenia. Although a number of genetic association studies have been reported, very few have systematically examined gene-wide tagging polymorphisms. Methods A total of 533 patients with schizophrenia (302 males: mean age ± standard deviation 43.4 ± 13.0 years; 233 females; mean age 44.8 ± 15.3 years and 1136 healthy controls (388 males: mean age 44.6 ± 17.3 years; 748 females; 46.3 ± 15.6 years were recruited for this study. All subjects were biologically unrelated Japanese individuals. Five tagging polymorphisms of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944 were examined for association with schizophrenia. Results Significant difference in allele distribution was found between patients with schizophrenia and controls for rs1143633 (P = 0.0089. When the analysis was performed separately in each gender, significant difference between patients and controls in allele distribution of rs1143633 was observed in females (P = 0.0073. A trend towards association was also found between rs16944 and female patients with schizophrenia (P = 0.032. Conclusions The present study shows the first evidence that the IL-1β gene polymorphism rs1143633 is associated with schizophrenia susceptibility in a Japanese population. The results suggest the possibility that the influence of IL-1β gene variations on susceptibility to schizophrenia may be greater in females than in males. Findings of the present study provide further support for the role of IL-1β in the etiology of schizophrenia.

  11. Epstein-Barr virus (EBV)–encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3

    Science.gov (United States)

    Iwakiri, Dai; Zhou, Li; Samanta, Mrinal; Matsumoto, Misako; Ebihara, Takashi; Seya, Tsukasa; Imai, Shosuke; Fujieda, Mikiya; Kawa, Keisei

    2009-01-01

    Epstein-Barr virus–encoded small RNA (EBER) is nonpolyadenylated, noncoding RNA that forms stem-loop structure by intermolecular base-pairing, giving rise to double-stranded RNA (dsRNA)–like molecules, and exists abundantly in EBV-infected cells. Here, we report that EBER induces signaling from the Toll-like receptor 3 (TLR3), which is a sensor of viral double-stranded RNA (dsRNA) and induces type I IFN and proinflammatory cytokines. A substantial amount of EBER, which was sufficient to induce signaling from TLR3, was released from EBV-infected cells, and the majority of the released EBER existed as a complex with a cellular EBER-binding protein La, suggesting that EBER was released from the cells by active secretion of La. Sera from patients with infectious mononucleosis (IM), chronic active EBV infection (CAEBV), and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), whose general symptoms are caused by proinflammatory cytokines contained EBER, and addition of RNA purified from the sera into culture medium induced signaling from TLR3 in EBV-transformed lymphocytes and peripheral mononuclear cells. Furthermore, DCs treated with EBER showed mature phenotype and antigen presentation capacity. These findings suggest that EBER, which is released from EBV-infected cells, is responsible for immune activation by EBV, inducing type I IFN and proinflammatory cytokines. EBER-induced activation of innate immunity would account for immunopathologic diseases caused by active EBV infection. PMID:19720839

  12. The M33 G Protein-Coupled Receptor Encoded by Murine Cytomegalovirus Is Dispensable for Hematogenous Dissemination but Is Required for Growth within the Salivary Gland

    Science.gov (United States)

    Bittencourt, Fabiola M.; Wu, Shu-En; Bridges, James P.

    2014-01-01

    ABSTRACT Human cytomegalovirus (HCMV) is a pathogen found worldwide and is a serious threat to immunocompromised individuals and developing fetuses. Due to the species specificity of cytomegaloviruses, murine cytomegalovirus (MCMV) has been used as a model for in vivo studies of HCMV pathogenesis. The MCMV genome, like the genomes of other beta- and gammaherpesviruses, encodes G protein-coupled receptors (GPCRs) that modulate host signaling pathways presumably to facilitate viral replication and dissemination. Among these viral receptors, the M33 GPCR carried by MCMV is an activator of CREB, NF-κB, and phospholipase C-β signaling pathways and has been implicated in aspects of pathogenesis in vivo, including persistence in the salivary glands of BALB/c mice. In this study, we used immunocompetent nonobese diabetic (NOD) and immunocompromised NOD-scid-gamma (NSG) mice to further investigate the salivary gland defect exhibited by M33 deficiency. Interestingly, we demonstrate that virus with an M33 deletion (ΔM33) can replicate in the salivary gland of immunocompromised animals, albeit with a 400-fold growth defect compared with the growth of wild-type virus. Moreover, we determined that M33 does not have a role in cell-associated hematogenous dissemination but is required for viral amplification once the virus reaches the salivary gland. We conclude that the reduced replicative capacity of the ΔM33 virus is due to a specific defect occurring within the localized environment of the salivary gland. Importantly, since the salivary gland represents a site essential for persistence and horizontal transmission, an understanding of the mechanisms of viral replication within this site could lead to the generation of novel therapeutics useful for the prevention of HCMV spread. IMPORTANCE Human cytomegalovirus infects the majority of the American people and can reside silently in infected individuals for the duration of their lives. Under a number of circumstances, the

  13. Amplification and propagation of interleukin-1β signaling by murine brain endothelial and glial cells.

    Science.gov (United States)

    Krasnow, Stephanie M; Knoll, J Gabriel; Verghese, Santhosh Chakkaramakkil; Levasseur, Peter R; Marks, Daniel L

    2017-07-01

    During acute infections and chronic illnesses, the pro-inflammatory cytokine interleukin-1β (IL-1β) acts within the brain to elicit metabolic derangements and sickness behaviors. It is unknown which cells in the brain are the proximal targets for IL-1β with respect to the generation of these illness responses. We performed a series of in vitro experiments to (1) investigate which brain cell populations exhibit inflammatory responses to IL-1β and (2) examine the interactions between different IL-1β-responsive cell types in various co-culture combinations. We treated primary cultures of murine brain microvessel endothelial cells (BMEC), astrocytes, and microglia with PBS or IL-1β, and then performed qPCR to measure inflammatory gene expression or immunocytochemistry to evaluate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. To evaluate whether astrocytes and/or BMEC propagate inflammatory signals to microglia, we exposed microglia to astrocyte-conditioned media and co-cultured endothelial cells and glia in transwells. Treatment groups were compared by Student's t tests or by ANOVA followed by Bonferroni-corrected t tests. IL-1β increased inflammatory gene expression and NF-κB activation in primary murine-mixed glia, enriched astrocyte, and BMEC cultures. Although IL-1β elicited minimal changes in inflammatory gene expression and did not induce the nuclear translocation of NF-κB in isolated microglia, these cells were more robustly activated by IL-1β when co-cultured with astrocytes and/or BMEC. We observed a polarized endothelial response to IL-1β, because the application of IL-1β to the abluminal endothelial surface produced a more complex microglial inflammatory response than that which occurred following luminal IL-1β exposure. Inflammatory signals are detected, amplified, and propagated through the CNS via a sequential and reverberating signaling cascade involving communication between brain endothelial cells and

  14. Interactions between stress, interleukin-1beta, interleukin-6 and cortisol in periodontally diseased patients.

    Science.gov (United States)

    Mengel, Reiner; Bacher, Michael; Flores-De-Jacoby, Lavin

    2002-11-01

    The aim of the present study was to measure interleukin-1beta, interleukin-6 and cortisol levels in the peripheral blood of periodontally diseased patients in order to record any interactions with psychosocial stress. The test group comprised 16 patients with untreated and 14 with treated aggressive generalized periodontitis (AGP), five patients with untreated aggressive localized periodontitis (ALP) and five with chronic generalized periodontitis (CGP). The control group comprised 40 periodontally healthy probands. Blood was taken from the cephalic vein of all patients and controls at the same time (8 a.m.) each day. IL-1beta, IL-6 and cortisol levels were then measured with a sensitive ELISA, the 'Quantikine HS Immunoassay Kit' (Biermann Diagnostica, Bad Nauheim, FRG). The clinical examination covered probing depth, gingival recession, gingival index, plaque index and clinical attachment level. A questionnaire was used to ask the patients and controls about their attitude to life and the stress induced by their jobs and their families. Previous and current levels of tobacco consumption were also recorded. Statistical evaluation was based on the Mann-Whitney U-Wilcoxon test for comparison of blood serum values and clinical parameters between patients and controls, and the Kruskal-Wallis test for intergroup comparison. All data were correlated by means of Spearman's rank correlation coefficient, and significance levels relating to stress and smoking were determined with the chi-square test. With respect to cortisol, the results showed no significant differences either between the patient groups or in comparison with the controls. IL-1beta was detected only in the AGP patients and their controls, but with no significant differences. IL-6 was detected in virtually all patients and controls, but with no significant differences. Only in the untreated AGP patients was IL-6 significantly elevated (P cortisol) and the registered stress values. However, the patients with

  15. Interleukin-1 beta: a potential link between stress and the development of visceral obesity.

    Science.gov (United States)

    Speaker, Kristin J; Fleshner, Monika

    2012-06-27

    A disproportionate amount of body fat within the abdominal cavity, otherwise known as visceral obesity, best predicts the negative health outcomes associated with high levels body fat. Growing evidence suggests that repeated activation of the stress response can favor visceral fat deposition and that visceral obesity may induce low-grade, systemic inflammation which is etiologically linked to the pathogenesis of obesity related diseases such as cardiovascular disease and type 2 diabetes. While the obesity epidemic has fueled considerable interest in these obesity-related inflammatory diseases, surprisingly little research is currently focused on understanding the functions of inflammatory proteins in healthy, non-obese white adipose tissue (WAT) and their possible role in modulating stress-induced shifts in body fat distribution. The current review presents evidence in support the novel hypothesis that stress-evoked interleukin-1 beta (IL-1β) signaling within subcutaneous adipose tissue, when repeatedly induced, contributes toward the development of visceral obesity. It is suggested that because acute stressor exposure differentially increases IL-1β levels within subcutaneous adipose relative to visceral adipose tissue in otherwise healthy, non-obese rats, repeated induction of this response may impair the ability of subcutaneous adipose tissue to uptake energy substrates, synthesize and retain triglycerides, and/or adapt to positive energy balance via hyperplasia. Consequently, circulating energy substrates may be disproportionately shunted to visceral adipose tissue for storage, thus driving the development of visceral obesity. This review establishes the following key points: 1) body fat distribution outweighs the importance of total body fat when predicting obesity-related disease risk; 2) repeated exposure to stress can drive the development of visceral obesity independent of changes in body weight; 3) because of the heterogeneity of WAT composition and

  16. Interleukin-1 beta: a potential link between stress and the development of visceral obesity

    Directory of Open Access Journals (Sweden)

    Speaker Kristin J

    2012-06-01

    Full Text Available Abstract Background A disproportionate amount of body fat within the abdominal cavity, otherwise known as visceral obesity, best predicts the negative health outcomes associated with high levels body fat. Growing evidence suggests that repeated activation of the stress response can favor visceral fat deposition and that visceral obesity may induce low-grade, systemic inflammation which is etiologically linked to the pathogenesis of obesity related diseases such as cardiovascular disease and type 2 diabetes. While the obesity epidemic has fueled considerable interest in these obesity-related inflammatory diseases, surprisingly little research is currently focused on understanding the functions of inflammatory proteins in healthy, non-obese white adipose tissue (WAT and their possible role in modulating stress-induced shifts in body fat distribution. Hypothesis The current review presents evidence in support the novel hypothesis that stress-evoked interleukin-1 beta (IL-1β signaling within subcutaneous adipose tissue, when repeatedly induced, contributes toward the development of visceral obesity. It is suggested that because acute stressor exposure differentially increases IL-1β levels within subcutaneous adipose relative to visceral adipose tissue in otherwise healthy, non-obese rats, repeated induction of this response may impair the ability of subcutaneous adipose tissue to uptake energy substrates, synthesize and retain triglycerides, and/or adapt to positive energy balance via hyperplasia. Consequently, circulating energy substrates may be disproportionately shunted to visceral adipose tissue for storage, thus driving the development of visceral obesity. Conclusions This review establishes the following key points: 1 body fat distribution outweighs the importance of total body fat when predicting obesity-related disease risk; 2 repeated exposure to stress can drive the development of visceral obesity independent of changes in body weight

  17. Increased circulating cytokine receptors and ex vivo interleukin-1 receptor antagonist and interleukin-1β production but decreased tumour necrosis factor-α production after a 5-km run

    NARCIS (Netherlands)

    Drenth, J.P.H.; Krebbers, R.J.M.; Bijzet, J.; Van Der Meer, J.W.M.

    1998-01-01

    Background The purpose of this study was to examine the effect of a 5-km run on blood leucocytes, acute-phase proteins and cytokines. In addition, cytokines were measured in the supernatants from whole-blood cell cultures incubated with lipolysaccharide (LPS). Methods Ten healthy, recreational

  18. The P2X7 receptor

    DEFF Research Database (Denmark)

    Kvist, Torben Madsen; Schwarz, Peter; Jørgensen, Niklas Rye

    2014-01-01

    from an increase in bone resorption and the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin 1 beta and has been shown to not only mediate the inflammatory response but also to strongly stimulate bone degradation. The purinergic P2X7 receptor is central in the processing...... receptor in immune-mediated bone loss and -osteoporosis....

  19. Evolution of interleukin-1 receptor-like 1 and its role in rainbow trout (Oncorhynchus mykiss) resistance to Flavobacterium psychrophilum

    Science.gov (United States)

    Rainbow trout exhibit extensive phenotypic variation in innate disease resistance and we have divergently selected lines with either increased or reduced survival following exposure to the gram-negative bacterium, Flavobacterium psychrophilum (Fp). Following five generations of selection, gene expr...

  20. Interleukin-1 receptor antagonist in neonates, children and adults, and in patients with pauci- and polyarticular onset juvenile chronic arthritis

    DEFF Research Database (Denmark)

    Müller, K; Zak, M; Nielsen, S

    2011-01-01

    lipopolysacharide (LPS) stimulated-cultures of MNC was also significantly higher in neonates (median 2451 pg/ml) than in children (1526 pg/ml), but similar to that in adults (2107 pg/ml). IL-1ra levels in the sera of both subgroups of JCA patients were significantly elevated (median 257 pg/ml), but did not reflect...

  1. Interleukin 1 receptor antagonist mediates the beneficial effects of systemic interferon beta in mice: implications for rheumatoid arthritis

    NARCIS (Netherlands)

    Corr, M.; Boyle, D.L.; Ronacher, L.M.; Lew, B.R.; van Baarsen, L.G.; Tak, P.P.; Firestein, G.S.

    2011-01-01

    Objectives Interferon beta (IFN beta) therapy is effective in multiple sclerosis and murine models of arthritis. Surprisingly, systemic IFN beta treatment induces only minimal improvement in rheumatoid arthritis (RA). To explain this paradox, the authors evaluated the mechanism of IFN beta benefit

  2. Autophagy Modulates Borrelia burgdorferi-induced Production of Interleukin-1beta (IL-1beta)

    NARCIS (Netherlands)

    Buffen, K.; Oosting, M.; Mennens, S.; Anand, P.K.; Plantinga, T.S.; Sturm, P.D.J.; Veerdonk, F.L. van de; Meer, J.W. van der; Xavier, R.J.; Kanneganti, T.D.; Netea, M.G.; Joosten, L.A.B.

    2013-01-01

    Borrelia burgdorferi sensu lato is the causative agent of Lyme disease. Recent studies have shown that recognition of the spirochete is mediated by TLR2 and NOD2. The latter receptor has been associated with the induction of the intracellular degradation process called autophagy. The present study

  3. Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth

    DEFF Research Database (Denmark)

    Hollegaard, Mads Vilhelm; Grove, Jakob; Thorsen, Poul

    2008-01-01

    OBJECTIVE: To investigate the relation between 19 selected single nucleotide polymorphisms in three cytokine genes, tumor necrosis factor alpha (TNFA), interleukin 1-beta (IL1B) and interleukin 6 (IL6) and preterm birth (

  4. Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth

    DEFF Research Database (Denmark)

    Hollegaard, Mads Vilhelm; Grove, Jakob; Thorsen, Poul

    2008-01-01

    Objective. To investigate the relation between 19 selected single nucleotide polymorphisms in three cytokine genes, tumor necrosis factor alpha (TNFA), interleukin 1-beta (IL1B) and interleukin 6 (IL6) and preterm birth (

  5. Interleukin-1 beta-induced nitric oxide production from isolated rat islets is modulated by D-glucose and 3-isobutyl-1-methyl xanthine

    DEFF Research Database (Denmark)

    Andersen, H U; Mauricio, D; Karlsen, Allan Ertman

    1996-01-01

    -glucose-mediated modulation of interleukin-1 beta effects on insulin release from isolated rat islets was related to modulation of nitric oxide production. Further, we wished to investigate the effects of agents increasing the intracellular concentration of cAMP on interleukin-1 beta-induced nitrite production. We......Interleukin-1 beta has been proposed to cause selective beta-cell destruction via the induction of nitric oxide synthesis. The cytotoxic effect of interleukin-1 beta is modulated by the concentration of D-glucose in the medium. The aim of this study was to investigate if D...... effects on acute insulin release was found at high (28 mmol/l) concentrations of D-glucose, and blocking nitrite production by the L-arginine analog aminoguanidine, which selectively inhibits the cytokine-inducible nitric oxide synthase, did not result in protection against the inhibitory action...

  6. Differing mechanisms of leukocyte recruitment and sensitivity to conditioning by shear stress for endothelial cells treated with tumour necrosis factor-alpha or interleukin-1beta.

    Science.gov (United States)

    Sheikh, Sajila; Rahman, Mahbub; Gale, Zoe; Luu, N Thin; Stone, Philip C W; Matharu, Nick M; Rainger, G Edward Luu; Nash, Gerard B

    2005-08-01

    The cytokines tumour necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1B) induce endothelial cells to recruit leukocytes. However, the exact adhesion and activation mechanisms induced by each cytokine, and their relative sensitivities to modulation by endothelial exposure to shear stress remain unclear. We cultured human umbilical vein endothelial cells (HUVEC) in glass capillaries at various shear stresses, with TNFalpha or IL-1B added for the last 4 h. Subsequently, human neutrophils were perfused over the HUVEC, and adhesion and migration were recorded. Both cytokines induced dose-dependent capture of neutrophils. However, while conditioning of HUVEC by increasing shear stress for 24 h diminished their response to TNFalpha, the response of HUVEC to IL-1B was similar at all shear stresses. The differing sensitivities were evident at levels of adhesive function and mRNA for adhesion molecules and chemokines. Analysis of nuclear factor kappaB (NF-kappaB)/Rel family of transcription factors showed that their expression and activation were modified by exposure to shear stress, but did not obviously explain differential responses to TNFalpha and IL-1B. Antibodies against selectins were effective against capture of neutrophils on TNFalpha-treated but not IL-1B-treated HUVEC. Stable adhesion was supported by beta2-integrins in each case. Activation of neutrophils occurred dominantly through CXC-chemokine receptor 2 (CXCR2) for TNFalpha-treated HUVEC, while blockade of CXCR1, CXCR2 and of platelet-activating factor receptors caused additive inhibition of migration on IL-1B-treated HUVEC. The mechanisms which underlie neutrophil recruitment, and their modulation by the haemodynamic environment, differ between cytokines. Interventions aimed against leukocyte recruitment may not operate equally in different inflammatory milieu.

  7. Differing mechanisms of leukocyte recruitment and sensitivity to conditioning by shear stress for endothelial cells treated with tumour necrosis factor-α or interleukin-1β

    Science.gov (United States)

    Sheikh, Sajila; Rahman, Mahbub; Gale, Zoe; Luu, N Thin; Stone, Philip C W; Matharu, Nick M; Rainger, G Edward Luu; Nash, Gerard B

    2005-01-01

    The cytokines tumour necrosis factor-α (TNFα) and interleukin-1β (IL-1B) induce endothelial cells to recruit leukocytes. However, the exact adhesion and activation mechanisms induced by each cytokine, and their relative sensitivities to modulation by endothelial exposure to shear stress remain unclear. We cultured human umbilical vein endothelial cells (HUVEC) in glass capillaries at various shear stresses, with TNFα or IL-1B added for the last 4 h. Subsequently, human neutrophils were perfused over the HUVEC, and adhesion and migration were recorded. Both cytokines induced dose-dependent capture of neutrophils. However, while conditioning of HUVEC by increasing shear stress for 24 h diminished their response to TNFα, the response of HUVEC to IL-1B was similar at all shear stresses. The differing sensitivities were evident at levels of adhesive function and mRNA for adhesion molecules and chemokines. Analysis of nuclear factor κB (NF-κB)/Rel family of transcription factors showed that their expression and activation were modified by exposure to shear stress, but did not obviously explain differential responses to TNFα and IL-1B. Antibodies against selectins were effective against capture of neutrophils on TNFα-treated but not IL-1B-treated HUVEC. Stable adhesion was supported by β2-integrins in each case. Activation of neutrophils occurred dominantly through CXC-chemokine receptor 2 (CXCR2) for TNFα-treated HUVEC, while blockade of CXCR1, CXCR2 and of platelet-activating factor receptors caused additive inhibition of migration on IL-1B-treated HUVEC. The mechanisms which underlie neutrophil recruitment, and their modulation by the haemodynamic environment, differ between cytokines. Interventions aimed against leukocyte recruitment may not operate equally in different inflammatory milieu. PMID:15912126

  8. Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer

    Science.gov (United States)

    Vucicevic-Boras, Vanja; Lukac, Josip; Biocina-Lukenda, Dolores; Zilic-Alajbeg, Iva; Milenovic, Aleksandar; Balija, Melita

    2012-01-01

    Objectives: The aim of study was to compare salivary and serum concentrations of interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in patients with oral leukoplakia, oral cancer and healthy controls. Study design: Eighty eight patients (28 with oral cancer, 29 leukoplakia, and 31 healthy controls) were included in this study. Cytokine concentrations were measured by commercial enzyme linked immunoassay. Results: Salivary IL-1β and IL-6 were significantly higher in oral cancer patients than in patients with leukoplakia and control group (pleukoplakia remains to be answered by further follow up studies. Key words: Cytokines, oral, leukoplakia, cancer. PMID:21743397

  9. Interleukin-1 and interleukin-6 production in mice's lungs induced by 2, 3 meso-dimercaptosuccinic-coated magnetic nanoparticles

    Science.gov (United States)

    Chaves, S. B.; Silva, L. P.; Lacava, Z. G. M.; Morais, P. C.; Azevedo, R. B.

    2005-05-01

    In the present study, we evaluated the effects of a water-based (physiological medium) magnetic fluid sample containing magnetite nanoparticles surface coated with a layer of 2, 3 meso-dimercaptosuccinic acid in mice. The animals were killed after times varying from 5minto24h. Tissue analysis was made by light microscopy using hematoxilin and eosin (HE) staining and interleukin 1 and 6 immunohistochemistry. The results showed accumulation of nanoparticles in lungs after 30min of sample administration, with inflammatory process associated to it. It also showed an increase in both interleukins expression, which confirms inflammatory response associated with magnetic nanoparticles.

  10. Mode of action of interleukin-1 in suppression of pituitary LH release in castrated male rats.

    Science.gov (United States)

    Bonavera, J J; Kalra, S P; Kalra, P S

    1993-05-28

    These studies were undertaken to elucidate the mechanisms whereby the cytokine, Interleukin (IL-1) suppresses pituitary LH release in orchidectomized rats. Since LH secretion is pulsatile in castrated rats, the effects of IL-1 on the components of the LH pulsatility were assessed. Intracerebroventricular (i.c.v.) administration of IL-1 alpha or IL-1 beta suppressed LH release, but IL-1 beta was relatively more effective than IL-1 alpha in terms of the onset (IL-1 beta = 30 min; IL-1 alpha = 105 min) as well as the magnitude and duration of LH suppression. Further, the marked suppression of LH secretion in IL-1 beta-treated rats was found to be due to significant reductions both in the frequency and amplitude of LH episodes. We next evaluated whether the IL-1 beta-induced suppression of LH release was mediated by either of the two inhibitory hypothalamic peptidergic systems, corticotrophin releasing hormone (CRH) and endogenous opioid peptides (EOP). Passive immunoneutralization of CRH by i.c.v. administration of a specific CRH-antibody, either once at 15 min or twice at 75 and 15 min before IL-1 beta injection, failed to block the suppressive effects of IL-1 beta on LH release. Similarly, pharmacological blockade of CRH by i.c.v. injection of the CRH receptor antagonist, alpha-helical CRH9-41 15 min before IL-1 beta was ineffective. However, i.v. infusion of the opiate receptor antagonist, naloxone, which on its own had no effect on LH secretion, counteracted the inhibitory effects of IL-1 beta. To further identify the opiate receptor subtype involved, we utilized specific opiate receptor subtype antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Inhibition of IRE1 signaling affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells.

    Science.gov (United States)

    Minchenko, D O; Riabovol, O O; Tsymbal, D O; Ratushna, O O; Minchenko, O H

    2016-07-01

    The aim of the present investigation was to examine the effect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoding glucocorticoid receptor (NR3C1) and some related proteins (SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, NNT) and their hypoxic regulation in U87 glioma cells for evaluation of their possible significance in the control of the glioma growth. The expression of NR3C1,SGK1,SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by quantitative polymerase chain reaction. Inhibition of IRE1 signaling enzyme function up-regulates the expression of NR3C1, SGK1, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells in comparison with the control glioma cells, with more significant changes for NR3C1, SGK1, and NNT genes. At the same time, the expression of SGK3 gene is strongly down-regulated in glioma cells upon inhibition of IRE1. We have also shown that hypoxia increases the expression of NR3C1, SGK1, NCOA2, ARHGAP35, and NNT genes but decreases SGK3 and NCOA1 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in U87 glioma cells enhances the eff ect of hypoxia on the expression of SGK1, SGK3, and NNT genes, but decreases the sensitivity of NR3C1 gene to hypoxic condition. Furthermore, the expression of NCOA1 gene is resistant to hypoxia in control glioma cells, but NCOA2 and ARHGAP35 genes are resistant to this condition in glioma cells without functional activity of IRE1 signaling enzyme. Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function affects the expression of NR3C1, SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells

  12. Interleukin-1beta and rhinovirus sensitize adenylyl cyclase in human airway smooth-muscle cells.

    Science.gov (United States)

    Billington, C K; Pascual, R M; Hawkins, M L; Penn, R B; Hall, I P

    2001-05-01

    Rhinovirus (RV) is a major cause of wheezing in asthmatics and has been reported to cause beta2 adrenergic receptor hyporesponsiveness in human airway smooth muscle (HASM) via cellular secretion of interleukin (IL)-1beta. We studied the effects of IL-1beta and RV on cyclic adenosine monophosphate (cAMP) production in HASM cells. Chronic incubation with IL-1beta or RV caused a significant increase (approximately 3- and approximately 2-fold, respectively) in forskolin (FSK)-stimulated cAMP production, suggesting a sensitization of adenylyl cyclase (AC). The observed augmentation of FSK-stimulated cAMP formation by IL-1beta was completely abrogated by pretreatment with an IL-1 receptor antagonist or cycloheximide, demonstrating that the effect is mediated via the IL-1 receptor 1 (IL-1R1) and that de novo protein synthesis is required. In contrast, RV-induced AC sensitization was not mediated via the IL-1R1 but was observed to be protein kinase C-dependent. We suggest that the sensitization of AC observed after exposure to IL-1beta or RV infection is a cellular defense mechanism to promote pathways that induce relaxation in the inflamed airway.

  13. Levels of interleukin-1β in gingival crevicular fluid in patients with coronary heart disease and its relationship to periodontal status

    Science.gov (United States)

    Lenggogeny, Putri; Masulili, Sri Lelyati C.; Tadjoedin, Fatimah M.; Radi, Basuni

    2017-02-01

    Periodontitis is a risk factor for coronary heart disease (CHD). Both diseases are an inflammatory diseases and have the same potential pathogenic mechanisms. Interleukin-1β as a pro-inflammatory main cytokine, can be found in this both diseases. Gingival crevicular fluid (GCF) derived from the serum of gingival sulcus, affected by inflammatory mechanism and the amount of this fluid will increase in that situation. Objective: To analyze the relationship of interleukin-1β levels in gingival crevicular fluid (GCF) of CHD and non-CHD patients with periodontal status. Methods: Oral clinical examination (plaque index, bleeding on probing, pocket depth and clinical attachment loss) for 35 subjects with CHD and 35 non CHD were checked, laboratory test to measure the levels of Interleukin-1β was checked with enzyme-linked immunosorbent assay (ELISA). Results: There was no significant differences between interleukin-1β levels in CHD and non-CHD patients (p>0.05); there was no significant difference between the level of Interleukin-1β with periodontal status in CHD and control (non CHD) patients (p>0.05). Conclusions: levels of Interleukin-1β in CHD patients do not have a relationships with plaque index, pocket depth and clinical attachment loss, but has a relationships with bleeding on probing.

  14. Study of the association between the interleukin-1 β c.3954C>T polymorphism and periodontitis in a population sample from Bahia, Brazil.

    Science.gov (United States)

    Mendonça, Samir A; Teixeira, Fernanda G; Oliveira, Kamilla M; Santos, Djanilson B; Marques, Lucas M; Amorim, Maise M; Gestinari, Raquel De S

    2015-01-01

    Periodontitis is an inflammatory disease characterized by the loss of connective tissue and alveolar bone. Different factors are associated with the onset and prognosis of this disease, both environmental and genetic. The latter particularly relate to molecules secreted as a function of the host immune response, such as pro-inflammatory cytokines. Studies indicate that the polymorphism c. 3954C > T in the interleukin-1 β encoding gene (IL1B) can be considered as an aggravating factor in the periodontitis condition. This study aimed to evaluate whether there is an association between the IL1B c. 3954C > T gene polymorphism and the prevalence of periodontitis in the population from Vitória da Conquista-Bahia, Brazil. A total of 347 subjects (134 cases and 213 controls) who provided epithelial tissue of the oral cavity and saliva samples for DNA extraction and quantification of IL1B, respectively, were selected. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism followed by electrophoresis in agarose gel. The evaluation of the cytokine concentration was performed by enzyme-linked immunosorbent assay. Statistical calculations involved in this work include Chi-square test, Fisher Exact test, Mann-Whitney and Kruskal-Wallis tests. Our findings revealed that: (i) No statistically significant relationship between periodontitis and the polymorphism studied was observed; (ii) no significant difference between the concentrations of IL1B in saliva between the case and control subjects and between the genotypes of these individuals and the concentrations of this cytokine. We conclude that, in the sample evaluated, the IL1B c. 3954C > T polymorphism did not present as an etiological factor for periodontitis.

  15. Effect of ether glycerol lipids on interleukin-1β release and experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Boomkamp, Stephanie D; Byun, Hoe-Sup; Ubhi, Satvir; Jiang, Hui-Rong; Pyne, Susan; Bittman, Robert; Pyne, Nigel J

    2016-01-01

    We have assessed the effect of two ether glycerol lipids, 77-6 ((2S, 3R)-4-(Tetradecyloxy)-2-amino-1,3-butanediol) and 56-5 ((S)-2-Amino-3-O-hexadecyl-1-propanol), which are substrates for sphingosine kinases, on inflammatory responses. Treatment of differentiated U937 macrophage-like cells with 77-6 but not 56-5 enhanced IL-1β release; either alone or in the presence of LPS. The stimulatory effect of sphingosine or 77-6 on LPS-stimulated IL-1β release was reduced by pretreatment of cells with the caspase-1 inhibitor, Ac-YVAD-CHO, thereby indicating a role for the inflammasome. The enhancement of LPS-stimulated IL-1β release in response to sphingosine, but not 77-6, was reduced by pretreatment of cells with the cathepsin B inhibitor, CA074Me, indicating a role for lysosomal destabilization in the effect of sphingosine. Administration of 56-5 to mice increased disease progression in an experimental autoimmune encephalomyelitis model and this was associated with a considerable increase in the infiltration of CD4(+) T-cells, CD11b(+) monocytes and F4/80(+) macrophages in the spinal cord. 56-5 and 77-6 were without effect on the degradation of myc-tagged sphingosine 1-phosphate 1 receptor in CCL39 cells. Therefore, the effect of 56-5 on EAE disease progression is likely to be independent of the inflammasome or the sphingosine 1-phosphate 1 receptor. However, 56-5 is chemically similar to platelet activating factor and the exacerbation of EAE disease progression might be linked to platelet activating factor receptor signaling. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Dental biofilm, gingivitis and interleukin-1 adjacent to approximal sites of a bonded ceramic.

    Science.gov (United States)

    Konradsson, Katarina; Claesson, Rolf; van Dijken, Jon W V

    2007-12-01

    The aim of this study was to investigate in vivo the influence of aged, resin-bonded, ceramic restorations on approximal dental biofilm formation and gingival inflammatory response, associated with and without customary oral hygiene. In a cross-sectional and in a 10-day experimental gingivitis study, Quigley-Hein plaque index, gingival index (GI), crevicular fluid and its levels of interleukin (IL)-1alpha, -1beta and receptor antagonist were measured at appoximal surfaces of leucite-reinforced bonded ceramic coverages, resin composite restorations and enamel and compared intra-individually in 17 participants. No differences were found between the ceramic, composite and enamel regarding plaque index, GI, levels of IL-1alpha, -1beta and the receptor antagonist. Throughout, higher crevicular fluid amounts were observed at ceramic sites compared with the enamel (p<0.05). In the experimental gingivitis, plaque index, GI, crevicular fluid and its IL-1alpha levels increased significantly. The need for optimal oral hygiene and professional preventive oral health care does not seem to be reduced with regard to approximal surfaces of aged, resin-bonded, leucite-reinforced ceramic restorations in comparison with those of a hybrid, resin composite and enamel.

  17. The NOD2 defect in Blau syndrome does not result in excess interleukin 1 activity

    Science.gov (United States)

    Martin, Tammy M.; Zhang, Zili; Kurz, Paul; Rose, Carlos D.; Chen, Hong; Lu, Huiying; Planck, Stephen R.; Davey, Michael P.; Rosenbaum, James T.

    2009-01-01

    Objective Blau syndrome is a rare, autosomal dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetic studies have shown that the disease is caused by single, nonsynonymous substitutions in NOD2, a member of the NOD-like receptor, or NACHT-LRR, (NLR) family of intracellular proteins. Several NLR function in the innate immune system as sensors of pathogen components and participate in immune-mediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD2, NLRP3, are responsible for excess caspase 1-dependent IL-1β in cryopyrinopathies like Muckle-Wells syndrome. Furthermore, functional studies demonstrate that caspase 1-mediated release of IL-1β also involves NOD2. Here we test the hypothesis that IL-1β may mediate the inflammation seen in Blau syndrome patients. Methods IL-1β release was measured from peripheral blood mononuclear cells cultured in vitro from five Blau syndrome individuals who have a NOD2 mutation. Results We report no evidence for increased IL-1β production in the cells obtained from Blau syndrome subjects compared to healthy controls. Furthermore, we present two Blau syndrome cases in which recombinant human IL-1 receptor antagonist (anakinra) was ineffective treatment. Conclusion Together, these data suggest that in contrast to related IL-1β dependent autoinflammatory cryopyrinopathies, Blau syndrome is not mediated by excess IL-1β or other IL-1 activity. PMID:19180500

  18. Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1β Production and Activation through CD47.

    Science.gov (United States)

    Stein, Erica V; Miller, Thomas W; Ivins-O'Keefe, Kelly; Kaur, Sukhbir; Roberts, David D

    2016-01-27

    Thrombospondin-1 regulates inflammation by engaging several cell surface receptors and by modulating activities of other secreted factors. We have uncovered a novel role of thrombospondin-1 in modulating production and activation of the proinflammatory cytokine IL-1β by human and murine macrophages. Physiological concentrations of thrombospondin-1 limit the induction by lipopolysaccharide of IL-1β mRNA and total protein production by human macrophages. This inhibition can be explained by the ability of thrombospondin-1 to disrupt the interaction between CD47 and CD14, thereby limiting activation of NFκB/AP-1 by lipopolysaccharide. Only the CD47-binding domain of thrombospondin-1 exhibits this activity. In contrast, CD47, CD36, and integrin-binding domains of thrombospondin-1 independently enhance the inflammasome-dependent maturation of IL-1β in human THP-1 monocyte-derived macrophages. Correspondingly, mouse bone marrow-derived macrophages that lack either thrombospondin-1 or CD47 exhibit diminished induction of mature IL-1β in response to lipopolysaccharide. Lack of CD47 also limits lipopolysaccharide induction of IL-1β, NLRP3, and caspase-1 mRNAs. These data demonstrate that thrombospondin-1 exerts CD47-dependent and -independent pro-and anti-inflammatory effects on the IL-1β pathway. Therefore, thrombospondin-1 and its receptor CD47 may be useful targets for limiting the pro-inflammatory effects of lipopolysaccharide and for treating endotoxemia.

  19. Interleukin-1β inhibitors for the treatment of cryopyrin-associated periodic syndrome

    Directory of Open Access Journals (Sweden)

    Eugen Dhimolea

    2011-01-01

    Full Text Available Eugen DhimoleaTufts University School of Medicine, Boston, MA, USAAbstract: Cryopyrin-associated periodic syndrome (CAPS comprises a group of rare, but severe, inherited autoinflammatory disorders associated with aberrant secretion of interleukin (IL-1. These distinct conditions of autoinflammatory origin include Muckle–Wells syndrome, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease (NOMID, which is also referred to as chronic infantile neurologic cutaneous and articular syndrome. Recently, this group of diseases has been associated with mutations in the NLRP3 gene that encodes for the protein cryopyrin, a component of the inflammasome complex that regulates the maturation and secretion of inflammatory cytokine IL-1β. Immune cells from patients with NOMID secrete higher levels of active IL-1β compared with monocytes from healthy subjects. Overproduction of IL-1 is believed to promote aberrant inflammatory response in CAPS patients. Evidence supporting the clinical value of IL-1β in CAPS has been provided from the complete response of patients after treatment with IL-1 blocking agents.Keywords: CAPS, IL-1β, NLRP3, canakinumab, anakinra

  20. Positive correlation between serum interleukin-1β and state anger in rugby athletes.

    Science.gov (United States)

    Pesce, Mirko; Speranza, Lorenza; Franceschelli, Sara; Ialenti, Valentina; Iezzi, Irene; Patruno, Antonia; Rizzuto, Alessia; Robazza, Claudio; De Lutiis, Maria Anna; Felaco, Mario; Grilli, Alfredo

    2013-01-01

    Recently, several studies reported a relationship between immune system activation and anger expression. Consequently, the aim of this study was to explore immunitary molecular mechanisms that potentially underlie anger expression. To this end, we applied the Frustration-Aggression Theory in a contact sport model, utilizing the nearing of sporting events to trigger anger feelings. In parallel, we evaluated the activation of immune system at mRNA levels. We enrolled 20 amateur rugby players (age ± SD, 27.2 ± 4.5) who underwent psychological assessment to evaluate anger, with the State-Trait Anger Expression Inventory-2 (STAXI-2), before rugby matches; at the same time blood samples were taken to analyze the variations of gene expression by microarray. During the 2 hr before each game, a significant increase was verified in the Rage State (RS) score compared to the score ascertained 72 hr before. At the same time, we found modulation in expression profile, in particular increased expression of gene that encodes interleukin l-β (IL-1β). In a regression analysis, RS score was related to IL-1β, and the potential risk factors age, body mass index, smoking, and drinking. The levels of cytokine were positively and independently related to RS score. Our results suggest that the nearing of sporting event can trigger anger state feelings and activate immune system in rugby players. We propose the IL-1β as a potential biological marker of anger. However, further research is necessary to clarify the correlation between cytokine and anger. © 2012 Wiley Periodicals, Inc.

  1. Interleukin-1β overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents.

    Science.gov (United States)

    Gui, Wen-Shan; Wei, Xiao; Mai, Chun-Lin; Murugan, Madhuvika; Wu, Long-Jun; Xin, Wen-Jun; Zhou, Li-Jun; Liu, Xian-Guo

    2016-01-01

    Chronic pain is often accompanied by short-term memory deficit and depression. Currently, it is believed that short-term memory deficit and depression are consequences of chronic pain. Here, we test the hypothesis that the symptoms might be caused by overproduction of interleukin-1beta (IL-1β) in the injured nerve independent of neuropathic pain following spared nerve injury in rats and mice. Mechanical allodynia, a behavioral sign of neuropathic pain, was not correlated with short-term memory deficit and depressive behavior in spared nerve injury rats. Spared nerve injury upregulated IL-1β in the injured sciatic nerve, plasma, and the regions in central nervous system closely associated with pain, memory and emotion, including spinal dorsal horn, hippocampus, prefrontal cortex, nucleus accumbens, and amygdala. Importantly, the spared nerve injury-induced memory deficits, depressive, and pain behaviors were substantially prevented by peri-sciatic administration of IL-1β neutralizing antibody in rats or deletion of IL-1 receptor type 1 in mice. Furthermore, the behavioral abnormalities induced by spared nerve injury were mimicked in naïve rats by repetitive intravenous injection of re combinant rat IL-1β (rrIL-1β) at a pathological concentration as determined from spared nerve injury rats. In addition, microglia were activated by both spared nerve injury and intravenous injection of rrIL-1β and the effect of spared nerve injury was substantially reversed by peri-sciatic administration of anti-IL-1β. Neuropathic pain was not necessary for the development of cognitive and emotional disorders, while the overproduction of IL-1β in the injured sciatic nerve following peripheral nerve injury may be a common mechanism underlying the generation of neuropathic pain, memory deficit, and depression. © The Author(s) 2016.

  2. Synergistic Costimulatory Effect of Chlamydia pneumoniae with Carbon Nanoparticles on NLRP3 Inflammasome-Mediated Interleukin-1β Secretion in Macrophages.

    Science.gov (United States)

    Matsuo, Junji; Nakamura, Shinji; Takeda, Seiji; Ishida, Kasumi; Yamazaki, Tomohiro; Yoshida, Mitsutaka; Chiba, Hitoshi; Hui, Shu-Ping; Yamaguchi, Hiroyuki

    2015-07-01

    The obligate intracellular bacterium Chlamydia pneumoniae is not only a causative agent of community-acquired pneumonia but is also associated with a more serious chronic disease, asthma, which might be exacerbated by air pollution containing carbon nanoparticles. Although a detailed mechanism of exacerbation remains unknown, the proinflammatory cytokine interleukin-1β (IL-1β) is a critical player in the pathogenesis of asthma. C. pneumoniae induces IL-1β in macrophages via NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activation and Toll-like receptor 2/4 (TLR2/4) stimulation. Carbon nanoparticles, such as carbon nanotubes (CNTs), can also evoke the NLRP3 inflammasome to trigger IL-1β secretion from lipopolysaccharide-primed macrophages. This study assessed whether costimulation of C. pneumoniae with CNTs synergistically enhanced IL-1β secretion from macrophages, and determined the molecular mechanism involved. Enhanced IL-1β secretion from C. pneumoniae-infected macrophages by CNTs was dose and time dependent. Transmission electron microscopy revealed that C. pneumoniae and CNTs were engulfed concurrently by macrophages. Inhibitors of actin polymerization or caspase-1, a component of the inflammasome, significantly blocked IL-1β secretion. Gene silencing using small interfering RNA (siRNA) targeting the NLRP3 gene also abolished IL-1β secretion. Other inhibitors (K(+) efflux inhibitor, cathepsin B inhibitor, and reactive oxygen species-generating inhibitor) also blocked IL-1β secretion. Taken together, these findings demonstrated that CNTs synergistically enhanced IL-1β secretion from C. pneumoniae-infected macrophages via the NLRP3 inflammasome and caspase-1 activation, providing novel insight into our understanding of how C. pneumoniae infection can exacerbate asthma. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  3. Interleukin-1β Promotes Ovarian Tumorigenesis through a p53/NF-κB-Mediated Inflammatory Response in Stromal Fibroblasts12

    Science.gov (United States)

    Schauer, Isaiah Gregory; Zhang, Jing; Xing, Zhen; Guo, Xiaoqing; Mercado-Uribe, Imelda; Sood, Anil K; Huang, Peng; Liu, Jinsong

    2013-01-01

    Cancer has long been considered a disease that mimics an “unhealed wound,” with oncogene-induced secretory activation signals from epithelial cancer cells facilitating stromal fibroblast, endothelial, and inflammatory cell participation in tumor progression. However, the underlying mechanisms that orchestrate cooperative interaction between malignant epithelium and the stroma remain largely unknown. Here, we identified interleukin-1β (IL-1β) as a stromal-acting chemokine secreted by ovarian cancer cells, which suppresses p53 protein expression in cancer-associated fibroblasts (CAFs). Elevated expression of IL-1β and cognate receptor IL-1R1 in ovarian cancer epithelial cells and CAFs independently predicted reduced overall patient survival, as did repressed nuclear p53 in ovarian CAFs. Knockdown of p53 expression in ovarian fibroblasts significantly enhanced the expression and secretion of chemokines IL-8, growth regulated oncogene-alpha (GRO-α), IL-6, IL-1β, and vascular endothelial growth factor (VEGF), significantly increased in vivo mouse xenograft ovarian cancer tumor growth, and was entirely dependent on interaction with, and transcriptional up-regulation of, nuclear factor-kappaB (NF-κB) p65. Our results have uncovered a previously unrecognized circuit whereby epithelial cancer cells use IL-1β as a communication factor instructing stromal fibroblasts through p53 to generate a protumorigenic inflammatory microenvironment. Attenuation of p53 protein expression in stromal fibroblasts generates critical protumorigenic functionality, reminiscent of the role that oncogenic p53 mutations play in cancer cells. These findings implicate CAFs as an important target for blocking inflammation in the tumor microenvironment and reducing tumor growth. PMID:23555186

  4. Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α.

    Science.gov (United States)

    Berda-Haddad, Yaël; Robert, Stéphane; Salers, Paul; Zekraoui, Leila; Farnarier, Catherine; Dinarello, Charles A; Dignat-George, Françoise; Kaplanski, Gilles

    2011-12-20

    Sterile inflammation resulting from cell death is due to the release of cell contents normally inactive and sequestered within the cell; fragments of cell membranes from dying cells also contribute to sterile inflammation. Endothelial cells undergoing stress-induced apoptosis release membrane microparticles, which become vehicles for proinflammatory signals. Here, we show that stress-activated endothelial cells release two distinct populations of particles: One population consists of membrane microparticles (bodies. Contrary to present concepts, endothelial microparticles do not contain IL-1α and do not induce neutrophilic chemokines in vitro. In contrast, the large apoptotic bodies contain the full-length IL-1α precursor and the processed mature form. In vitro, these apoptotic bodies induce monocyte chemotactic protein-1 and IL-8 chemokine secretion in an IL-1α-dependent but IL-1β-independent fashion. Injection of these apoptotic bodies into the peritoneal cavity of mice induces elevated serum neutrophil-inducing chemokines, which was prevented by cotreatment with the IL-1 receptor antagonist. Consistently, injection of these large apoptotic bodies into the peritoneal cavity induced a neutrophilic infiltration that was prevented by IL-1 blockade. Although apoptosis is ordinarily considered noninflammatory, these data demonstrate that nonphagocytosed endothelial apoptotic bodies are inflammatory, providing a vehicle for IL-1α and, therefore, constitute a unique mechanism for sterile inflammation.

  5. Rhinovirus-mediated changes in airway smooth muscle responsiveness: induced autocrine role of interleukin-1beta.

    Science.gov (United States)

    Hakonarson, H; Carter, C; Maskeri, N; Hodinka, R; Grunstein, M M

    1999-07-01

    An important interplay exists between specific viral respiratory pathogens, most commonly rhinovirus (RV), and altered airway responsiveness in the development and exacerbations of asthma. Given that RV infection reportedly induces the release of various cytokines in different cell types and that the reported effects of RV on airway smooth muscle (ASM) responsiveness are highly comparable to those obtained in ASM exposed to the proinflammatory cytokine interleukin (IL)-1beta, this study examined whether RV (serotype 16)-mediated pertubations in ASM responsiveness are mechanistically coupled to altered induced expression and action of IL-1beta in RV-exposed isolated rabbit and human ASM tissue and cultured cells. Relative to control tissues, ASM inoculated with RV exhibited significantly increased maximal isometric contractility to ACh (P exposure; and 3) the latter effect of RV was inhibited in the presence of a monoclonal antibody to intercellular adhesion molecule-1, the endogenous receptor for most RV. Collectively, these observations provide new evidence demonstrating that "pro-asthmatic-like" pertubations in agonist responsiveness elicited in RV-exposed ASM are largely attributed to the induced autologous expression and autocrine action of IL-1beta in the virus-infected ASM.

  6. Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1β

    Directory of Open Access Journals (Sweden)

    Alice C-H. Chen

    2017-10-01

    Full Text Available Protracted bacterial bronchitis (PBB in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL-1β signature, the contribution of the IL-1β pathway to host defence is not clear. This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway. Non-typeable Haemophilus influenzae (NTHi stimulation of peripheral blood mononuclear cells (PBMCs from control subjects (n=20, those with recurrent PBB (n=20 and bronchiectasis (n=20 induced high concentrations of IL-1β, IL-6, interferon (IFN-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort. Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells. Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.

  7. A common W556S mutation in the LDL receptor gene of Danish patients with familial hypercholesterolemia encodes a transport-defective protein

    DEFF Research Database (Denmark)

    Jensen, H K; Holst, H; Jensen, L G

    1997-01-01

    In a group of unrelated Danish patients with familial hypercholesterolemia (FH) we recently reported two common low-density lipoprotein (LDL) receptor mutations, W23X and W66G, accounting for 30% of the cases. In this study, we describe another common LDL receptor mutation, a G to C transition at c...... in the endoplasmic reticulum. The transport-defective W556S mutation and the W23X and W66G mutations seem to account for about 40% of the LDL receptor defects in Danish families with FH....

  8. Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer.

    Science.gov (United States)

    Brailo, Vlaho; Vucicevic-Boras, Vanja; Lukac, Josip; Biocina-Lukenda, Dolores; Zilic-Alajbeg, Iva; Milenovic, Aleksandar; Balija, Melita

    2012-01-01

    The aim of study was to compare salivary and serum concentrations of interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in patients with oral leukoplakia, oral cancer and healthy controls. Eighty eight patients (28 with oral cancer, 29 leukoplakia, and 31 healthy controls) were included in this study. Cytokine concentrations were measured by commercial enzyme linked immunoassay. Salivary IL-1β and IL-6 were significantly higher in oral cancer patients than in patients with leukoplakia and control group (pcancer patients. Patients with oral cancer have elevated levels of inflammatory cytokines in their saliva. Whether this elevation can be used for monitoring the malignant transformation of oral leukoplakia remains to be answered by further follow up studies.

  9. Trimeric form of intracellular ATP synthase subunit β of Aggregatibacter actinomycetemcomitans binds human interleukin-1β.

    Directory of Open Access Journals (Sweden)

    Annamari Paino

    Full Text Available Bacterial biofilms resist host defenses and antibiotics partly because of their decreased metabolism. Some bacteria use proinflammatory cytokines, such as interleukin (IL-1β, as cues to promote biofilm formation and to alter virulence. Although one potential bacterial IL-1β receptor has been identified, current knowledge of the bacterial IL-1β sensing mechanism is limited. In chronic biofilm infection, periodontitis, Aggregatibacter actinomycetemcomitans requires tight adherence (tad-locus to form biofilms, and tissue destroying active lesions contain more IL-1β than inactive ones. The effect of IL-1β on the metabolic activity of A. actinomycetemcomitans biofilm was tested using alamarBlue™. The binding of IL-1β to A. actinomycetemcomitans cells was investigated using transmission electron microscopy and flow cytometry. To identify the proteins which interacted with IL-1β, different protein fractions from A. actinomycetemcomitans were run in native-PAGE and blotted using biotinylated IL-1β and avidin-HRP, and identified using mass spectroscopy. We show that although IL-1β slightly increases the biofilm formation of A. actinomycetemcomitans, it reduces the metabolic activity of the biofilm. A similar reduction was observed with all tad-locus mutants except the secretin mutant, although all tested mutant strains as well as wild type strains bound IL-1β. Our results suggest that IL-1β might be transported into the A. actinomycetemcomitans cells, and the trimeric form of intracellular ATP synthase subunit β interacted with IL-1β, possibly explaining the decreased metabolic activity. Because ATP synthase is highly conserved, it might universally enhance biofilm resistance to host defense by binding IL-1β during inflammation.

  10. Vitamin D differentially regulates Salmonella-induced intestine epithelial autophagy and interleukin-1β expression.

    Science.gov (United States)

    Huang, Fu-Chen

    2016-12-21

    To investigate the effects of active vitamin D3 on autophagy and interleukin (IL)-1β expression in Salmonella-infected intestinal epithelial cells (IECs). Caco-2 cells, NOD2 siRNA-, Atg16L1 siRNA- or vitamin D receptor (VDR) siRNA-transfected Caco-2 cells were pretreated with 1,25-dihydroxyvitamin D3 (1,25D3), and then infected by wild-type S. typhimurium strain SL1344. The conversion of LC3-I to LC3-II was detected by Western blot analysis and LC3+ autophagosome was analyzed by immunofluorescence. Caco-2 cells or VDR siRNA-transfected cells were pretreated with 1,25D3, and then infected by SL1344. Membrane protein and total RNA were analyzed by Western blot and RT-PCR for VDR and Atg16L1 protein and mRNA expression, respectively. Atg16L1 siRNA-transfected Caco-2 cells were pretreated by 1,25D3 and then infected with SL1344. Total RNA was analyzed by RT-PCR for IL-1β mRNA expression. The active form of vitamin D, 1,25D3, showed enhanced VDR-mediated Atg16L1 mRNA expression, membranous Atg16L1 protein expression leading to enhanced autophagic LC3II protein expression and LC3 punctae in Salmonella-infected Caco-2 cells which was counteracted by Atg16L1 and VDR siRNA, but Atg16L1 mediated suppression of IL-1β expression. Thus, active vitamin D may enhance autophagy but suppress inflammatory IL-1β expression in Salmonella-infected IECs. Active vitamin D might enhance autophagic clearance of Salmonella infection, while modulation of inflammatory responses prevents the host from detrimental effects of overwhelming inflammation.

  11. Interferon-tau attenuates uptake of nanoparticles and secretion of interleukin-1β in macrophages.

    Directory of Open Access Journals (Sweden)

    Kyoko Hara

    Full Text Available BACKGROUND: Type I interferons (IFNs, including IFN-alpha (IFNA and IFN-beta (IFNB, have anti-inflammatory properties and are used to treat patients with autoimmune and inflammatory disorders. However, little is known of the role of IFN-tau (IFNT, a type I IFN produced by ruminant animals for inflammation. Because IFNB has recently been shown to inhibit nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3 (NLRP3 inflammasome activation and subsequent secretion of the potent inflammatory cytokine interleukin (IL-1β, we examined the effects of ruminant IFNT on NLRP3 inflammasome-mediated IL-1β secretion in human THP-1 macrophages. METHODS AND RESULTS: IFNT dose-dependently inhibited IL-1β secretion induced by nano-silica, a well-known activators of NLRP3 inflammasomes, in human macrophages primed with lipopolysaccharide (LPS, TLR4 agonist and Pam3CSK4 (TLR1/2 agonist. IFNT also suppressed phagocytosis of nano-silica and reactive oxygen species (ROS generation. Western blot analysis showed that IFNT inhibited both pro-IL-1β and mature IL-1β. In addition, real-time RT-PCR analysis showed that IFNT suppressed IL-1β mRNA expression induced by LPS and Pam3CSK4. Although nano-silica particles did not induce IL-10 secretion, IFNT induced IL-10 secretion in a dose-dependent manner. Furthermore, IFNT-suppressed IL-1β secretion was restored by anti-IL-10 neutralizing antibody. CONCLUSIONS: Ruminant IFNT inhibits NLRP3 inflammasome-driven IL-1β secretion in human macrophages via multiple pathways, including the uptake of nano-silica particles, generation of ROS, and IL-10-mediated inhibition of pro-IL-1β induction. It may be a therapeutic alternative to IFNA and IFNB.

  12. Necrosis-Induced Sterile Inflammation Mediated by Interleukin-1α in Retinal Pigment Epithelial Cells.

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    Yang Liu

    Full Text Available Endogenous danger signals released from necrotic cells contribute to retinal inflammation. We have now investigated the effects of necrotic cell extracts prepared from ARPE-19 human retinal pigment epithelial cells (ANCE on the release of proinflammatory cytokines and chemokines by healthy ARPE-19 cells. ANCE were prepared by subjection of ARPE-19 cells to freeze-thaw cycles. The release of various cytokines and chemokines from ARPE-19 cells was measured with a multiplex assay system or enzyme-linked immunosorbent assays. The expression of interleukin (IL-1α and the phosphorylation and degradation of the endogenous nuclear factor-κB (NF-κB inhibitor IκB-α were examined by immunoblot analysis. Among the various cytokines and chemokines examined, we found that ANCE markedly stimulated the release of the proinflammatory cytokine IL-6 and the chemokines IL-8 and monocyte chemoattractant protein (MCP-1 by ARPE-19 cells. ANCE-induced IL-6, IL-8, and MCP-1 release was inhibited by IL-1 receptor antagonist and by an IKK2 inhibitor (a blocker of NF-κB signaling in a concentration-dependent manner, but was not affected by a pan-caspase inhibitor (Z-VAD-FMK. Recombinant IL-1α also induced the secretion of IL-6, IL-8, and MCP-1 from ARPE-19 cells, and IL-1α was detected in ANCE. Furthermore, ANCE induced the phosphorylation and degradation of IκB-α in ARPE-19 cells. Our findings thus suggest that IL-1α is an important danger signal that is released from necrotic retinal pigment epithelial cells and triggers proinflammatory cytokine and chemokine secretion from intact cells in a manner dependent on NF-κB signaling. IL-1α is therefore a potential therapeutic target for amelioration of sterile inflammation in the retina.

  13. Molecular cloning and characterization of two novel genes from hexaploid wheat that encode double PR-1 domains coupled with a receptor-like protein kinase

    Science.gov (United States)

    Hexaploid wheat (Triticum aestivum L.) contains at least 23 TaPr-1 genes encoding the group 1 pathogenesis-related (PR-1) proteins as identified in our previous work. Here we report the cloning and characterization of TaPr-1-rk1 and TaPr-1-rk2, two novel genes closely related to the wheat PR-1 famil...

  14. Paradoxical mineralocorticoid receptor-mediated effect in fear memory encoding and expression of rats submitted to an olfactory fear conditioning task

    NARCIS (Netherlands)

    Souza, R.R.; Dal Bó, S.; de Kloet, E.R.; Oitzl, M.S.; Carobrez, A.P.

    2014-01-01

    There is general agreement that the substantial modification in memory and motivational states exerted by corticosteroids after a traumatic experience is mediated in complementary manner by the mineralocorticoid (MR) and glucocorticoid (GR) receptors. Here we tested the hypothesis that

  15. Identification of a novel bacterial outer membrane interleukin-1Β-binding protein from Aggregatibacter actinomycetemcomitans.

    Directory of Open Access Journals (Sweden)

    Annamari Paino

    Full Text Available Aggregatibacter actinomycetemcomitans is a gram-negative opportunistic oral pathogen. It is frequently associated with subgingival biofilms of both chronic and aggressive periodontitis, and the diseased sites of the periodontium exhibit increased levels of the proinflammatory mediator interleukin (IL-1β. Some bacterial species can alter their physiological properties as a result of sensing IL-1β. We have recently shown that this cytokine localizes to the cytoplasm of A. actinomycetemcomitans in co-cultures with organotypic gingival mucosa. However, current knowledge about the mechanism underlying bacterial IL-1β sensing is still limited. In this study, we characterized the interaction of A. actinomycetemcomitans total membrane protein with IL-1β through electrophoretic mobility shift assays. The interacting protein, which we have designated bacterial interleukin receptor I (BilRI, was identified through mass spectrometry and was found to be Pasteurellaceae specific. Based on the results obtained using protein function prediction tools, this protein localizes to the outer membrane and contains a typical lipoprotein signal sequence. All six tested biofilm cultures of clinical A. actinomycetemcomitans strains expressed the protein according to phage display-derived antibody detection. Moreover, proteinase K treatment of whole A. actinomycetemcomitans cells eliminated BilRI forms that were outer membrane specific, as determined through immunoblotting. The protein was overexpressed in Escherichia coli in both the outer membrane-associated form and a soluble cytoplasmic form. When assessed using flow cytometry, the BilRI-overexpressing E. coli cells were observed to bind 2.5 times more biotinylated-IL-1β than the control cells, as detected with avidin-FITC. Overexpression of BilRI did not cause binding of a biotinylated negative control protein. In a microplate assay, soluble BilRI bound to IL-1β, but this binding was not specific, as a control

  16. Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells

    Directory of Open Access Journals (Sweden)

    Iida Hiroki

    2011-06-01

    Full Text Available Abstract Background Peripheral-type benzodiazepine receptor (PBR expression levels are low in normal human brain, but their levels increase in inflammation, brain injury, neurodegenerative states and gliomas. It has been reported that PBR functions as an immunomodulator. The mechanisms of action of midazolam, a benzodiazepine, in the immune system in the CNS remain to be fully elucidated. We previously reported that interleukin (IL-1β stimulates IL-6 synthesis from rat C6 glioma cells and that IL-1β induces phosphorylation of inhibitory kappa B (IκB, p38 mitogen-activated protein (MAP kinase, stress-activated protein kinase (SAPK/c-Jun N-terminal kinase (JNK, extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription (STAT3. It has been shown that p38 MAP kinase is involved in IL-1β-induced IL-6 release from these cells. In the present study, we investigated the effect of midazolam on IL-1β-induced IL-6 release from C6 cells, and the mechanisms of this effect. Methods Cultured C6 cells were stimulated by IL-1β. IL-6 release from C6 cells was measured using an enzyme-linked immunosorbent assay, and phosphorylation of IκB, the MAP kinase superfamily, and STAT3 was analyzed by Western blotting. Results Midazolam, but not propofol, inhibited IL-1β-stimulated IL-6 release from C6 cells. The IL-1β-stimulated levels of IL-6 were suppressed by wedelolactone (an inhibitor of IκB kinase, SP600125 (an inhibitor of SAPK/JNK, and JAK inhibitor I (an inhibitor of JAK 1, 2 and 3. However, IL-6 levels were not affected by PD98059 (an inhibitor of MEK1/2. Midazolam markedly suppressed IL-1β-stimulated STAT3 phosphorylation without affecting the phosphorylation of p38 MAP kinase, SAPK/JNK or IκB. Conclusion These results strongly suggest that midazolam inhibits IL-1β-induced IL-6 release in rat C6 glioma cells via suppression of STAT3 activation. Midazolam may affect immune system function in the CNS.

  17. Characterization of a naturally-occurring polymorphism in the UHR-1 gene encoding the putative rat prolactin-releasing peptide receptor.

    Science.gov (United States)

    Ellacott, Kate L J; Donald, Emma L; Clarkson, Paul; Morten, John; Masters, Dave; Brennand, John; Luckman, Simon M

    2005-04-01

    The rat orphan receptor UHR-1 and its human orthologue, GPR10, were first isolated in 1995. The ligand for this receptor, prolactin-releasing peptide (PrRP), was identified in 1998 by reverse pharmacology and has subsequently been implicated in a number of physiological processes. As supported by its localization and regulation in the hypothalamus and brainstem, we have shown previously that PrRP is involved in energy homeostasis. Here we describe a naturally occurring polymorphism in the UHR-1 gene that results in an ATG to ATA change at the putative translational initiation site. The presence of the polymorphism abolished the binding of 125I PrRP in rat brain slices but did not affect the ability of PrRP to reduce fast-induced food intake. Together this data suggest that PrRP may be exerting its feeding effects through a receptor other than UHR-1.

  18. Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses.

    Science.gov (United States)

    Russell, Ryan F; McDonald, Jacqueline U; Ivanova, Maria; Zhong, Ziyun; Bukreyev, Alexander; Tregoning, John S

    2015-09-01

    The small hydrophobic (SH) gene of respiratory syncytial virus (RSV), a major cause of infant hospitalization, encodes a viroporin of unknown function. SH gene knockout virus (RSV ΔSH) is partially attenuated in vivo, but not in vitro, suggesting that the SH protein may have an immunomodulatory role. RSV ΔSH has been tested as a live attenuated vaccine in humans and cattle, and here we demonstrate that it protected against viral rechallenge in mice. We compared the immune response to infection with RSV wild type and RSV ΔSH in vivo using BALB/c mice and in vitro using epithelial cells, neutrophils, and macrophages. Strikingly, the interleukin-1β (IL-1β) response to RSV ΔSH infection was greater than to wild-type RSV, in spite of a decreased viral load, and when IL-1β was blocked in vivo, the viral load returned to wild-type levels. A significantly greater IL-1β response to RSV ΔSH was also detected in vitro, with higher-magnitude responses in neutrophils and macrophages than in epithelial cells. Depleting macrophages (with clodronate liposome) and neutrophils (with anti-Ly6G/1A8) demonstrated the contribution of these cells to the IL-1β response in vivo, the first demonstration of neutrophilic IL-1β production in response to viral lung infection. In this study, we describe an increased IL-1β response to RSV ΔSH, which may explain the attenuation in vivo and supports targeting the SH gene in live attenuated vaccines. There is a pressing need for a vaccine for respiratory syncytial virus (RSV). A number of live attenuated RSV vaccine strains have been developed in which the small hydrophobic (SH) gene has been deleted, even though the function of the SH protein is unknown. The structure of the SH protein has recently been solved, showing it is a pore-forming protein (viroporin). Here, we demonstrate that the IL-1β response to RSV ΔSH is greater in spite of a lower viral load, which contributes to the attenuation in vivo. This potentially suggests a

  19. Single nucleotide polymorphisms in genes encoding toll-like receptors 7, 8 and 9 in Danish patients with systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Enevold, C; Nielsen, Claus Henrik; Jacobsen, Rasmus Sleimann

    2014-01-01

    Several studies indicate a role for toll-like receptors (TLRs) in the pathogenesis of systemic lupus erythematosus (SLE). We aimed to investigate the risk of SLE and typical clinical and serological manifestations of SLE potentially conferred by selected single nucleotide polymorphisms (SNPs...

  20. High constitutive activity of a virus-encoded seven transmembrane receptor in the absence of the conserved DRY motif (Asp-Arg-Tyr) in transmembrane helix 3

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Kledal, Thomas N; Schwartz, Thue W

    2005-01-01

    of activated T cells. Coexpression of the ORF74-EHV2 receptor with the promiscuous G protein Gqi4myr supported the constitutive Gi activation as determined by inositol phosphate turnover and CREB activation. The constitutive activity was inhibited by nonpeptide inverse agonists with micromolar potencies...

  1. Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation

    Directory of Open Access Journals (Sweden)

    Soliman Mahmoud L

    2012-03-01

    Full Text Available Abstract Background Long-term acetate supplementation reduces neuroglial activation and cholinergic cell loss in a rat model of lipopolysaccharide-induced neuroinflammation. Additionally, a single dose of glyceryl triacetate, used to induce acetate supplementation, increases histone H3 and H4 acetylation and inhibits histone deacetylase activity and histone deacetylase-2 expression in normal rat brain. Here, we propose that the therapeutic effect of acetate in reducing neuroglial activation is due to a reversal of lipopolysaccharide-induced changes in histone acetylation and pro-inflammatory cytokine expression. Methods In this study, we examined the effect of a 28-day-dosing regimen of glyceryl triacetate, to induce acetate supplementation, on brain histone acetylation and interleukin-1β expression in a rat model of lipopolysaccharide-induced neuroinflammation. The effect was analyzed using Western blot analysis, quantitative real-time polymerase chain reaction and enzymic histone deacetylase and histone acetyltransferase assays. Statistical analysis was performed using one-way analysis of variance, parametric or nonparametric when appropriate, followed by Tukey's or Dunn's post-hoc test, respectively. Results We found that long-term acetate supplementation increased the proportion of brain histone H3 acetylated at lysine 9 (H3K9, histone H4 acetylated at lysine 8 and histone H4 acetylated at lysine 16. However, unlike a single dose of glyceryl triacetate, long-term treatment increased histone acetyltransferase activity and had no effect on histone deacetylase activity, with variable effects on brain histone deacetylase class I and II expression. In agreement with this hypothesis, neuroinflammation reduced the proportion of brain H3K9 acetylation by 50%, which was effectively reversed with acetate supplementation. Further, in rats subjected to lipopolysaccharide-induced neuroinflammation, the pro-inflammatory cytokine interleukin-1β protein

  2. Interleukin-1 beta Attenuates Myofibroblast Formation and Extracellular Matrix Production in Dermal and Lung Fibroblasts Exposed to Transforming Growth Factor-beta 1

    NARCIS (Netherlands)

    Mia, Masum M.; Boersema, Miriam; Bank, Ruud A.

    2014-01-01

    One of the most potent pro-fibrotic cytokines is transforming growth factor (TGF beta). TGF beta is involved in the activation of fibroblasts into myofibroblasts, resulting in the hallmark of fibrosis: the pathological accumulation of collagen. Interleukin-1 beta (IL1 beta) can influence the

  3. Association between HLA-DR2 and production of tumour necrosis factor alpha and interleukin 1 by mononuclear cells activated by lipopolysaccharide

    DEFF Research Database (Denmark)

    Bendtzen, K; Morling, N; Fomsgaard, A

    1988-01-01

    The production of tumour necrosis factor (TNF) and interleukin 1 (IL-1) by lipopolysaccharide-activated mononuclear cells from 39 healthy donors was studied in vitro by bioassay and ELISA. The donors were typed for HLA-A, -B, -C, -DR, and -DP antigens. There was no detectable production of TNF beta...

  4. Modulator effects of interleukin-1beta and tumor necrosis factor-alpha on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Bernardino, Liliana; Xapelli, Sara; Silva, Ana P

    2005-01-01

    The inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects of th...

  5. Radioprotection of bone marrow stem cell subsets by interleukin-1 and kit-ligand : Implications for CFU-S as the responsible target cell population

    NARCIS (Netherlands)

    van Os, Ronald; Lamont, G; Witsell, A; Mauch, PM

    Various cytokines have been reported to have radioprotective effects on the bone marrow. Of these, c-kit-ligand (KL) and interleukin-1 (IL-1) have the most dramatic effect when given prior to total body irradiation (TBI). Given simultaneously, KL and IL-1 demonstrated a strong effect on increasing

  6. Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

    DEFF Research Database (Denmark)

    Bashamboo, Anu; Eozenou, Caroline; Jorgensen, Anne

    2018-01-01

    Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation......, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified...... establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent...

  7. Polymorphism screening of four genes encoding advanced glycation end-product putative receptors. Association study with nephropathy in type 1 diabetic patients

    DEFF Research Database (Denmark)

    Poirier, Odette; Nicaud, Viviane; Vionnet, N

    2001-01-01

    Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes....... The minor allele of a polymorphism located in the promoter region of the RAGE gene (C-1152A) conferred a weak protective effect (P

  8. Massive parallel gene expression profiling of RINm5F pancreatic islet beta-cells stimulated with interleukin-1beta

    DEFF Research Database (Denmark)

    Rieneck, K; Bovin, L F; Josefsen, K

    2000-01-01

    found that 146 full-length genes and a large number of expressed sequence tags were differentially regulated 3-fold or more. Most of the differentially regulated transcripts have not previously been described to be regulated by IL-1beta in beta-cells. We have analysed the expression data and sorted......Interleukin 1 (IL-1) is a pleiotropic cytokine with the potential to kill pancreatic beta-cells, and this unique property is thought to be involved in the pathogenesis of type I diabetes mellitus. We therefore determined the quantitative expression of 24,000 mRNAs of RINm5F, an insulinoma cell line...... derived from rat pancreatic beta-cells, before and after challenge with 30 and 1,000 pg/ml of recombinant human IL-1beta. The highest concentration resulted in decreased insulin production and cell death over a period of 4 days. Using three different time points, 2, 4 and 24 hours after challenge, we...

  9. Association study of interleukin-1 family and interleukin-6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis.

    Science.gov (United States)

    Najafi, S; Yousefi, H; Mohammadzadeh, M; Bidoki, A Z; Firouze Moqadam, I; Farhadi, E; Amirzargar, A A; Rezaei, N

    2015-12-01

    Recurrent aphthous stomatitis (RAS) is a common painful, ulcerative oral inflammatory disorder with unknown aetiology. Immune system and aberrant cytokine cascade deemed to be critical in outbreaks of RAS ulcers. Interleukin-1 (IL-1) and IL-6 are the most potent pro-inflammatory cytokines. Single nucleotide polymorphisms (SNPs) of IL-1 and IL-6 genes can affect the secretion of these cytokines. The aim of this study was to investigate the association between RAS and IL-6 and IL-1 in Iranian subjects with minor RAS. Genomic DNA was obtained from 64 Iranian patients with RAS. IL-1α C -889 T, IL-1β C -511 T, IL-1β C +3962 T, IL-1R C pst-I 1970 T, IL-1Ra C Mspa-I11100 T, IL-6 C -174 G and IL-6 A nt +565 G polymorphisms were determined using polymerase chain reaction with sequence-specific primers (PCR-SSP). The frequency of C -174 C genotype in the patients group was significantly different from the healthy control. No other significant differences were found in genotype and alleles frequencies between the two groups. These results indicate that certain SNPs of IL-6 gene at position -174 which located in promoter have association with predisposition of individuals to RAS. © 2015 John Wiley & Sons Ltd.

  10. Chondrocalcin is internalized by chondrocytes and triggers cartilage destruction via an interleukin-1β-dependent pathway.

    Science.gov (United States)

    Bantsimba-Malanda, Claudie; Cottet, Justine; Netter, Patrick; Dumas, Dominique; Mainard, Didier; Magdalou, Jacques; Vincourt, Jean-Baptiste

    2013-01-01

    Chondrocalcin is among the most highly synthesized polypeptides in cartilage. This protein is released from its parent molecule, type II pro-collagen, after secretion by chondrocytes. A participation of extracellular, isolated chondrocalcin in mineralization was proposed more than 25 years ago, but never demonstrated. Here, exogenous chondrocalcin was found to trigger MMP13 secretion and cartilage destruction ex vivo in human cartilage explants and did so by modulating the expression of interleukin-1β in primary chondrocyte cultures in vitro. Chondrocalcin was found internalized by chondrocytes. Uptake was found mediated by a single 18-mer peptide of chondrocalcin, which does not exhibit homology to any known cell-penetrating peptide. The isolated peptide, when artificially linked as a tetramer, inhibited gene expression regulation by chondrocalcin, suggesting a functional link between uptake and gene expression regulation. At the same time, the tetrameric peptide potentiated chondrocalcin uptake by chondrocytes, suggesting a cooperative mechanism of entry. The corresponding peptide from type I pro-collagen supported identical cell-penetration, suggesting that this property may be conserved among C-propeptides of fibrillar pro-collagens. Structural modeling localized this peptide to the tips of procollagen C-propeptide trimers. Our findings shed light on unexpected function and mechanism of action of these highly expressed proteins from vertebrates. © 2013. Published by Elsevier B.V. All rights reserved.

  11. Impact of interleukin 1 gene polymorphism and smoking on long-term stability following gingival recession treatment.

    Science.gov (United States)

    Jankovic, Sasha; Aleksic, Zoran; Dimitrijevic, Bozidar; Camargo, Paulo; Kenney, Barry; Lekovic, Vojislav

    2013-01-01

    Risk factors such as smoking, genetic factors, and tissue biotype play an important role in the etiology, predictability, and long-term stability of gingival recession treatment. This study was designed to evaluate the influence of interleukin 1 (IL-1) polymorphism and smoking on the stability of gingival recession treatment after 1 and 3 years. All patients (n = 55) were treated for type I and II recession defects using a connective tissue graft. Clinical evaluations were performed, which included assessment of vertical recession depth, gingival inflammation, and clinical attachment level. A fingerstick blood sample was collected using specially provided DNA filter paper and mailed for processing in a laboratory using polymerase chain reaction-based methodology. The results indicated that 19 subjects were genotype positive (34.5%). Treatment of the localized recessions was effective and provided a similar amount of coverage in genotype-positive and genotype-negative subjects within smoking and nonsmoking groups after 1 year. In a 3-year period, nonsmoking patients with positive IL-1 genotype lost approximately 20% of the root coverage gained at 1 year and were almost four times more inferior compared with genotype-negative patients. Patients who smoked and had a positive IL-1 genotype lost approximately 35% of the gained root coverage. IL-1 polymorphism and smoking habit did not affect gingival recession treatment at 1 year but had a great impact on long-term stability.

  12. Association between the interleukin-1β C-511T polymorphism and periodontitis: a meta-analysis in the Chinese population.

    Science.gov (United States)

    Wang, H F; He, F Q; Xu, C J; Li, D M; Sun, X J; Chi, Y T; Guo, W

    2017-02-23

    The association between the interleukin-1 beta (IL-1β) C-511T (or rs16944) polymorphism and periodontitis remains inconclusive, even though there have been previous studies on this association. To assess the effects of IL-1β C-511T variants on the risk of development of periodontitis, a meta-analysis was performed in a single ethnic population. Studies, published up to December 2015, were selected for the meta-analysis from PubMed and Chinese databases. The associations were assessed with pooled OR and 95%CI. This meta-analysis identified 8 studies, including 1276 periodontitis cases and 1558 controls. Overall, a significant association between the IL-1β C-511T polymorphism and periodontitis was found in the Chinese population (TT vs CC: OR = 1.48, 95%CI = 1.19-1.85; TT + CT vs CC: OR = 1.50, 95%CI = 1.25-1.81; T vs C: OR = 1.33, 95%CI = 1.06-1.68). In the subgroup analyses based on geographical area(s), source of controls, and type of periodontitis, significant results were obtained for the association between IL-1β C-511T variants and periodontitis. Our meta-analysis indicated that the IL-1β C-511T polymorphism may be a genetic susceptibility factor for periodontitis in the Chinese population. This marker could be used to identify Chinese individuals at a high risk for periodontitis.

  13. Protective effect of niacinamide on interleukin-1beta-induced annulus fibrosus type II collagen degeneration in vitro.

    Science.gov (United States)

    Duan, Deyu; Yang, Shuhua; Shao, Zengwu; Wang, Hong; Xiong, Xiaoqian

    2007-02-01

    The protective effect of niacinamide on interleukin-1beta (IL-1beta)-induced annulus fibrosus (AF) type II collagen degeneration in vitro and the mechanism were investigated. Chiba's intervertebral disc (IVD) culture models in rabbits were established and 48 IVDs from 12 adult Japanese white rabbits were randomly divided into 4 groups: normal control group, niacinamide-treated group, type II collagen degneration group (IL-1beta) and treatment group (niacinamide+IL-1beta). After culture for one week, AFs were collected for inducible nitric oxide synthase (iNOS), cysteine containing aspartate specific protease-3 (Caspase-3) and type II collagen immunohistochemical examination, and type II collagen reverse transcription polymerase chain reaction (RT-PCR). The results showed that rate of iNOS positive staining AF cells in the 4 groups was 17.6%, 10.9%, 73.9% and 19.3% respectively. The positive rate in treatment group was significantly lower than in the type II collagen degeneration group (Pniacinamide could effectively inhibit IL-1beta stimulated increase of iNOS and Caspase-3 in AF, and alleviate IL-1beta-caused destruction and synthesis inhibition of type II collagen. Niacinamide is of potential for clinical treatment of IVD degeneration.

  14. A dose titration of triamcinolone acetonide on insulin-like growth factor-1 and interleukin-1-conditioned equine cartilage explants.

    Science.gov (United States)

    Sandler, E A; Frisbie, D D; McIlwraith, C W

    2004-01-01

    Previous in vitro pilot studies have defined a potentially beneficial effect of insulin-like growth factor-1 (IGF-1) and triamcinolone acetonide (TA) on interleukin-1 (IL-1)-conditioned equine cartilage. Furthermore, an optimal dose for IGF-1 treatment alone has been documented previously using the same test system as in the current project. To perform a dose titration of TA on IL-1-conditioned equine articular cartilage explants in the presence of an optimised IGF-1 dose, in order to optimise a triamcinolone concentration for use in combination with IGF-1 for future investigations. Cartilage explants were harvested from the distal femur of a normal horse. The effect of a clinically relevant TA dose range was evaluated in the presence of IL-1 and IGF-1 through measurement of proteoglycan (PG) matrix metabolism (synthesis and degradation). TA and IGF-1 in combination inhibited the IL-1-induced release of PG matrix components (glycosaminoglycan or GAG) from the articular cartilage, as well as producing a significant increase in GAG synthesis. This experiment provided proof of principle that a combination treatment appears to be able to combat the IL-1-induced matrix depletion, while enhancing anabolic metabolism within the articular cartilage. The use of IGF-1 in conjunction with TA in vivo has the potential to provide beneficial anabolic effects not seen with TA alone.

  15. Increase of crevicular interleukin 1beta under academic stress at experimental gingivitis sites and at sites of perfect oral hygiene.

    Science.gov (United States)

    Deinzer, R; Förster, P; Fuck, L; Herforth, A; Stiller-Winkler, R; Idel, H

    1999-01-01

    This study analyses the effects of academic stress on crevicular interleukin-1beta(I1-1beta) both at experimental gingivitis sites and at sites of perfect oral hygiene. I1-1beta is thought to play a predominant role in periodontal tissue destruction. 13 medical students participating in a major medical exam (exam group) and 13 medical students not participating in any exam throughout the study period (control group) volunteered for the study. In a split-mouth-design, they refrained from any oral hygiene procedures in two opposite quadrants for 21 days (experimental gingivitis) while they maintained perfect hygiene levels at the remaining sites. Crevicular fluid was sampled for further I1-1beta analysis at teeth 5 and 6 of the upper jaw at days 1, 5, 8, 11, 14, 18 and 21 of the experimental gingivitis period. Exam students showed significantly higher I1-1beta levels than controls both at experimental gingivitis sites (area under the curve, exam group: 1240.64+/-140.07; control group: 697.61+/-111.30; p=0.004) and at sites of perfect oral hygiene (exam group: 290.42+/-63.19; control group: 143.98+/-42.71; p = 0.04). These results indicate that stress might affect periodontal health by increasing local I1-1beta levels especially when oral hygiene is neglected.

  16. Combined effects of interleukin-1β and cyclic stretching on metalloproteinase expression in corneal fibroblasts in vitro.

    Science.gov (United States)

    Feng, Pengfei; Li, Xiaona; Chen, Weiyi; Liu, Chengxing; Rong, Shuo; Wang, Xiaojun; Du, Genlai

    2016-06-10

    Corneal tensile strain increases if the cornea becomes thin or if intraocular pressure increases. However, the effects of mechanical stress on extracellular matrix (ECM) remodelling in the corneal repair process and the corneal anomalies are unknown. In this study, the combined effects of interleukin-1β (IL-1β) on matrix metalloproteinases (MMPs) in corneal fibroblasts under cyclic stretching were investigated in vitro. Cultured rabbit corneal fibroblasts were subjected to 5, 10 or 15 % cyclic equibiaxial stretching at 0.1 Hz for 36 h in the presence of IL-1β. Conditioned medium was harvested for the analysis of MMP2 and MMP9 protein production using the gelatin zymography and western blot techniques. Cyclic equibiaxial stretching changed the cell morphology by increasing the contractility of F-actin fibres. IL-1β alone induced the expression of MMP9 and increased the production of MMP2, and 5 % stretching alone decreased the production of MMP2, which indicates that a low stretching magnitude can reduce ECM degradation. In the presence of IL-1β, 5 and 10 % stretching increased the production of MMP2, whereas 15 % stretching increased the production of MMP9. These results indicate that MMP expression is enhanced by cyclic mechanical stimulation in the presence of IL-1β, which is expected to contribute to corneal ECM degradation, leading to the development of post-refractive surgery keratectasia.

  17. Interleukin 1β (+3954; -511) Genotype Polymorphism and its Association with Severe Chronic Generalized Periodontitis in the Malaysian Population.

    Science.gov (United States)

    Arora, Shelly; Ramachandra, Srinivas Sulugodu; Abdullah, Fawzia; Gundavarapu, Kalyan C

    2017-01-01

    Single-nucleotide polymorphisms (SNPs) in interleukin 1β (IL-1β) gene have been known to be associated with increased susceptibility to chronic periodontitis among various ethnic populations. SNPs are more commonly observed at loci + 3954 and - 511. The aim of this study was to evaluate the role of IL-1β gene polymorphism at loci +3954 and - 511, and its association with severe chronic generalized periodontitis among the ethnic Malay, Chinese, and Indians within the Malaysian population. Saliva samples from 120 subjects (60 cases and 60 controls) in the age group of 25-50 years were collected for isolation of genetic material using Norgen technique. Clinical attachment loss of ≥5 mm was considered as severe chronic generalized periodontitis. SNP's at loci +3954 and - 511 were identified and analyzed using Kompetitive Allele Specific Polymerase Chain Reaction Genotyping System (KASP™). Differences in the allele/genotype frequencies were assessed by Chi-square test ( P Malaysian population was similar. IL-1β genotype polymorphism at +3954 and - 511 was found to be not associated with severe chronic generalized periodontitis among the three ethnicities in Malaysia. Studies with larger sample size should be done to confirm the findings of this study.

  18. PERUBAHAN POLA KADAR INTERLEUKIN-1β, FUNGSI FAGOSITOSIS DAN STATUS PERIODONTIUM PADA PENYANDANG DIABETES MELITUS TIPE 2

    Directory of Open Access Journals (Sweden)

    Oedijami Santoso

    2015-06-01

    Full Text Available Hyperglycemia, which occurs in type 2 diabetic patients increases prostaglandin E2 (PGE2, cytokine expression, and decreases neutrophil phagocytic function. This will induce inflammation and periodontal tissue destruction, thus decreasing periodontal status. The aim of the study was to analyze the pattern alteration of interleukin-1β (IL-1β level, phagocytic function, and periodontal status. The study’s design was cross-sectional on 45 controlled diabetes mellitus (CDM and 45 uncontrolled diabetes mellitus (UCDM subjects and 45 non diabetic subjects, 40-60 years old in Metabolic-Endocrinology Clinic Cipto Mangunkusumo Hospital. Statistical analysis was performed using a Stata 7.0 software computer. The result showed that the pattern alteration of increasing IL-1β level was in 2 hours-post prandial glucose level of >150 mg/dL, decreasing phagocytic function in glucose level of >170 mg/dL, and decreasing periodontal status in flucose level of >240 mg/dL. Therefore it is concluded that the pattern alteration of decreasing periodontal status, increasing IL-1β, and decreasing phagocytic function showed on certain blood glucose levels.

  19. Nutrition, anthropometry, gastrointestinal dysfunction, and circulating levels of tumour necrosis factor alpha receptor I and interleukin-1 receptor antagonist in children during stem cell transplantation

    DEFF Research Database (Denmark)

    Andreassen, B. U.; Pærregaard, Anders; Michaelsen, Kim F.

    2008-01-01

    intake was below recommended levels. There was a loss of lean body mass (arm muscle area)(median, 2031 mm(2) (day -3) vs 1477 mm(2) (day 31); p = 0.04), and of fat mass (arm fat area) (791 mm(2) (day -3) vs 648 mm(2) (day +31); p = 0.04). sTNFRI was elevated throughout the course of transplantation...... (r = 0.83; p = 0.01) and with the change in weight SDS (r = 0.77; p = 0.03). This study suggests that pretransplant levels of inflammatory markers are associated with posttransplant symptoms of gastrointestinal dysfunction and loss of both fat and lean body mass. Future studies should adress......, and peaked after the day of graft infusion (day 0). sTNFRI levels at day 0 predicted changes in weight SDS (r = 0.65; p = 0.05), triceps skinfold SDS (r = 0.85; p = 0.007) and gastrointestinal dysfunction (r = 0.88; p = 0.004). Likewise, IL-1Ra levels at day 0 correlated with the gastrointestinal dysfunction...

  20. DIFFERENTIAL BINDING OF HUMAN INTERLEUKIN-1 (IL-1) RECEPTOR ANTAGONIST TO NATURAL AND RECOMBINANT SOLUBLE AND CELLULAR IL-1 TYPE-I RECEPTORS

    DEFF Research Database (Denmark)

    Svenson, Morten; Nedergaard, Susanne; Heegaard, Peter M. H.

    1995-01-01

    electrophoresis in the presence of sodium dodecylsulfate, ligand binding interference analyses, N-glycosidase treatment, concanavalin A affinity chromatography, and with the use of monoclonal antibodies (mAb) to human recombinant IL-1ra. We also evaluated the binding of IL-1ra to cellular IL-1RI on MRC5...

  1. DISTRIBUCIÓN DE POLIMORFISMOS GENÉTICOS DE INTERLEUQUINA-1 EN INDIVIDUOS DE LA REGIÓN CENTROCCIDENTAL DE VENEZUELA Distribution of Interleukin-1 Genetic Polymorphisms in Central-Western Region Individuals of Venezuela

    Directory of Open Access Journals (Sweden)

    YEINMY MORAN

    Full Text Available Las citoquinas pertenecientes a familia de la interleuquina-1 (IL-1 están codificadas por tres genes diferentes: IL-1A, IL-1B, e IL-1RN, los cuales codifican para IL-1 α, IL-1β, y el antagonista endógeno del receptor de IL-1 (IL-1ra, respectivamente. Las IL-1α e IL-1β actúan como citoquinas pro-inflamatorias, mientras que la IL-1ra se comporta como anti-inflamatoria. Han sido reportados varios polimorfismos bialélicos en los genes de IL-1B, incluyendo IL-1B-511(C/T e IL-1B+3954(C/T, mientras que IL-1RN presenta en el intrón 2 un polimorfismo VNTR penta-alélico. Los polimorfismos funcionalmente relevantes de estos genes han sido correlacionados con un amplio conjunto de condiciones autoinmunes e inflamatorias crónicas, así como con cáncer. Con el fin de determinar la distribución de estos polimorfismos en la región centroccidental de Venezuela, se estudiaron 100 individuos no relacionados aparentemente sanos. Se extrajo ADN genómico a partir de sangre periférica, y se procedió a la tipificación de los polimorfismos IL-1B-511 e IL-1B+3954 por PCR-RFLP y VNTR de IL-1RN por PCR. Se determinaron las frecuencias alélicas y genotípicas con el programa Arlequín ver. 2.000. Se observó un predominio del alelo T (52% y del alelo C (82% en IL-1B-511 y IL-1B+3954, respectivamente. Mientras que para IL-1RN los genotipos más frecuente fueron el 1/1 (47% y 1/2 (41%. Se compararon los resultados con las frecuencias poblacionales encontradas en otros países, destacándose diferencias significativas con poblaciones de diferente origen étnico. Los resultados podrían proporcionar una referencia valiosa para estudios futuros de asociación con cáncer y enfermedades inflamatorias en Venezuela.The cytokines belonging to the family of interleukin-1 (IL-1 are encoded by three different genes: IL-1A, IL-1B, and IL-1RN, which encode for IL-1α, IL-1β and the endogenous receptor antagonist for IL-1 (IL-1Ra, respectively. IL-1α and IL-1

  2. Evidence that luteinizing hormone suppression in response to inhibitory neuropeptides, beta-endorphin, interleukin-1 beta, and neuropeptide-K, may involve excitatory amino acids.

    Science.gov (United States)

    Bonavera, J J; Kalra, S P; Kalra, P S

    1993-07-01

    A large body of recent evidence suggests that a number of inhibitory and excitatory neuropeptides and amino acids may participate in the episodic secretion of hypothalamic LHRH and pituitary LH in castrated rats. However, the precise functional relationships among these messenger molecules in the control of LH secretion remain to be ascertained. The aim of this study was to test the hypothesis that inhibition of LH release by an opioid [beta-endorphin (beta END)], cytokine [interleukin-1 beta (IL-1 beta)], or tachykinin [neuropeptide-K (NPK)] is a result of diminished excitatory amino acid (EAA) signaling. Adult male rats were castrated and received an intracerebroventricular cannula in the third ventricle for administration of beta END (10 micrograms/rat), NPK (2.5 nmol/rat), or IL-1 beta (100 ng/rat) 2 weeks postcastration. One day before the experiments, rats received an intraatrial cannula for frequent blood sampling and for iv injection of the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 5 mg/kg) at 30-min intervals. Blood samples for LH measurements were withdrawn immediately before and 10 min after each NMDA injection. The results show that intracerebroventricular beta END, IL-1 beta, or NPK inhibited LH release. Multiple injections of NMDA did not alter the existing pattern of LH secretion in castrated control rats. However, similar NMDA injections completely prevented the decrease in LH release by beta END, IL-1 beta, or NPK. Plasma LH levels in these rats remained within the range seen in untreated control rats throughout the 120-min duration of the experiment, and NMDA injections at 30-min intervals evoked pulses of LH that resembled those seen normally in castrated rats. The blockade of the inhibitory effects of the three peptides by NMDA and previous knowledge of hypothalamic sites of NMDA action suggest that EAA systems may represent a common pathway down-stream in the hypothalamic LHRH-regulating circuitry to mediate diminution of LH

  3. The tomato I gene for Fusarium wilt resistance encodes an atypical leucine-rich repeat receptor-like protein whose function is nevertheless dependent on SOBIR1 and SERK3/BAK1.

    Science.gov (United States)

    Catanzariti, Ann-Maree; Do, Huong T T; Bru, Pierrick; de Sain, Mara; Thatcher, Louise F; Rep, Martijn; Jones, David A

    2017-03-01

    We have identified the tomato I gene for resistance to the Fusarium wilt fungus Fusarium oxysporum f. sp. lycopersici (Fol) and show that it encodes a membrane-anchored leucine-rich repeat receptor-like protein (LRR-RLP). Unlike most other LRR-RLP genes involved in plant defence, the I gene is not a member of a gene cluster and contains introns in its coding sequence. The I gene encodes a loopout domain larger than those in most other LRR-RLPs, with a distinct composition rich in serine and threonine residues. The I protein also lacks a basic cytosolic domain. Instead, this domain is rich in aromatic residues that could form a second transmembrane domain. The I protein recognises the Fol Avr1 effector protein, but, unlike many other LRR-RLPs, recognition specificity is determined in the C-terminal half of the protein by polymorphic amino acid residues in the LRRs just preceding the loopout domain and in the loopout domain itself. Despite these differences, we show that I/Avr1-dependent necrosis in Nicotiana benthamiana depends on the LRR receptor-like kinases (RLKs) SERK3/BAK1 and SOBIR1. Sequence comparisons revealed that the I protein and other LRR-RLPs involved in plant defence all carry residues in their last LRR and C-terminal LRR capping domain that are conserved with SERK3/BAK1-interacting residues in the same relative positions in the LRR-RLKs BRI1 and PSKR1. Tyrosine mutations of two of these conserved residues, Q922 and T925, abolished I/Avr1-dependent necrosis in N. benthamiana, consistent with similar mutations in BRI1 and PSKR1 preventing their interaction with SERK3/BAK1. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

  4. A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses.

    OpenAIRE

    Hwang, S.Y.; Hertzog, P J; Holland, K A; Sumarsono, S H; Tymms, M J; Hamilton, J A; Whitty, G; Bertoncello, I.; Kola, I.

    1995-01-01

    To examine the in vivo role(s) of type I interferons (IFNs) and to determine the role of a component of the type I IFN receptor (IFNAR1) in mediating responses to these IFNs, we generated mice with a null mutation (-/-) in the IFNAR1 gene. Despite compelling evidence for modulation of cell proliferation and differentiation by type I IFNs, there were no gross signs of abnormal fetal development or morphological changes in adult IFNAR1-/- mice. However, abnormalities of hemopoietic cells were d...

  5. Interleukin-1 beta inhibits rat thyroid cell function in vivo and in vitro by an NO-independent mechanism and induces hypothyroidism and accelerated thyroiditis in diabetes-prone BB rats

    DEFF Research Database (Denmark)

    Reimers, J I; Rasmussen, A K; Karlsen, A E

    1996-01-01

    hypothyroidism in non-diabetic diabetes-prone BB rats. The data suggest that NO does not mediate interleukin-1 beta-induced inhibition of rat thyroid function in vivo or in vitro in FRTL-5 cells, and the induction of hypothyroidism by interleukin-1 beta in diabetes-prone BB rats is speculated to be due...

  6. Clinical phenotype of recurrent aphthous stomatitis and interleukin-1β genotype in a Polish cohort of patients.

    Science.gov (United States)

    Ślebioda, Zuzanna; Krawiecka, Ewa; Rozmiarek, Marta; Szponar, Elżbieta; Kowalska, Anna; Dorocka-Bobkowska, Barbara

    2017-09-01

    The aim of this study was to evaluate the relation between a clinical profile and the interleukin-1β (IL-1β) genotype in a Polish cohort of patients with RAS. One hundred and four patients with RAS were enrolled in the study and all were subject to an oral examination. The severity of RAS was assessed according to the clinical type of the disease, the number of lesions per flare-up and the length of intervals between the episodes. The genotyping of two SNPs of the IL-1β gene, IL-1β c.-511 T>C (rs16944) and IL-1β c.+3954 C>T (rs1143634), was carried out by genomic DNA isolated from blood samples and by using the PCR-RFLP approach. The results were statistically analysed with chi-square and Fisher's tests and Spearman's rank correlation, with P minor, major or herpetiform RAS nor after the stratification using the RAS severity score and the classification based on the number of lesions per one flare-up. A weak correlation was found between the number of lesions per one flare-up and heterozygosity promoting the A type of RAS, characterized by a low number of eruptions. The presence of IL-1 β *2 allele within the c.+3954 and c.-511 SNPs was found to be neither a significant risk factor for a higher incidence of any type of RAS, nor did it influence the disease severity and mode of recurrences. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan.

    Science.gov (United States)

    Furuta, Takahisa; El-Omar, Emad M; Xiao, Fang; Shirai, Naohito; Takashima, Misako; Sugimura, Haruhiko; Sugimurra, Haruhiko

    2002-07-01

    Interleukin-1 beta (IL-1beta) polymorphisms are associated with increased risk of gastric cancer in whites. This study aimed to examine effects of these polymorphisms on gastric acid secretion, atrophic gastritis, and risk of peptic ulcer in Japan. We determined IL-1B-511/-31 and IL-1RN genotypes and measured gastric juice pH, serum pepsinogen (PG) I and II levels, and gastritis and atrophy scores in Helicobacter pylori-positive patients with gastritis only, gastric ulcers, or duodenal ulcers (DUs), and H. pylori-negative controls. In the H. pylori-positive group, subjects with the proinflammatory IL-1B-511 T/T genotype had the highest atrophy and gastritis scores, the highest median gastric juice pH, and the lowest median serum PG I/PG II ratios. Although gastric juice pH significantly increased and serum PG I and PG I/PG II ratios significantly decreased in the IL-1B-511 T/T genotype group with age, no such age-dependent changes were observed in the C/C genotype group. Changes in the C/T genotype group were intermediate. In the H. pylori-negative group, the IL-1 loci had no effect on any of the physiologic or morphologic parameters. Carriage of IL-1RN allele 2 significantly protected against DU disease while the IL-1B-511 T/T genotype significantly protected against DU recurrence in patients older than 60 years. Proinflammatory IL-1beta polymorphisms are associated with hypochlorhydria and atrophic gastritis in Japan. The effects are dependent on H. pylori infection and become more significant with advancing age. This may explain the high incidence of gastric cancer in Japan and also the age-dependent decrease in DU recurrence in infected subjects.

  8. Dosagem de interleucina 1beta na doença periodontal Concentration of interleukine 1beta in periodontal disease

    Directory of Open Access Journals (Sweden)

    Gastão Valle Nicolau

    2003-03-01

    Full Text Available Determinar o papel da interleucina - 1beta (IL-1beta como mediador das reações inflamatórias e imunitárias na doença periodontal. FORMA DE ESTUDO: Clínico prospectivo. MATERIAL E MÉTODO: Determinação da concentração da IL-1beta no grupo I (20 indivíduos sadios e no grupo II (20 indivíduos com doença periodontal, empregando o Kit Easia (Medgenix IL-1beta, com resultados analisados pelo teste t de Student. RESULTADOS: No grupo controle, os valores da IL-1beta foram de 71,28 ± 280,05 pg/ml, e na doença periodontal de 3618,49 ± 2864,75 pg/ml. CONCLUSÃO: A dosagem do IL1-beta no fluido gengival é acentuadamente maior que na doença periodontal.Determine the role of interleukine - 1beta (IL-1beta as intercellular mediator in generation, amplification and maintenance of inflammatory and immune responses in periodontal disease. STUDY DESIGN: Clinical prospective. MATERIAL AND METHOD: Assessment of concentration of 1L-1beta in group I (20 samples of healthy people and in group II (20 samples of patients with periodontal disease, employing Easia Kit (Medgenix 1L-1beta, with results statistically analyzed through Student t Test. RESULTS: In control group, media and standard deviation of 1L-1beta concentration were 71,28 ± 280,05 pg/ml and in periodontal disease 3618,49 ± 2864,75 pg/ml. CONCLUSION: The increase of Interleucine 1beta in periodontal disease distinguish from healthy oral mucosa.

  9. Infection with Mycobacterium avium subsp. paratuberculosis Results in Rapid Interleukin-1β Release and Macrophage Transepithelial Migration

    Science.gov (United States)

    Lamont, Elise A.; O'Grady, Scott M.; Davis, William C.; Eckstein, Torsten

    2012-01-01

    Pathogen processing by the intestinal epithelium involves a dynamic innate immune response initiated by pathogen-epithelial cell cross talk. Interactions between epithelium and Mycobacterium avium subsp. paratuberculosis have not been intensively studied, and it is currently unknown how the bacterium-epithelial cell cross talk contributes to the course of infection. We hypothesized that M. avium subsp. paratuberculosis harnesses host responses to recruit macrophages to the site of infection to ensure its survival and dissemination. We investigated macrophage recruitment in response to M. avium subsp. paratuberculosis using a MAC-T bovine macrophage coculture system. We show that M. avium subsp. paratuberculosis infection led to phagosome acidification within bovine epithelial (MAC-T) cells as early as 10 min, which resulted in upregulation of interleukin-1β (IL-1β) at transcript and protein levels. Within 10 min of infection, macrophages were recruited to the apical side of MAC-T cells. Inhibition of phagosome acidification or IL-1β abrogated this response, while MCP-1/CCL-2 blocking had no effect. IL-1β processing was dependent upon Ca2+ uptake from the extracellular medium and intracellular Ca2+ oscillations, as determined by EGTA and BAPTA-AM [1,2-bis(2-aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester)] treatments. Thus, M. avium subsp. paratuberculosis is an opportunist that takes advantage of extracellular Ca2+-dependent phagosome acidification and IL-1β processing in order to efficiently transverse the epithelium and enter its niche—the macrophage. PMID:22778093

  10. Achyranthes bidentate saponins protect rat articular chondrocytes against interleukin-1β-induced inflammation and apoptosis in vitro

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    Xian-Xiang Xu

    2017-02-01

    Full Text Available Achyranthes bidentate Blume (Niuxi is often employed for treatment of arthritis in Traditional Chinese Medicine and possesses anti-inflammatory properties. Phytochemical and pharmacological studies proved the oleanane-type saponins to be the main bioactive principles. In the present study, protective effects of A. bidentata saponins (ABS on inflammation and apoptosis in interleukine-1β (IL-1β-induced chondrocytes were investigated. Rat chondrocytes were pretreated with ABS at 3 μg/mL, 10 μg/mL, and 30 μg/mL, and subsequently stimulated with IL-1β (10 ng/mL. Methylthiazolyldiphenyl-tetrazolium bromide assay and annexin V/propidium iodide dual staining demonstrated that ABS could protect IL-1β-induced chondrocyte injury. ABS suppressed IL-1β-induced apoptosis by suppressing the activation of caspase-3, inhibiting levels of proapoptotic proteins Bax and Bad, decreasing p53 protein phosphorylation, and promoting the expression of antiapoptotic protein Bcl-xL and proliferating cell nuclear antigen. IL-1β-induced inflammation and matrix degradation were also alleviated by ABS through the downregulation of the expressions of matrix metalloproteinases 3 and 9 and cyclooxygenase-2. Moreover, ABS inhibited IL-1β-induced nuclear factor κB activation in rat chondrocytes. We demonstrated, for the first time, the protective effects of ABS on IL-1β-stimulated chondrocytes and their molecular mechanisms. Thus, it is suggested that ABS might be a potential drug in the treatment of osteoarthritis.

  11. Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis.

    Science.gov (United States)

    Simonini, Gabriele; Xu, Zhaohui; Caputo, Roberto; De Libero, Cinzia; Pagnini, Ilaria; Pascual, Virginia; Cimaz, Rolando

    2013-02-01

    To report on the clinical response to canakinumab in a patient with sporadic nucleotide-binding oligomerization domain-containing protein 2 (NOD-2)-associated pediatric granulomatous arthritis (Blau syndrome) and severe resistant panuveitis, and to describe gene expression profile changes throughout such treatment. A 4-year-old boy was diagnosed as having Blau syndrome on the basis of typical clinical features, histologic evidence of noncaseating granulomas, and a NOD2 mutation. Ocular involvement was initially controlled by topical and oral corticosteroids, but over the years visual impairment and complications, such as macular edema and retinal detachment, progressed. Ocular disease remained persistently active despite treatment with multiple different immunosuppressants; therefore, canakinumab treatment was started. Before and during the first 6 months of treatment, the gene expression profile was determined each month. Canakinumab treatment was well tolerated and led to rapid quiescence of uveitis, which had been continuously active before this treatment. Gene expression profiling analysis of the patient's blood prior to initiation of interleukin-1 (IL-1) blockade revealed differential expression of 1,993 transcripts when compared to healthy controls, and among the up-regulated transcripts, pathway analysis showed that the predominant network consisted of innate immunity-related transcripts. The transcriptional signature of the patient overlapped with the transcriptional signature of patients with systemic-onset juvenile idiopathic arthritis, and canakinumab treatment led to the normalization of most of these transcriptional changes. The pathogenesis of Blau syndrome may be mediated by IL-1, and canakinumab may be useful when this disorder is unresponsive to more conventional treatments. Copyright © 2013 by the American College of Rheumatology.

  12. Interleukin-1 gene polymorphisms in chronic gastritis patients infected with Helicobacter pylori as risk factors of gastric cancer development.

    Science.gov (United States)

    Hnatyszyn, Andrzej; Wielgus, Karolina; Kaczmarek-Rys, Marta; Skrzypczak-Zielinska, Marzena; Szalata, Marlena; Mikolajczyk-Stecyna, Joanna; Stanczyk, Jerzy; Dziuba, Ireneusz; Mikstacki, Adam; Slomski, Ryszard

    2013-12-01

    Epidemiological investigations indicated association of the Helicobacter pylori infections with the occurrence of inflammatory conditions of the gastric mucosa and development of chronic gastritis and intestinal type of gastric cancer. IL1A and IL1B genes have been proposed as key factors in determining risk of gastritis and malignant transformation. The aim of this paper was to evaluate association of interleukin-1 gene polymorphisms with chronic gastritis, atrophy, intestinal metaplasia, dysplasia and intestinal type of gastric cancer in H. pylori-infected patients. Patients subjected to analysis represent group of 144 consecutive cases that suffered from dyspepsia with coexisting infection of H. pylori and chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer. Molecular studies involved analysis of -889C>T polymorphism of IL1A gene and +3954C>T polymorphism of IL1B gene. Statistical analysis of association of polymorphism -889C>T of gene IL1A with changes in gastric mucosa showed lack of significance, whereas +3954C>T polymorphism of IL1B gene showed significant association. Frequency of allele T of +3954C>T polymorphism of IL1B gene was higher in group of patients with chronic gastritis, atrophy, intestinal metaplasia, dysplasia or intestinal type of gastric cancer (32.1 %) as compared with population group (23 %), χ(2) = 4.61 and p = 0.03. This corresponds to odds ratio: 1.58, 95 % CI: 1.04-2.4. Our results indicate that +3954C>T polymorphism of IL1B gene increase susceptibility to inflammatory response of gastric mucosa H. pylori-infected patients and plays a significant role in the development of chronic gastritis, atrophy, intestinal metaplasia, dysplasia and the initiation of carcinogenesis.

  13. The effect of sodium hyaluronate treating knee osteoarthritis on synovial fluid interleukin -1β and clinical treatment mechanism.

    Science.gov (United States)

    Yang, Libin; Zhang, Jun; Wang, Guodong

    2015-01-01

    In order to explore the influence of sodium hyaluronate on knee osteoarthritis (KOA) patients synovial fluid interleukin -1β (IL-1β) and analyze its clinical mechanism, this study analyzed 40 cases of KOA patients in our hospital's orthopaedic department, randomly divided them into two groups: Sodium hyaluronate group (group A) and normal saline group (group B), each consists 20 patients. Besides, we selected another 20 patients as normal control group. Group A treated knee joint cavity by injecting sodium hyaluronate, and group B injected knee joint cavity in equal amount of normal saline, once a week for five weeks. Collect respectively knee joint synovial fluid in patients of group A and group B before treatment and after five weeks of treatment, detect the content of knee joint synovial fluid IL-1βin of all the three groups by using enzyme linked immunosorbent assay (ELISA). We can conclude that (1) IL-1β content of knee joint synovial fluid in KOA patients before treatment was significantly higher than healthy people; (2) IL-1β content of group A knee joint synovial fluid after treatment was significantly reduced than before treatment, there was no significant difference for group BIL-1β content before and after treatment; (3) there was no significant difference between group A knee joint synovial fluid IL-1β content after treatment and healthy people. Thus it can be proved that content of IL-1β in knee joint synovial fluid KOA patients is higher than healthy people; sodium hyaluronate can reduce the content of IL-1β in synovial joints and can be effective in the treatment of knee osteoarthritis.

  14. Influence of Interleukin-1 Beta on Platelet-Poor Plasma Clot Formation: A Potential Impact on Early Bone Healing.

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    Xin Wang

    Full Text Available Hematoma quality (especially the fibrin matrix plays an important role in the bone healing process. Here, we investigated the effect of interleukin-1 beta (IL-1β on fibrin clot formation from platelet-poor plasma (PPP.Five-milliliter of rat whole-blood samples were collected from the hepatic portal vein. All blood samples were firstly standardized via a thrombelastograph (TEG, blood cell count, and the measurement of fibrinogen concentration. PPP was prepared by collecting the top two-fifths of the plasma after centrifugation under 400 × g for 10 min at 20°C. The effects of IL-1β cytokines on artificial fibrin clot formation from PPP solutions were determined by scanning electronic microscopy (SEM, confocal microscopy (CM, turbidity, and clot lysis assays.The lag time for protofibril formation was markedly shortened in the IL-1β treatment groups (243.8 ± 76.85 in the 50 pg/mL of IL-1β and 97.5 ± 19.36 in the 500 pg/mL of IL-1β compared to the control group without IL-1β (543.8 ± 205.8. Maximal turbidity was observed in the control group. IL-1β (500 pg/mL treatment significantly decreased fiber diameters resulting in smaller pore sizes and increased density of the fibrin clot structure formed from PPP (P < 0.05. The clot lysis assay revealed that 500 pg/mL IL-1β induced a lower susceptibility to dissolution due to the formation of thinner and denser fibers.IL-1β can significantly influence PPP fibrin clot structure, which may affect the early bone healing process.

  15. A study of the interleukin-1 gene cluster polymorphisms and inflammatory external root resorption in replanted permanent teeth.

    Science.gov (United States)

    Bastos, J V; Côrtes, M I S; Silva, J F C; Goulart, E M A; Colosimo, E A; Gomez, R S; Dutra, W O

    2015-09-01

    To investigate whether single nucleotide polymorphisms (SNPs) within the interleukin-1 gene cluster (IL1) are associated with the occurrence and severity of inflammatory external root resorption (IERR) after replantation of avulsed permanent teeth. Indexes of IERR were radiographically assessed in 182 mature replanted permanent teeth from 146 patients at the onset of endodontic therapy. DNA was extracted from buccal mucosa cells and genotyped using TaqMan probes-based assays for the SNPs IL1A -889C/T (rs 180058), IL1B +3954C/T (rs1143634) and IL1RN +2018C/T (rs419598). Teeth were grouped into two categories: IERR absent to mild (indexes ≤ 4) and moderate to severe IERR (indexes > 4). Genetic variations in the IL1 gene cluster were tested for their effect on the occurrence and extension of IERR using the GEE model (generalized estimation equation). Patient's age at the moment of injury, timing of pulpectomy, extra-alveolar period and storage condition of the avulsed teeth was included as possible confounders. No association was found between SNPs IL1A -889C/T, IL1B +3954C/T (rs1143634) and IL1RN +2018C/T (rs419598) and IERR indexes. Timing of pulpectomy (OR 3.5 IC 95% 2.0-6.2 P pulpectomy and patient's age at the moment of trauma were confirmed as important risk factors, SNPs within the IL1 gene cluster did not affect the susceptibility for IERR after replantation of permanent teeth. © 2014 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  16. Interleukin 1β (+3954; −511 genotype polymorphism and its association with severe chronic generalized periodontitis in the Malaysian Population

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    Shelly Arora

    2017-01-01

    Full Text Available Introduction: Single-nucleotide polymorphisms (SNPs in interleukin 1β (IL-1β gene have been known to be associated with increased susceptibility to chronic periodontitis among various ethnic populations. SNPs are more commonly observed at loci + 3954 and − 511. The aim of this study was to evaluate the role of IL-1β gene polymorphism at loci +3954 and − 511, and its association with severe chronic generalized periodontitis among the ethnic Malay, Chinese, and Indians within the Malaysian population. Materials and Methods: Saliva samples from 120 subjects (60 cases and 60 controls in the age group of 25–50 years were collected for isolation of genetic material using Norgen technique. Clinical attachment loss of ≥5 mm was considered as severe chronic generalized periodontitis. SNP's at loci +3954 and − 511 were identified and analyzed using Kompetitive Allele Specific Polymerase Chain Reaction Genotyping System (KASP™. Differences in the allele/genotype frequencies were assessed by Chi-square test (P < 0.05. Results: On the comparison between cases and controls of IL-1β genotype polymorphism (+3954 and − 511, the difference in the genotype frequencies was statistically insignificant in all the three ethnicities. The genotype frequency in both groups in all three ethnicities of the Malaysian population was similar. Conclusion: IL-1β genotype polymorphism at +3954 and − 511 was found to be not associated with severe chronic generalized periodontitis among the three ethnicities in Malaysia. Studies with larger sample size should be done to confirm the findings of this study.

  17. Interleukin-1β gene variants are associated with QTc interval prolongation following cardiac surgery: a prospective observational study.

    Science.gov (United States)

    Kertai, Miklos D; Ji, Yunqi; Li, Yi-Ju; Mathew, Joseph P; Daubert, James P; Podgoreanu, Mihai V

    2016-04-01

    We characterized cardiac surgery-induced dynamic changes of the corrected QT (QTc) interval and tested the hypothesis that genetic factors are associated with perioperative QTc prolongation independent of clinical and procedural factors. All study subjects were ascertained from a prospective study of patients who underwent elective cardiac surgery during August 1999 to April 2002. We defined a prolonged QTc interval as > 440 msec, measured from 24-hr pre- and postoperative 12-lead electrocardiograms. The association of 37 single nucleotide polymorphisms (SNPs) in 21 candidate genes -involved in modulating arrhythmia susceptibility pathways with postoperative QTc changes- was investigated in a two-stage design with a stage I cohort (n = 497) nested within a stage II cohort (n = 957). Empirical P values (Pemp) were obtained by permutation tests with 10,000 repeats. After adjusting for clinical and procedural risk factors, we selected four SNPs (P value range, 0.03-0.1) in stage I, which we then tested in the stage II cohort. Two functional SNPs in the pro-inflammatory cytokine interleukin-1β (IL1β), rs1143633 (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.53 to 0.95; Pemp = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; Pemp = 0.04), remained independent predictors of postoperative QTc prolongation. The ability of a clinico-genetic model incorporating the two IL1B polymorphisms to classify patients at risk for developing prolonged postoperative QTc was superior to a clinical model alone, with a net reclassification improvement of 0.308 (P = 0.0003) and an integrated discrimination improvement of 0.02 (P = 0.000024). The results suggest a contribution of IL1β in modulating susceptibility to postoperative QTc prolongation after cardiac surgery.

  18. Acetate supplementation reduces microglia activation and brain interleukin-1β levels in a rat model of Lyme neuroborreliosis

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    Brissette Catherine A

    2012-11-01

    Full Text Available Abstract Background We have found that acetate supplementation significantly reduces neuroglia activation and pro-inflammatory cytokine release in a rat model of neuroinflammation induced with lipopolysaccharide. To test if the anti-inflammatory effect of acetate supplementation is specific to a TLR4-mediated injury, we measured markers of neuroglia activation in rats subjected to B. burgdorferi-induced neuroborreliosis that is mediated in large part by a TLR2-type mechanism. Methods In this study, rats were subjected to Lyme neuroborreliosis following an intravenous infusion of B. burgdorferi (B31-MI-16. Acetate supplementation was induced using glyceryl triacetate (6g/kg by oral gavage. Immunohistochemistry, qPCR, and western blot analyses were used to measure bacterial invasion into the brain, neuroglial activation, and brain and circulating levels of interleukin 1β. Statistical analysis was performed using one-way analysis of variance (ANOVA followed by a Tukey’s post hoc tests or using a Student’s t test assuming unequal variances when appropriate. Results We found that acetate supplementation significantly reduced microglia activation by 2-fold as determined by immunohistochemical and western blot analysis. Further, acetate supplementation also reduced the expression of the pro-inflammatory cytokine IL-1β by 2-fold as compared to controls. On the other hand, the inoculation of rats with B. burgdorferi had no effect on astroglial activation as determined by immunocytochemistry and western blot analysis despite significant increases in circulation levels of antigen toward B. burgdorferi and presence of the bacteria in the central nervous system. Conclusions These results suggest that microglial activation is an essential component to neuroborreliosis and that acetate supplementation may be an effective treatment to reduce injury phenotype and possibly injury progression in Lyme neuroborreliosis.

  19. Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis.

    Science.gov (United States)

    Rudolphi, K; Gerwin, N; Verzijl, N; van der Kraan, P; van den Berg, W

    2003-10-01

    To study the effect of pralnacasan, the orally bioavailable pro-drug of a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE), RU 36384/VRT-18858, on joint damage in two mouse models of knee osteoarthritis (OA). In a collagenase-induced OA model, pralnacasan was given orally by gavage to female Balb/c mice at 0, 12.5, 25 and 50 mg/kg twice a day. In the second study, pralnacasan was tested in male STR/1N mice, which develop OA spontaneously, by administering food-drug mixtures ad libitum at concentrations of 0, 700 and 4200 ppm (mg/kg food). OA joint damage was assessed by a semi-quantitative histopathological score in both studies. In the STR/1N mouse study, urinary levels of collagen cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) were determined by high-pressure liquid chromatography at baseline, after 3 and 6 weeks of treatment and RU 36384/VRT-18858 plasma concentrations was measured after 6 weeks. In both studies, the mice developed moderate to severe knee joint OA in the medial joint compartments (tibial plateau and femoral condyle), the non-treated control groups showing median histopathological scores from 18 to 21 of a maximal score of 32. Pralnacasan was well tolerated. At the doses of 12.5 and 50 mg/kg in collagenase-induced OA and at the high dose of 4200 ppm in STR/1N mice pralnacasan treatment significantly reduced OA by 13-22%. In the STR/1N mice, urinary levels of HP cross-links and the ratio of HP/LP, which are indicators of joint damage in OA, were significantly reduced in the high dose group by 59 and 84%, respectively. The ICE inhibitor pralnacasan reduced joint damage in two experimental models of OA and has the potential to become a disease-modifying drug for the treatment of OA.

  20. Expression of interleukin-1 (IL-1 ligands system in the most common endometriosis-associated ovarian cancer subtypes

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    Keita Mamadou

    2010-01-01

    Full Text Available Abstract Objectives Endometrioid carcinoma of the ovary is one of the most types of epithelial ovarian cancer associated to endometrioisis. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of booth, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors. Pro-inflammatory cytokines, including interleukin-1 (IL-1 have been reported to be involved in both endometriosis and ovarian carcinogenesis. The major objective of this study was to determine the level expression of IL-1 ligands system (IL-1α, IL-1β and IL-1RA in the most common subtypes of ovarian cancer cells compared to endometrial cells. Methods We used primary endometrial cells, endometrial cell line RL-952 and different subtypes of epithelial ovarian cancer cell lines including TOV-112D (endometrioid, TOV-21G (clear cell and OV-90 (serous. Immunofluorescence and real-time PCR analysis were used respectively for detecting IL-1 ligands at the levels of cell-associated protein and mRNA. Soluble IL-1 ligands were analyzed by ELISA. Results We demonstrated that IL-1 ligands were expressed by all endometriosis-associated ovarian cancer subtypes and endometrial cells. In contrast to other cancer ovarian cells, endometrioid cells exhibit a specific decrease of cell-associated IL-1RA expression and its soluble secretion. Conclusion Endometrioid ovarian cancer exhibits an alteration in the expression of IL-1RA, a key protector against tumorogenic effects of IL-1. This alteration evokes the same alteration observed in endometriotic cells in previous studies. This suggests a possible link between the endometrium, the tissue ectopic endometriosis and endometrioid ovarian cancer.

  1. The role genes encoding of killer cell immunoglobulin-like receptors (KIRs) and their ligands in susceptibility to and progression of HIV infection.

    Science.gov (United States)

    Błachowicz, Olga; Zwolińska, Katarzyna

    2016-12-31

    NK cells are a part of the innate antiviral response. Their activity is regulated by signals from the surface receptors. Some of them, known as killer cell immunoglobulin-like receptors (KIRs), determine the quality and intensity of the immunological response, together with their ligands (HLA class I). KIR genes are very polymorphic, and this is reflected in the NK activity modulation. The stimulation of NK cells, especially in the early stages of the infection, can reduce the transmission of HIV or slow down the progression of infection. The varied KIR/HLA repertoire is a limiting factor for the risk of HIV infection and disease progression. Such diversity enables optimal regulation of NK cells and maintenance of the balance between activation to eliminate infected cells and inhibition. The control of NK cell activity via KIR3DL1/3DS1 and HLA-Bw4 (especially Bw4-80I) seems to be very important in the HIV context. With a few exceptions, it leads to a reduction of susceptibility to HIV infection and better viremia control, and slows down depletion of CD4+ T cells. Incompatibility of sexual partners for KIRs and HLA may oblige NK cells from the exposed partner to reject incoming cells from the HIV-positive partner. The presence of the inhibitory KIR, in the absence of its ligand, results in a lower threshold of NK cell activation, which reduces the chance of infection. The presence of an inhibitory receptor with a low affinity to the ligand (KIR2DL3+HLA-C1) is associated with lower susceptibility, and the effective NK cell inhibition (KIR2DL2+HLA-C1) results in increased susceptibility to HIV infection. The advantage of activating KIRs, especially in the presence of their ligands, is associated with higher cytolytic abilities, and thus reduced risk of HIV infection. If the virus is not eliminated in an early stage of infection, massive activation of NK is unfavorable due to the excessive stimulation of the immune system.

  2. MTUS1, a gene encoding angiotensin-II type 2 (AT2) receptor-interacting proteins, in health and disease, with special emphasis on its role in carcinogenesis.

    Science.gov (United States)

    Bozgeyik, Ibrahim; Yumrutas, Onder; Bozgeyik, Esra

    2017-08-30

    Loss of tumor suppressor activity is a frequent event in the formation and progression of tumors and has been listed as an important hallmark of cancers. Microtubule-Associated Scaffold Protein 1 (MTUS1) is a candidate tumor suppressor gene which is reported to be frequently down-regulated in a variety of human cancers including pancreas, colon, bladder, head-and-neck, ovarian, breast cancers, gastric, lung cancers. It is also reported to be implicated in several types of pathologies such as cardiac hypertrophy, atherosclerosis, and SLE-like lymphoproliferative diseases. Moreover, MTUS1-encoded proteins are shown to be involved in the regulation of vital cellular processes such as proliferation, differentiation, DNA repair, inflammation, vascular remodeling and senescence. However, the current knowledge is very limited about the role of this gene in human cancers as well as other type diseases. Besides, there is no literature report which summarizes and criticizes the importance of MTUS1 in the cellular processes, especially in the processes of carcinogenesis. Accordingly, in this comprehensive review, we tried to shed light on the role of tumor suppressor MTUS1/ATIP in health and disease, putting special emphasis on its role in the development and progression of human cancers as well as associated molecular mechanisms and the reasons behind MTUS1/ATIP deficiency, which have been not well documented previously. Copyright © 2017. Published by Elsevier B.V.

  3. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  4. Distribution of the mRNAs encoding the thyrotropin-releasing hormone (TRH) precursor and three TRH receptors in the brain and pituitary of Xenopus laevis: Effect of background color adaptation on TRH and TRH receptor gene expression

    NARCIS (Netherlands)

    Bidaud, I.; Galas, L.; Bulant, M.; Jenks, B.G.; Ouwens, D.T.W.M.; Jegou, S.; Ladram, A.; Roubos, E.W.; Tonon, M.C.; Nicolas, P.; Vaudry, H.

    2004-01-01

    In amphibians, thyrotropin-releasing hormone (TRH) is a potent stimulator of et-melanotropin (alpha-MSH) secretion, so TRH plays a major role in the neuroendocrine regulation of skin-color adaptation. We have recently cloned a third type of TRH receptor in Xenopus laevis (xTRHR3) that has not yet

  5. Comparative mapping on the mouse and human X chromosomes of a human cDNA clone encoding the vasopressin renal-type receptor (AVP2R)

    Energy Technology Data Exchange (ETDEWEB)

    Faust, C.J.; Gonzales, J.C.; Seibold, A.; Birnbaumer, M.; Herman, G.E. (Baylor College of Medicine, Houston, TX (United States))

    1993-02-01

    Mutation in the gene for the human renal-type vasopressin receptor (V2R) have recently been identified in patients with nephrogenic diabetes insipidus (NDI). Both V2R and NDI have been independently mapped to Xq28. Using a combination of genetic and physical mapping, we have localized the murine V2r locus to within 100 kb of L1Cam on the mouse X chromosome in a region syntenic with human Xq28. Based on conserved gene order of mouse and human loci in this region, physical mapping using DNA derived form human lymphoblasts has established that the corresponding human loci V2R and L1CAM are linked within 210 kb. The efficiency and precision of genetic mapping of V2r and other loci in the mouse suggest that it might be easier to map additional human genes in the mouse first and infer the corresponding human location. More precise physical mapping in man could then be performed using pulsed-field gel electrophoresis and/or yeast artificial chromosomes. 16 refs., 1 fig. 1 tab.

  6. The potentiation of Mangifera casturi bark extract on interleukin- 1β and bone morphogenic protein-2 expressions during bone remodeling after tooth extraction

    OpenAIRE

    Bayu Indra Sukmana; Theresia Indah Budhy; I Gusti Aju Wahju Ardani

    2017-01-01

    Background: The main oral health problem in Indonesia is the high number of tooth decay. Tooth extraction is the treatment often received by patients who experience tooth decay and the wound caused by alveolar bone resorption. Bark of Mangifera casturi has been studied and proven to contain secondary metabolite which has the ability to increase osteoblast’s activity and suppress osteoclast’s activity. Purpose: The purpose of this study was to analyze interleukin-1 beta (IL-1β) and bone morpho...

  7. Anti-proliferative effects of Salacia reticulata leaves hot-water extract on interleukin-1β-activated cells derived from the synovium of rheumatoid arthritis model mice

    OpenAIRE

    Sekiguchi Yuusuke; Mano Hiroshi; Nakatani Sachie; Shimizu Jun; Kobata Kenji; Wada Masahiro

    2012-01-01

    Abstract Background Salacia reticulata (SR) is a plant native to Sri Lanka. In ayurvedic medicine, SR bark preparations, taken orally, are considered effective in the treatment of rheumatism and diabetes. We investigated the ability of SR leaves (SRL) to inhibit in vitro the interleukin-1β (IL-1β)-activated proliferation of synoviocyte-like cells derived from rheumatoid arthritis model mice. Findings Inflammatory synovial tissues were harvested from type II collagen antibody-induced arthritic...

  8. Intervertebral disc cells produce tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 immediately after herniation: an experimental study using a new hernia model.

    Science.gov (United States)

    Yoshida, Masakazu; Nakamura, Takafumi; Sei, Akira; Kikuchi, Taro; Takagi, Katsumasa; Matsukawa, Akihiro

    2005-01-01

    A new hernia model that simulates human disc herniations was developed in rabbits. The herniated discs were examined by gross appearance and histology and production of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 was investigated. To clarify the early mechanism of spontaneous herniated disc resorption. Macrophage infiltration in herniated discs is essential for disc resorption. However, surgically removed human herniated disc tissues and existing animal hernia models are not suitable for analyzing the mechanism of macrophage infiltration. Recently, we have demonstrated that intervertebral disc cells are capable of producing monocyte chemoattractant protein-1, a potent macrophage chemoattractant, after stimulation with tumor necrosis factor alpha and interleukin-1beta. Intervertebral disc herniations were surgically developed in rabbits using a new technique. The herniated discs were excised at appropriate time intervals after the surgery, and the size and histologic findings were examined. Expressions of tumor necrosis factor alpha, interleukin-1beta, and monocyte chemoattractant protein-1 in herniated discs were investigated immunohistochemically. A new rabbit model of disc herniation was established. The herniated discs spontaneously reduced in size by 12 weeks postsurgery. Infiltrating cells, mainly composed of macrophages, were observed from day 3. Immunohistochemically, intervertebral disc cells in the herniated discs produced tumor necrosis factor alpha and interleukin-1beta on day 1, followed by monocyte chemoattractant protein-1 on day 3. The new hernia model appears to be very useful for studying herniated disc resorption. Intervertebral disc cells may produce inflammatory cytokines/chemokine immediately after the onset of disc herniation, possibly triggering subsequent macrophage infiltration that leads to disc resorption.

  9. Effectiveness and tuberculosis-related safety profile of interleukin-1 blocking agents in the management of Behçet's disease.

    Science.gov (United States)

    Cantarini, Luca; Lopalco, Giuseppe; Caso, Francesco; Costa, Luisa; Iannone, Florenzo; Lapadula, Giovanni; Anelli, Maria Grazia; Franceschini, Rossella; Menicacci, Cristina; Galeazzi, Mauro; Selmi, Carlo; Rigante, Donato

    2015-01-01

    Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. Although the primum movens of this condition remains unknown, a tangled plot combining autoimmune and autoinflammatory pathways has been hypothesized to explain its start and recurrence. In-depth analysis of BD pathogenetic mechanisms, involving dysfunction of multiple proinflammatory molecules, has opened new modalities of treatment: different agents targeting interleukin-1 have been studied in recent years to manage the most difficult and multi-resistant cases of BD. Growing experience with anakinra, canakinumab and gevokizumab is discussed in this review, highlighting the relative efficacy of each drug upon the protean BD clinical manifestations. Safety and tolerability of interleukin-1 antagonists in different doses have been confirmed by numerous observational studies on both large and small cohorts of patients with BD. In particular, the potential for Mycobacterium tuberculosis reactivation and tuberculosis development appears to be significantly lower with interleukin-1 blockers compared to tumor necrosis factor-α inhibitors, thus increasing the beneficial profile of this approach. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Differential effects of central and peripheral injection of interleukin-1 beta on brain c-fos expression and neuroendocrine functions.

    Science.gov (United States)

    Rivest, S; Torres, G; Rivier, C

    1992-07-31

    Cytokines such as interleukin-1 beta (IL-1 beta) alter the activity of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in the rat. However, the brain sites at which IL-1 beta exerts these effects have not been well identified. The present study sought to identify some of these sites, using c-fos protein expression as an index of cellular activation. We also attempted to determine possible differences between the effects of peripheral and central injection of IL-1 beta on the activation of specific brain areas. Castrated male rats received intravenous (i.v.) or intracerebroventricular (i.c.v.) injections of IL-1 beta through a jugular catheter or a permanent cannula implanted in the right lateral ventricle, respectively. Blood samples were taken before, as well as 30 and 120 min after i.v. or i.c.v. IL-1 beta infusion in order to measure plasma ACTH and LH levels. Immediately thereafter, the rats were anesthetized with pentobarbital, then perfused. Their brains were removed and postfixed for one hour. Thirty-microns frozen sections were cut and approximately every fourth tissue section was processed for c-fos expression by an avidin-biotin-peroxidase method. Both i.v. (1 microgram) and i.c.v. (100 ng) injection of IL-1 beta significantly increased plasma ACTH levels, but only i.c.v. treatment measurably inhibited LH secretion. I.c.v. infusion of the cytokine markedly augmented c-fos expression in the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the hypothalamus. A large amount of CRF cells in the PVN contained labelled c-fos protein (as measured by a double labelling technique), which indicates that CRF perikarya in this hypothalamic region are activated by the central administration of IL-1 beta. In contrast, i.v. injection of IL-1 beta did not significantly alter c-fos expression in the PVN or the ARC of the hypothalamus. These results suggest that the increased HPA axis activity which follows the peripheral

  11. Effects of dosage titration of methylprednisolone acetate and triamcinolone acetonide on interleukin-1-conditioned equine articular cartilage explants in vitro.

    Science.gov (United States)

    Dechant, J E; Baxter, G M; Frisbie, D D; Trotter, G W; McIlwraith, C W

    2003-07-01

    Osteoarthritis is a frequent sequela of joint disease, especially with severe injuries or if attempts at therapy are unsuccessful. Negative and positive effects of corticosteroid treatment of articular cartilage have been demonstrated by in vitro and in vivo studies. To assess the metabolic effects of varying dosages of methylprednisolone acetate (MPA) and triamcinolone acetonide (TA) on interleukin-1alpha (IL-1) conditioned equine cartilage explants. Our hypothesis was that lower dosages of corticosteroids would be less detrimental to cartilage metabolism than higher dosages. TA would be less detrimental to cartilage metabolism than MPA. Treatment groups included articular cartilage explants with no IL-1 (control), IL-1 alone, and IL-1 plus 10, 5, 1 and 0.5 mg/ml MPA or 1.2, 0.6, 0.12 and 0.06 mg/ml TA. Explants were labelled with 35SO4 prior to the beginning and end of the experiment to assess glycosaminoglycan (GAG) degradation and synthesis, respectively. Total GAG content in media and explants and total cartilage DNA were also analysed. MPA and TA reduced GAG synthesis compared to control and IL-1 alone. The highest dosage of MPA (10 mg/ml) reduced GAG synthesis less than lower dosages of MPA and all dosages of TA. Compared to IL-1 alone, all dosages of TA and lower dosages of MPA increased GAG degradation. MPA at 10 mg/ml reduced GAG degradation. Both MPA and TA increased media GAG content compared to control and IL-1 explants. Total cartilage GAGs were unchanged with MPA, but reduced with TA, compared with IL-1 alone. Total cartilage DNA was decreased with MPA and increased with TA compared to IL-1 and control explants. MPA and TA did not counteract the negative effects of IL-1 and did not maintain cartilage metabolism at control levels. Lower dosages of MPA and TA were not less detrimental to cartilage metabolism than higher dosages. TA did not appear to be less harmful than MPA on cartilage metabolism. The results of this study differ from the findings of

  12. Glucocorticoid-induced reversal of interleukin-1β-stimulated inflammatory gene expression in human oviductal cells.

    Directory of Open Access Journals (Sweden)

    Stéphanie Backman

    Full Text Available Studies indicate that high-grade serous ovarian carcinoma (HGSOC, the most common epithelial ovarian carcinoma histotype, originates from the fallopian tube epithelium (FTE. Risk factors for this cancer include reproductive parameters associated with lifetime ovulatory events. Ovulation is an acute inflammatory process during which the FTE is exposed to follicular fluid containing both pro- and anti-inflammatory molecules, such as interleukin-1 (IL1, tumor necrosis factor (TNF, and cortisol. Repeated exposure to inflammatory cytokines may contribute to transforming events in the FTE, with glucocorticoids exerting a protective effect. The global response of FTE cells to inflammatory cytokines or glucocorticoids has not been investigated. To examine the response of FTE cells and the ability of glucocorticoids to oppose this response, an immortalized human FTE cell line, OE-E6/E7, was treated with IL1β, dexamethasone (DEX, IL1β and DEX, or vehicle and genome-wide gene expression profiling was performed. IL1β altered the expression of 47 genes of which 17 were reversed by DEX. DEX treatment alone altered the expression of 590 genes, whereas combined DEX and IL1β treatment altered the expression of 784 genes. Network and pathway enrichment analysis indicated that many genes altered by DEX are involved in cytokine, chemokine, and cell cycle signaling, including NFκΒ target genes and interacting proteins. Quantitative real time RT-PCR studies validated the gene array data for IL8, IL23A, PI3 and TACC2 in OE-E6/E7 cells. Consistent with the array data, Western blot analysis showed increased levels of PTGS2 protein induced by IL1β that was blocked by DEX. A parallel experiment using primary cultured human FTE cells indicated similar effects on PTGS2, IL8, IL23A, PI3 and TACC2 transcripts. These findings support the hypothesis that pro-inflammatory signaling is induced in FTE cells by inflammatory mediators and raises the possibility that

  13. Impairment of the hematological response and interleukin-1β production in protein-energy malnourished mice after endotoxemia with lipopolysaccharide

    Energy Technology Data Exchange (ETDEWEB)

    Fock, R.A.; Vinolo, M.A.R.; Blatt, S.L.; Borelli, P. [Laboratório de Hematologia Experimental, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-09-21

    The objectives of this study were to determine if protein-energy malnutrition (PEM) could affect the hematologic response to lipopolysaccharide (LPS), the interleukin-1β (IL-1β) production, leukocyte migration, and blood leukocyte expression of CD11a/CD18. Two-month-old male Swiss mice were submitted to PEM (N = 30) with a low-protein diet (14 days) containing 4% protein, compared to 20% protein in the control group (N = 30). The total cellularity of blood, bone marrow, spleen, and bronchoalveolar lavage evaluated after the LPS stimulus indicated reduced number of total cells in all compartments studied and different kinetics of migration in malnourished animals. The in vitro migration assay showed reduced capacity of migration after the LPS stimulus in malnourished animals (45.7 ± 17.2 × 10{sup 4} cells/mL) compared to control (69.6 ± 7.1 × 10{sup 4} cells/mL, P ≤ 0.05), but there was no difference in CD11a/CD18 expression on the surface of blood leukocytes. In addition, the production of IL-1β in vivo after the LPS stimulus (180.7 pg·h{sup −1}·mL{sup −1}), and in vitro by bone marrow and spleen cells (41.6 ± 15.0 and 8.3 ± 4.0 pg/mL) was significantly lower in malnourished animals compared to control (591.1 pg·h{sup −1}·mL{sup −1}, 67.0 ± 23.0 and 17.5 ± 8.0 pg/mL, respectively, P ≤ 0.05). The reduced expression of IL-1β, together with the lower number of leukocytes in the central and peripheral compartments, different leukocyte kinetics, and reduced leukocyte migration capacity are factors that interfere with the capacity to mount an adequate immune response, being partly responsible for the immunodeficiency observed in PEM.

  14. The Brassica napus receptor-like protein RLM2 is encoded by a second allele of the LepR3/Rlm2 blackleg resistance locus.

    Science.gov (United States)

    Larkan, Nicholas J; Ma, Lisong; Borhan, Mohammad Hossein

    2015-09-01

    Leucine-rich repeat receptor-like proteins (LRR-RLPs) are highly adaptable parts of the signalling apparatus for extracellular detection of plant pathogens. Resistance to blackleg disease of Brassica spp. caused by Leptosphaeria maculans is largely governed by host race-specific R-genes, including the LRR-RLP gene LepR3. The blackleg resistance gene Rlm2 was previously mapped to the same genetic interval as LepR3. In this study, the LepR3 locus of the Rlm2 Brassica napus line 'Glacier DH24287' was cloned, and B. napus transformants were analysed for recovery of the Rlm2 phenotype. Multiple B. napus, B. rapa and B. juncea lines were assessed for sequence variation at the locus. Rlm2 was found to be an allelic variant of the LepR3 LRR-RLP locus, conveying race-specific resistance to L. maculans isolates harbouring AvrLm2. Several defence-related LRR-RLPs have previously been shown to associate with the RLK SOBIR1 to facilitate defence signalling. Bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation of RLM2-SOBIR1 studies revealed that RLM2 interacts with SOBIR1 of Arabidopsis thaliana when co-expressed in Nicotiana benthamiana. The interaction of RLM2 with AtSOBIR1 is suggestive of a conserved defence signalling pathway between B. napus and its close relative A. thaliana. © 2015 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

  15. Paradoxical mineralocorticoid receptor-mediated effect in fear memory encoding and expression of rats submitted to an olfactory fear conditioning task.

    Science.gov (United States)

    Souza, Rimenez R; Dal Bó, Silvia; de Kloet, E Ronald; Oitzl, Melly S; Carobrez, Antonio P

    2014-04-01

    There is general agreement that the substantial modification in memory and motivational states exerted by corticosteroids after a traumatic experience is mediated in complementary manner by the mineralocorticoid (MR) and glucocorticoid (GR) receptors. Here we tested the hypothesis that pharmacological manipulation of MR activity would affect behavioral strategy and information storage in an olfactory fear conditioning (OFC) task. Male Wistar rats were submitted to the OFC with different training intensities. We observed that following high intensity OFC acquisition, a set of defensive coping strategies, which includes avoidance and risk assessment behaviors, was elicited when subjects were exposed to the conditioned stimulus (CS) 48 h later. In addition, following either OFC acquisition or retrieval (CS-I test) a profound corticosterone secretion was also detected. Systemic administration of the MR antagonist spironolactone altered the behavioral coping style irrespective the antagonist was administered 60 min prior to the acquisition or before the retrieval session. Surprisingly, the MR agonist fludrocortisone given 60 min prior to acquisition or retrieval of OFC had similar effects as the antagonist. In addition, post-training administration of fludrocortisone, following a weak training procedure, facilitated the consolidation of OFC. Fludrocortisone rather than spironolactone reduced serum corticosterone levels, suggesting that, at least in part, the effects of the MR agonist may derive from additional GR-mediated HPA-axis suppression. In conclusion, the present study suggests the involvement of the MR in the fine-tuning of behavioral adaptation necessary for optimal information storage and expression, as revealed by the marked alterations in the risk assessment behavior. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Common polymorphisms within the NR4A3 locus, encoding the orphan nuclear receptor Nor-1, are associated with enhanced β-cell function in non-diabetic subjects

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    Kuusisto Johanna

    2009-08-01

    Full Text Available Abstract Background Neuron-derived orphan receptor (Nor 1, nuclear receptor (Nur 77, and nuclear receptor-related protein (Nurr 1 constitute the NR4A family of orphan nuclear receptors which were recently found to modulate hepatic glucose production, insulin signalling in adipocytes, and oxidative metabolism in skeletal muscle. In this study, we assessed whether common genetic variation within the NR4A3 locus, encoding Nor-1, contributes to the development of prediabetic phenotypes, such as glucose intolerance, insulin resistance, or β-cell dysfunction. Methods We genotyped 1495 non-diabetic subjects from Southern Germany for the five tagging single nucleotide polymorphisms (SNPs rs7047636, rs1526267, rs2416879, rs12686676, and rs10819699 (minor allele frequencies ≥ 0.05 covering 100% of genetic variation within the NR4A3 locus (with D' = 1.0, r2 ≥ 0.9 and assessed their association with metabolic data derived from the fasting state, an oral glucose tolerance test (OGTT, and a hyperinsulinemic-euglycemic clamp (subgroup, N = 506. SNPs that revealed consistent associations with prediabetic phenotypes were subsequently genotyped in a second cohort (METSIM Study; Finland; N = 5265 for replication. Results All five SNPs were in Hardy-Weinberg equilibrium (p ≥ 0.7, all. The minor alleles of three SNPs, i.e., rs1526267, rs12686676, and rs10819699, consistently tended to associate with higher insulin release as derived from plasma insulin at 30 min(OGTT, AUCC-peptide-to-AUCGluc ratio and the AUCIns30-to-AUCGluc30 ratio with rs12686676 reaching the level of significance (p ≤ 0.03, all; additive model. The association of the SNP rs12686676 with insulin secretion was replicated in the METSIM cohort (p ≤ 0.03, additive model. There was no consistent association with glucose tolerance or insulin resistance in both study cohorts. Conclusion We conclude that common genetic variation within the NR4A3 locus determines insulin secretion. Thus, NR4A3

  17. HIV exposed seronegative (HESN compared to HIV infected individuals have higher frequencies of telomeric Killer Immunoglobulin-like Receptor (KIR B motifs; Contribution of KIR B motif encoded genes to NK cell responsiveness.

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    Elise Jackson

    Full Text Available Previously, we showed that Killer Immunoglobulin-like Receptor (KIR3DS1 homozygotes (hmz are more frequent in HIV exposed seronegative (HESN than in recently HIV infected (HIV+ individuals. KIR3DS1 encodes an activating Natural Killer (NK cell receptor (NKR. The link between KIR genotype and HIV outcomes likely arises from the function that NK cells acquire through expression of particular NKRs. An initial screen of 97 HESN and 123 HIV+ subjects for the frequency of KIR region gene carriage observed between-group differences for several telomeric KIR region loci. In a larger set of up to 106 HESN and 439 HIV+ individuals, more HESN than HIV+ subjects were KIR3DS1 homozygotes, lacked a full length KIR2DS4 gene and carried the telomeric group B KIR haplotype motif, TB01. TB01 is characterized by the presence of KIR3DS1, KIR2DL5A, KIR2DS3/5 and KIR2DS1, in linkage disequilibrium with each other. We assessed which of the TB01 encoded KIR gene products contributed to NK cell responsiveness by stimulating NK cells from 8 HIV seronegative KIR3DS1 and TB01 motif homozygotes with 721.221 HLA null cells and evaluating the frequency of KIR3DS1+/-KIR2DL5+/-, KIR3DS1+/-KIR2DS1+/-, KIR3DS1+/-KIR2DS5+/- NK cells secreting IFN-γ and/or expressing CD107a. A higher frequency of NK cells expressing, versus not, KIR3DS1 responded to 721.221 stimulation. KIR2DL5A+, KIR2DS1+ and KIR2DS5+ NK cells did not contribute to 721.221 responses or modulate those by KIR3DS1+ NK cells. Thus, of the TB01 KIR gene products, only KIR3DS1 conferred responsiveness to HLA-null stimulation, demonstrating its ligation can activate ex vivo NK cells.

  18. NEMO is essential for Kaposi's sarcoma-associated herpesvirus-encoded vFLIP K13-induced gene expression and protection against death receptor-induced cell death, and its N-terminal 251 residues are sufficient for this process.

    Science.gov (United States)

    Tolani, Bhairavi; Matta, Hittu; Gopalakrishnan, Ramakrishnan; Punj, Vasu; Chaudhary, Preet M

    2014-06-01

    Kaposi's sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 was originally believed to protect virally infected cells against death receptor-induced apoptosis by interfering with caspase 8/FLICE activation. Subsequent studies revealed that K13 also activates the NF-κB pathway by binding to the NEMO/inhibitor of NF-κB (IκB) kinase gamma (IKKγ) subunit of an IKK complex and uses this pathway to modulate the expression of genes involved in cellular survival, proliferation, and the inflammatory response. However, it is not clear if K13 can also induce gene expression independently of NEMO/IKKγ. The minimum region of NEMO that is sufficient for supporting K13-induced NF-κB has not been delineated. Furthermore, the contribution of NEMO and NF-κB to the protective effect of K13 against death receptor-induced apoptosis remains to be determined. In this study, we used microarray analysis on K13-expressing wild-type and NEMO-deficient cells to demonstrate that NEMO is required for modulation of K13-induced genes. Reconstitution of NEMO-null cells revealed that the N-terminal 251 amino acid residues of NEMO are sufficient for supporting K13-induced NF-κB but fail to support tumor necrosis factor alpha (TNF-α)-induced NF-κB. K13 failed to protect NEMO-null cells against TNF-α-induced cell death but protected those reconstituted with the NEMO mutant truncated to include only the N-terminal 251 amino acid residues [the NEMO(1-251) mutant]. Taken collectively, our results demonstrate that NEMO is required for modulation of K13-induced genes and the N-terminal 251 amino acids of NEMO are sufficient for supporting K13-induced NF-κB. Finally, the ability of K13 to protect against TNF-α-induced cell death is critically dependent on its ability to interact with NEMO and activate NF-κB. Kaposi's sarcoma-associated herpesvirus-encoded vFLIP K13 is believed to protect virally infected cells against death receptor-induced apoptosis and to

  19. Endothelial protein C receptor in renal tubular epithelial cells and ...

    African Journals Online (AJOL)

    Jane

    2011-07-20

    Jul 20, 2011 ... However, troglitazone had protective effects of EPCR on injured cells. Key words: Endothelial protein C receptor, renal tubular epithelial cell, troglitazone, tumor necrosis factor-α, interleukin-1β; high glucose. ..... induce apoptosis of vascular smooth muscle cells through an extracellular signal- regulated ...

  20. Tyrosylprotein sulfotransferase-1 and tyrosine sulfation of chemokine receptor 4 are induced by Epstein-Barr virus encoded latent membrane protein 1 and associated with the metastatic potential of human nasopharyngeal carcinoma.

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    Juan Xu

    Full Text Available The latent membrane protein 1 (LMP1, which is encoded by the Epstein-Barr virus (EBV, is an important oncogenic protein that is closely related to carcinogenesis and metastasis of nasopharyngeal carcinoma (NPC, a prevalent cancer in China. We previously reported that the expression of the functional chemokine receptor CXCR4 is associated with human NPC metastasis. In this study, we show that LMP1 induces tyrosine sulfation of CXCR4 through tyrosylprotein sulfotransferase-1 (TPST-1, an enzyme that is responsible for catalysis of tyrosine sulfation in vivo, which is likely to contribute to the highly metastatic character of NPC. LMP1 could induce tyrosine sulfation of CXCR4 and its associated cell motility and invasiveness in a NPC cell culture model. In contrast, the expression of TPST-1 small interfering RNA reversed LMP1-induced tyrosine sulfation of CXCR4. LMP1 conveys signals through the epidermal growth factor receptor (EGFR pathway, and EGFR-targeted siRNA inhibited the induction of TPST-1 by LMP1. We used a ChIP assay to show that EGFR could bind to the TPST-1 promoter in vivo under the control of LMP1. A reporter gene assay indicated that the activity of the TPST-1 promoter could be suppressed by deleting the binding site between EGFR and TPST-1. Finally, in human NPC tissues, the expression of TPST-1 and LMP1 was directly correlated and clinically, the expression of TPST-1 was associated with metastasis. These results suggest the up-regulation of TPST-1 and tyrosine sulfation of CXCR4 by LMP1 might be a potential mechanism contributing to NPC metastasis.

  1. Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1.

    Science.gov (United States)

    Sasmono, R Tedjo; Ehrnsperger, Achim; Cronau, Stephen L; Ravasi, Timothy; Kandane, Rangi; Hickey, Michael J; Cook, Andrew D; Himes, S Roy; Hamilton, John A; Hume, David A

    2007-07-01

    The differentiation of macrophages from their progenitors is controlled by macrophage colony-stimulating factor (CSF-1), which binds to a receptor (CSF-1R) encoded by the c-fms proto-oncogene. We have previously used the promoter region of the CSF-1R gene to direct expression of an enhanced green fluorescent protein (EGFP) reporter gene to resident macrophage populations in transgenic mice. In this paper, we show that the EGFP reporter is also expressed in all granulocytes detected with the Gr-1 antibody, which binds to Ly-6C and Ly-6G or with a Ly-6G-specific antibody. Transgene expression reflects the presence of CSF-1R mRNA but not CSF-1R protein. The same pattern is observed with the macrophage-specific F4/80 marker. Based on these findings, we performed a comparative array profiling of highly purified granulocytes and macrophages. The patterns of mRNA expression differed predominantly through granulocyte-specific expression of a small subset of transcription factors (Egr1, HoxB7, STAT3), known abundant granulocyte proteins (e.g., S100A8, S100A9, neutrophil elastase), and specific receptors (fMLP, G-CSF). These findings suggested that appropriate stimuli might mediate rapid interconversion of the major myeloid cell types, for example, in inflammation. In keeping with this hypothesis, we showed that purified Ly-6G-positive granulocytes express CSF-1R after overnight culture and can subsequently differentiate to form F4/80-positive macrophages in response to CSF-1.

  2. Bestrophin-encoded Ca²⁺-activated Cl⁻ channels underlie a current with properties similar to the native current in the moth Spodoptera littoralis olfactory receptor neurons.

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    Adrien François

    Full Text Available Responses of insect olfactory receptor neurons (ORNs involve an entry of Ca²⁺ through olfactory heterodimeric receptor complexes. In moths, the termination of ORN responses was found to strongly depend on the external Ca²⁺ concentration through the activation of unknown Ca²⁺-dependent Cl⁻ channels. We thus investigated the molecular identity of these Cl⁻ channels. There is compelling evidence that bestrophins form Cl⁻ channels when expressed in heterologous systems. Here we provide evidence that antennae of the moth Spodoptera littoralis express three transcripts encoding proteins with hallmarks of bestrophins. One of these transcripts, SlitBest1b, is expressed in ORNs. The heterologous expression of SlitBest1b protein in CHO-K1 cells yielded a Ca²⁺-activated Cl⁻ current that shares electrophysiological properties with the native Ca²⁺-activated Cl⁻ current of ORNs. Both currents are anionic, present similar dependence on the intracellular Ca²⁺ concentration, partly inactivate over time, have the same anion permeability sequence, the same sequence of inhibitory efficiency of blockers, the same almost linear I-V relationships and finally both currents do not depend on the cell volume. Therefore, our data suggest that SlitBest1b is a good candidate for being a molecular component of the olfactory Ca²⁺-activated Cl⁻ channel and is likely to constitute part of the insect olfactory transduction pathway. A different function (e.g. regulation of other proteins, maintenance of the anionic homeostasis in the sensillar lymph and a different role (e.g. involvement in the olfactory system development cannot be excluded however.

  3. The herpes simplex virus 1-encoded envelope glycoprotein B activates NF-κB through the Toll-like receptor 2 and MyD88/TRAF6-dependent signaling pathway.

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    Mingsheng Cai

    Full Text Available The innate immune response plays a critical role in the host defense against invading pathogens, and TLR2, a member of the Toll-like receptor (TLR family, has been implicated in the immune response and initiation of inflammatory cytokine secretion against several human viruses. Previous studies have demonstrated that infectious and ultraviolet-inactivated herpes simplex virus 1 (HSV-1 virions lead to the activation of nuclear factor kappa B (NF-κB and secretion of proinflammatory cytokines via TLR2. However, except for the envelope glycoprotein gH and gL, whether there are other determinants of HSV-1 responsible for TLR2 mediated biological effects is not known yet. Here, we demonstrated that the HSV-1-encoded envelope glycoprotein gB displays as molecular target recognized by TLR2. gB coimmunoprecipitated with TLR2, TLR1 and TLR6 in transfected and infected human embryonic kidney (HEK 293T cells. Treatment of TLR2-transfected HEK293T (HEK293T-TLR2 cells with purified gB results in the activation of NF-κB reporter, and this activation requires the recruitment of the adaptor molecules myeloid differentiation primary-response protein 88 (MyD88 and tumor necrosis factor receptor-associated factor 6 (TRAF6 but not CD14. Furthermore, activation of NF-κB was abrogated by anti-gB and anti-TLR2 blocking antibodies. In addition, the expression of interleukin-8 induced by gB was abrogated by the treatment of the human monocytic cell line THP-1 with anti-TLR2 blocking antibody or by the incubation of gB with anti-gB antibody. Taken together, these results indicate the importance and potency of HSV-1 gB as one of pathogen-associated molecular patterns (PAMPs molecule recognized by TLR2 with immediate kinetics.

  4. Interleukin 1 β-induced SMAD2/3 linker modifications are TAK1 dependent and delay TGFβ signaling in primary human mesenchymal stem cells.

    Science.gov (United States)

    van den Akker, Guus G; van Beuningen, Henk M; Vitters, Elly L; Koenders, Marije I; van de Loo, Fons A; van Lent, Peter L; Blaney Davidson, Esmeralda N; van der Kraan, Peter M

    2017-12-01

    Chondrogenic differentiation of mesenchymal stem cells (MSC) requires transforming growth factor beta (TGFβ) signaling. TGFβ binds to the type I receptor activin-like kinase (ALK)5 and results in C-terminal SMAD2/3 phosphorylation (pSMAD2/3C). In turn pSMAD2/3C translocates to the nucleus and regulates target gene expression. Inflammatory mediators are known to exert an inhibitory effect on MSC differentiation. In this study we investigated the effect of interleukin 1 β (IL1β) on SMAD2/3 signaling dynamics and post-translational modifications. Co-stimulation of MSC with TGFβ and IL1β did not affect peak pSMAD2C levels at 1h post-stimulation. Surprisingly, SMAD3 transcriptional activity, as determined by the CAGA12-luciferase reporter construct, was enhanced by co-stimulation of TGFβ and IL1β compared to TGFβ alone. Furthermore, IL1β stimulation induced CAGA12-luciferase activity in a SMAD dependent way. As SMAD function can be modulated independent of canonical TGFβ signaling through the SMAD linker domain, we studied SMAD2 linker phosphorylation at specific threonine and serine residues. SMAD2 linker threonine and serine modifications were observed within 1h following TGFβ, IL1β or TGFβ and IL1β stimulation. Upon co-stimulation linker modified SMAD2 accumulated in the cytoplasm and SMAD2/3 target gene transcription (ID1, JUNB) at 2-4h was inhibited. A detailed time course analysis of IL1β-induced SMAD2 linker modifications revealed a distinct temperospatial pattern compared to TGFβ. Co-stimulation with both factors resulted in a similar kinetic profile as TGFβ alone. Nevertheless, IL1β did subtly alter TGFβ-induced pSMAD2C levels between 8 and 24h post-stimulation, which was reflected by TGFβ target gene expression (PAI1, JUNB). Direct evidence for the importance of SMAD3 linker modifications for the effect of IL1β on TGFβ signaling was obtained by over-expression of SMAD3 or a SMAD3 linker phospho-mutant. Finally, an inhibitor screening was

  5. Interleukin-1 (IL-1) signaling in intestinal stromal cells controls KC/ CXCL1 secretion, which correlates with recruitment of IL-22- secreting neutrophils at early stages of Citrobacter rodentium infection.

    Science.gov (United States)

    Lee, Yong-Soo; Yang, Hyungjun; Yang, Jin-Young; Kim, Yeji; Lee, Su-Hyun; Kim, Ji Heui; Jang, Yong Ju; Vallance, Bruce A; Kweon, Mi-Na

    2015-08-01

    Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli in humans and Citrobacter rodentium in mice, raise serious public health concerns. Here we demonstrate that interleukin-1 receptor (IL-1R) signaling is indispensable for protection against C. rodentium infection in mice. Four days after infection with C. rodentium, there were significantly fewer neutrophils (CD11b+ Ly6C+ Ly6G+) in the colons of IL-1R−/− mice than in wild-type mice. Levels of mRNA and protein of KC/CXCL1 were also significantly reduced in colon homogenates of infected IL-1R−/− mice relative to wild-type mice. Of note, infiltrated CD11b+ Ly6C+ Ly6G+ neutrophils were the main source of IL-22 secretion after C. rodentium infection. Interestingly, intestinal stromal cells isolated from IL-1R−/− mice secreted lower levels of KC/CXCL1 than stromal cells from wild-type mice during C. rodentium infection. Similar effects were found when mouse intestinal stromal cells and human nasal polyp stromal cells were treated with IL-1R antagonists (i.e., anakinra) in vitro. These results suggest that IL-1 signaling plays a pivotal role in activating mucosal stromal cells to secrete KC/CXCL1, which is essential for infiltration of IL-22-secreting neutrophils upon bacterial infection.

  6. Porcine circovirus type 2 increases interleukin-1beta and interleukin-10 production via the MyD88-NF-kappa B signaling pathway in porcine alveolar macrophagesin vitro.

    Science.gov (United States)

    Han, Junyuan; Zhang, Shuxia; Zhang, Yaqun; Chen, Mengmeng; Lv, Yingjun

    2017-06-30

    Porcine alveolar macrophages (PAMs) represent the first line of defense in the porcine lung after infection with porcine circovirus type 2 (PCV2) via the respiratory tract. However, PCV2 infection impairs the microbicidal capability of PAMs and alters cytokine production and/or secretion. At present, the reason for the imbalance of cytokines has not been fully elucidated, and the regulatory mechanisms involved are unclear. In this study, we investigated the expression levels and regulation of interleukin-1beta (IL-1β) and IL-10 in PAMs following incubation with PCV2 in vitro. Levels of IL-1β and IL-10 increased in PAM supernatants, and the distribution of nuclear factor kappa B (NF-κB) p65staining in nucleus, expression of MyD88 and p-IκB in cytoplasm, and DNA-binding activity of NF-κB increased after incubation with PCV2, while p65 expression in PAM cytoplasm decreased. However, when PAMs were co-incubated with PCV2 and small interfering RNA targeting MyD88, those effects were reversed. Additionally, mRNA expression levels of Toll-like receptors (TLR)-2, -3, -4, -7, -8, and -9 increased when PAMs were incubated with PCV2. These results show that PCV2 induces increased IL-1β and IL-10 production in PAMs, and these changes in expression are related to the TLR-MyD88-NF-κB signaling pathway.

  7. Mapping of the gene encoding the melanocortin-1 ([alpha]-melanocyte stimulating hormone) receptor (MC1R) to human chromosome 16q24. 3 by fluorescence in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Gantz, I.; Yamada, Tadataka; Tashiro, Takao; Konda, Yoshitaka; Shimoto, Yoshimasa; Miwa, Hiroto; Trent, J.M. (Univ. of Michigan Medical Center, Ann Arbor, MI (United States))

    1994-01-15

    [alpha]-Melanocyte stimulating hormone ([alpha]-MSH), a hormone originally named for its ability to regulate pigmentation of melanocytes, is a 13-amino-acid post-translational product of the pro-opiomelanocortin (POMC) gene. [alpha]-MSH and the other products of POMC processing, which share the core heptapeptide amino acid sequence Met-Glu (Gly)-His-Phe-Arg-Trp-Gly (Asp), the adrenocorticotropic hormone (ACTH), [beta]-MSH, and [gamma]-MSH, are collectively referred to as melanocortins. While best known for their effects on the melanocyte (pigmentation) and adrenal cortical cells (steroidogenesis), melanocortins have been postulated to function in diverse activities, including enhancement of learning and memory, control of the cardiovascular system, analgesia, thermoregulation, immunomodulation, parturition, and neurotrophism. To identify the chromosomal band encoding the human melanocortin-1 receptor gene, 1 [mu]g of an EMBL clone coding region of the human MC1R and approximately 15 kb of surrounding DNA was labeled with biotin and hybridized to human metaphase chromosomes as previously described. The results indicate that the human MC1R gene is localized to 16q24.3. 15 refs., 1 fig.

  8. Functional differentiation and spatial-temporal co-expression networks of the NBS-encoding gene family in Jilin ginseng, Panax ginseng C.A. Meyer.

    Science.gov (United States)

    Yin, Rui; Zhao, Mingzhu; Wang, Kangyu; Lin, Yanping; Wang, Yanfang; Sun, Chunyu; Wang, Yi; Zhang, Meiping

    2017-01-01

    Ginseng, Panax ginseng C.A. Meyer, is one of the most important medicinal plants for human health and medicine. It has been documented that over 80% of genes conferring resistance to bacteria, viruses, fungi and nematodes are contributed by the nucleotide binding site (NBS)-encoding gene family. Therefore, identification and characterization of NBS genes expressed in ginseng are paramount to its genetic improvement and breeding. However, little is known about the NBS-encoding genes in ginseng. Here we report genome-wide identification and systems analysis of the NBS genes actively expressed in ginseng (PgNBS genes). Four hundred twelve PgNBS gene transcripts, derived from 284 gene models, were identified from the transcriptomes of 14 ginseng tissues. These genes were classified into eight types, including TNL, TN, CNL, CN, NL, N, RPW8-NL and RPW8-N. Seven conserved motifs were identified in both the Toll/interleukine-1 receptor (TIR) and coiled-coil (CC) typed genes whereas six were identified in the RPW8 typed genes. Phylogenetic analysis showed that the PgNBS gene family is an ancient family, with a vast majority of its genes originated before ginseng originated. In spite of their belonging to a family, the PgNBS genes have functionally dramatically differentiated and been categorized into numerous functional categories. The expressions of the across tissues, different aged roots and the roots of different genotypes. However, they are coordinating in expression, forming a single co-expression network. These results provide a deeper understanding of the origin, evolution and functional differentiation and expression dynamics of the NBS-encoding gene family in plants in general and in ginseng particularly, and a NBS gene toolkit useful for isolation and characterization of disease resistance genes and for enhanced disease resistance breeding in ginseng and related species.

  9. The Efficacy and Safety of Treatments for Acute Gout: Results from a Series of Systematic Literature Reviews Including Cochrane Reviews on Intraarticular Glucocorticoids, Colchicine, Nonsteroidal Antiinflammatory Drugs, and Interleukin-1 Inhibitors

    NARCIS (Netherlands)

    Wechalekar, Mihir D.; Vinik, Ophir; Moi, John H. Y.; Sivera, Francisca; van Echteld, Irene A. A. M.; van Durme, Caroline; Falzon, Louise; Bombardier, Claire; Carmona, Loreto; Aletaha, Daniel; Landewé, Robert B.; van der Heijde, Désirée M. F. M.; Buchbinder, Rachelle

    2014-01-01

    Objective. To determine the efficacy and safety of glucocorticoids (GC), colchicine, nonsteroidal antiinflammatory drugs (NSAID), interleukin-1 (IL-1) inhibitors, and paracetamol to treat acute gout. Methods. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to

  10. Molecular cloning and characterization of a Toll receptor gene from Macrobrachium rosenbergii.

    Science.gov (United States)

    Srisuk, Chutima; Longyant, Siwaporn; Senapin, Saengchan; Sithigorngul, Paisarn; Chaivisuthangkura, Parin

    2014-02-01

    Toll receptors are cell surface molecules acting as pattern recognition receptors (PRRs) that have been implicated in the signaling pathway of innate immune responses. In this study, the full-length cDNA of a Toll receptor gene of Macrobrachium rosenbergii, designated MrToll, was successfully isolated using designed degenerate primers and the rapid amplification of cDNA ends (RACE). The MrToll gene sequence contained an open reading frame (ORF) of 2799 nucleotides encoding a protein of 932 amino acid residues. The protein contained distinct structural motifs of the Toll-like receptor (TLR) family, including an extracellular domain containing 15 leucine-rich repeats (LRRs), a transmembrane segment of 23 amino acids, and a cytoplasmic Toll/interleukin-1R (TIR) domain of 139 residues. Phylogenetic analysis revealed that MrToll and Toll receptor of Marsupenaeus japonicus (MjToll) evolved closely. However, the MrToll ORF demonstrated only 48-49% identity with shrimp Toll1, suggesting that MrToll isolated from a palaemonid shrimp might belong to a novel class of Toll receptors in shrimp. The transcripts of the MrToll gene were constitutively expressed in various tissues, with high levels in hemocytes, the stomach and muscle. A reverse transcriptase PCR assay demonstrated that the expression patterns of MrToll were distinctly modulated after Aeromonas caviae stimulation, with significant enhancement at 3-12 h post-challenge and a decline to basal levels at 24 h post-challenge. In addition, when MrToll-silenced shrimp were challenged with A. caviae, there was a significant increase in mortality and bacterial CFU counts. These results suggest that MrToll might be involved in host innate defense, especially against the pathogen A. caviae. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Differential Expression of the Activator Protein 1 Transcription Factor Regulates Interleukin-1ß Induction of Interleukin 6 in the Developing Enterocyte.

    Directory of Open Access Journals (Sweden)

    Catherine M Cahill

    Full Text Available The innate immune response is characterized by activation of transcription factors, nuclear factor kappa B and activator protein-1 and their downstream targets, the pro-inflammatory cytokines including interleukin 1β and interleukin 6. Normal development of this response in the intestine is critical to survival of the human neonate and delays can cause the onset of devastating inflammatory diseases such as necrotizing enterocolitis. Previous studies have addressed the role of nuclear factor kappa B in the development of the innate immune response in the enterocyte, however despite its central role in the control of multiple pro-inflammatory cytokine genes, little is known on the role of Activator Protein 1 in this response in the enterocyte. Here we show that the canonical Activator Protein 1 members, cJun and cFos and their upstream kinases JNK and p38 play an essential role in the regulation of interleukin 6 in the immature enterocyte. Our data supports a model whereby the cFos/cJun heterodimer and the more potent cJun homodimer downstream of JNK are replaced by less efficient JunD containing dimers, contributing to the decreased responsiveness to interleukin 1β and decreased interleukin 6 secretion observed in the mature enterocyte. The tissue specific expression of JunB in colonocytes and colon derived tissues together with its ability to repress Interleukin-1β induction of an Interleukin-6 gene reporter in the NCM-460 colonocyte suggests that induction of JunB containing dimers may offer an attractive therapeutic strategy for the control of IL-6 secretion during inflammatory episodes in this area of the intestine.

  12. A role for protein kinase C activity in interleukin-1 (IL-1) induction of IL-2 gene expression but not in IL-1 signal transduction.

    OpenAIRE

    Macchia, G; Baldari, C T; Massone, A; Telford, J L

    1990-01-01

    Interleukin-1 (IL-1) is known to synergize with phorbol esters in the induction of interleukin-2 (IL-2) expression in T-lymphoid leukemia cells and proliferation of mouse thymocytes. We used a plasmid construct containing the bacterial gene for chloramphenicol acetyltransferase under the control of the human IL-2 promoter to study the nature of this synergism in the murine thymoma cell line EL4. Although IL-1 induction of the IL-2 promoter in these cells required costimulus with phorbol myris...

  13. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

    DEFF Research Database (Denmark)

    Clausen, Bettina Hjelm; Lambertsen, Kate Lykke; Babcock, Alicia

    2008-01-01

    BACKGROUND: Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We...... investigated whether IL-1beta and TNF-alpha are synthesized by overlapping or segregated populations of cells after ischemic stroke in mice. METHODS: We used flow cytometry and immunohistochemistry to examine cellular co-expression of IL-1beta and TNF-alpha at 6, 12 and 24 hours after permanent middle cerebral...

  14. The interleukin 1 (IL-1 system in the uteroplacental complex of a cartilaginous fish, the smoothhound shark, Mustelus canis

    Directory of Open Access Journals (Sweden)

    Hamlett William C

    2003-02-01

    Full Text Available Abstract Cartilaginous fish are the oldest extant jawed vertebrates and the oldest line to have placentae. Their pivotal evolutionary position makes them attractive models to investigate the mechanisms involved in the maternal-fetal interaction. This study describes the tissue expression of the cytokine interlukin-1 (IL-1 α, IL-1 β and its specific membrane receptor, IL-1 receptor type I (IL-1R tI in a placental cartilaginous fish, the smoothhound shark, Mustelus canis. The presence of this cytokine has been reported in many mammalian placentae, as well as in the placenta of a squamate reptile and this study extends these observations to the cartilaginous fishes. The uteroplacental complex in M. canis consists of a yolk sac modified into a functional yolk sac placenta and complimentary uterine attachment sites. Immunohistochemistry for IL-1 α, IL-1 β and the receptor reveals leucocytes of both the mother and fetus to be positive, as well as the apical aspect of paraplacental cells and the apical vesicles in the umbilical cord epithelium. Yolk sac endoderm is also positive with all the stains while the ectoderm is positive only for IL-1 α. Immunoreactivity in the uterine epithelium was obtained for IL-1 α and the receptor. The egg envelope is always negative. In light of the recent finding of IL-1 β gene in a cartilaginous fish and of the high level of conservation of proteins implicated in IL-1 action, our data suggest that IL-1 system is a key mediator of the materno-fetal interaction since the oldest extant placental vertebrates.

  15. Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4-/- mouse model

    Science.gov (United States)

    Reiter, Florian P; Wimmer, Ralf; Wottke, Lena; Artmann, Renate; Nagel, Jutta M; Carranza, Manuel O; Mayr, Doris; Rust, Christian; Fickert, Peter; Trauner, Michael; Gerbes, Alexander L; Hohenester, Simon; Denk, Gerald U

    2016-01-01

    AIM: To study the interleukin-1 (IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4-/- (Abcb4-/-) mouse model. METHODS: Female and male Abcb4-/- mice from 6 to 13 mo of age were analysed for the degree of cholestasis (liver serum tests), extent of liver fibrosis (hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction (qPCR)]. For in vivo experiments, murine hepatic stellate cells (HSCs) were isolated via pronase-collagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/mL IL-1β with or without 2.5 μg/mL Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the BrdU assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis (FDH) assay. In vivo 8-wk-old Abcb4-/- mice with an already fully established hepatic phenotype were treated with Anakinra (1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, qPCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4-/- animals as defined by a lower hydroxyproline content (274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test) and lower mRNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1 (TIMP) (1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 mRNA expression (1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β mRNA expression levels (1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann

  16. Dynorphin 1-17 and Its N-Terminal Biotransformation Fragments Modulate Lipopolysaccharide-Stimulated Nuclear Factor-kappa B Nuclear Translocation, Interleukin-1beta and Tumor Necrosis Factor-alpha in Differentiated THP-1 Cells.

    Directory of Open Access Journals (Sweden)

    Siti Sarah Fazalul Rahiman

    Full Text Available Dynorphin 1-17, (DYN 1-17 opioid peptide produces antinociception following binding to the kappa-opioid peptide (KOP receptor. Upon synthesis and release in inflamed tissues by immune cells, DYN 1-17 undergoes rapid biotransformation and yields a unique set of opioid and non-opioid fragments. Some of these major fragments possess a role in immunomodulation, suggesting that opioid-targeted therapeutics may be effective in diminishing the severity of inflammatory disorders. This study aimed to examine the immunomodulatory effects of DYN 1-17 and major N-terminal fragments found in the inflammatory environment on nuclear factor-kappaB/p65 (NF-κB/p65 nuclear translocation and the release of interleukin-1beta (IL-1β and tumor necrosis factor-alpha (TNF-α from lipopolysaccharide (LPS-stimulated, differentiated THP-1 cells. The results demonstrate that NF-κB/p65 nuclear translocation was significantly attenuated following treatment with DYN 1-17 and a specific range of fragments, with the greatest reduction observed with DYN 1-7 at a low concentration (10 nM. Antagonism with a selective KOP receptor antagonist, ML-190, significantly reversed the inhibitory effects of DYN 1-17, DYN 1-6, DYN 1-7 and DYN 1-9, but not other DYN 1-17 N-terminal fragments (DYN 1-10 and 1-11 on NF-κB/p65 nuclear translocation. DYN 1-17 and selected fragments demonstrated differential modulation on the release of IL-1β and TNF-α with significant inhibition observed with DYN 1-7 at low concentrations (1 nM and 10 pM. These effects were blocked by ML-190, suggesting a KOP receptor-mediated pathway. The results demonstrate that DYN 1-17 and certain N-terminal fragments, produced in an inflamed environment, play an anti-inflammatory role by inhibiting NF-κB/p65 translocation and the subsequent cytokine release through KOP receptor-dependent and independent pathways.

  17. Effects of Thymoquinone on Interleukin-1 and Interferon Gamma Gene Expression and Antibody Titers against Newcastle Disease in Broiler Chickens under Oxidative Stress

    Directory of Open Access Journals (Sweden)

    A Rastad

    Full Text Available ABSTRACT An experiment was conducted to determine the effects of the dietary inclusion of different levels of thymoquinone (TQ of broilers subjected to oxidative stress or not on the antibody titers against Newcastle disease and on the gene expression of interleukine-1 and interferon gamma. A total of 320 one-day-old broilers was randomly assigned to eight treatments with four replicates of 10 birds each, in a 4 × 2 factorial arrangement, consisting of four thymoquinone (TQ levels (0, 5, 8, or 11 mg/kg body weight and two levels tert-butyl hydroperoxide (t-BHP injection (0 or 0.02 mmol/kg of body weight. Blood samples were collected from two birds per replicate to determine antibody titers against Newcastle disease. At the end of experiment, two birds per replicate were randomly selected, sacrificed and their spleens were collected to evaluate the genes expressioninterleukin-1 and interferon gamma (p<0.05. The dietary inclusion of TQ of broilers subjected or not oxidative stress increased antibody production against Newcastle disease (p<0.05. Both individual and combined dietary inclusion of t-BHP and TQ promote the differentiation and proliferation of spleen cells and the gene expression of interleukin-1 and interferon gamma (p<0.05.

  18. Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1β and inhibited by peroxisome proliferator activated receptor α agonist

    NARCIS (Netherlands)

    Clockaerts, S.; Bastiaansen-Jenniskens, Y.M.; Feijt, C.; Clerck, L.de; Verhaar, J.A.N.; Zuurmond, A.M.; Stojanovic-Susulic, V.; Somville, J.; Kloppenburg, M.; Osch, G.J.V.M. van

    2012-01-01

    Background: Infrapatellar fat pad (IPFP) might be involved in osteoarthritis (OA) by production of cytokines. It was hypothesised that production of cytokines is sensitive to environmental conditions. Objectives: To evaluate cytokine production by IPFP in response to interleukin (IL)1β and

  19. The Multifaceted Effects of Polysaccharides Isolated from Dendrobium huoshanense on Immune Functions with the Induction of Interleukin-1 Receptor Antagonist (IL-1ra) in Monocytes

    Science.gov (United States)

    Lin, Juway; Chang, Ya-Jen; Yang, Wen-Bin; Yu, Alice L.; Wong, Chi-Huey

    2014-01-01

    Dendrobium huoshanense is a valuable and versatile Chinese herbal medicine with the anecdotal claims of cancer prevention and anti-inflammation. However, its immunological activities are limited to in vitro studies on a few cytokines and immune cell functions. First, we investigated the effects of polysaccharides isolated from DH (DH-PS) on inducing a panel of cytokines/chemokines in mice in vivo and human in vitro. We found that DH polysaccharides (DH-PS) induced TH1, TH2, inflammatory cytokines and chemokines in mouse in vivo and human cells in vitro. Secondly, we demonstrated that DH-PS expanded mouse splenocytes in vivo including CD4+ T cells, CD8+ T cells, B cells, NK cells, NKT cells, monocytes/macrophages, granulocytes and regulatory T cells. Notably, DH-PS induced an anti-inflammatory molecule, IL-1ra, in mouse and human immune cells, especially monocytes. The serum level of IL-1ra elicited by the injection of DH-PS was over 10 folds of IL-1β, suggesting that DH-PS-induced anti-inflammatory activities might over-ride the inflammatory ones mediated by IL-1β. The signaling pathways of DH-PS-induced IL-1ra production was shown to involve ERK/ELK, p38 MAPK, PI3K and NFκB. Finally, we observed that IL-1ra level induced by DH-PS was significantly higher than that by F3, a polysaccharide extract isolated from another popular Chinese herbal medicine, Ganoderma lucidum. These results indicated that DH-PS might have potential applications for ameliorating IL-1-induced pathogenic conditions. PMID:24705413

  20. The multifaceted effects of polysaccharides isolated from Dendrobium huoshanense on immune functions with the induction of interleukin-1 receptor antagonist (IL-1ra in monocytes.

    Directory of Open Access Journals (Sweden)

    Juway Lin

    Full Text Available Dendrobium huoshanense is a valuable and versatile Chinese herbal medicine with the anecdotal claims of cancer prevention and anti-inflammation. However, its immunological activities are limited to in vitro studies on a few cytokines and immune cell functions. First, we investigated the effects of polysaccharides isolated from DH (DH-PS on inducing a panel of cytokines/chemokines in mice in vivo and human in vitro. We found that DH polysaccharides (DH-PS induced TH1, TH2, inflammatory cytokines and chemokines in mouse in vivo and human cells in vitro. Secondly, we demonstrated that DH-PS expanded mouse splenocytes in vivo including CD4(+ T cells, CD8(+ T cells, B cells, NK cells, NKT cells, monocytes/macrophages, granulocytes and regulatory T cells. Notably, DH-PS induced an anti-inflammatory molecule, IL-1ra, in mouse and human immune cells, especially monocytes. The serum level of IL-1ra elicited by the injection of DH-PS was over 10 folds of IL-1β, suggesting that DH-PS-induced anti-inflammatory activities might over-ride the inflammatory ones mediated by IL-1β. The signaling pathways of DH-PS-induced IL-1ra production was shown to involve ERK/ELK, p38 MAPK, PI3K and NFκB. Finally, we observed that IL-1ra level induced by DH-PS was significantly higher than that by F3, a polysaccharide extract isolated from another popular Chinese herbal medicine, Ganoderma lucidum. These results indicated that DH-PS might have potential applications for ameliorating IL-1-induced pathogenic conditions.

  1. Distribution of interleukin-1 receptor antagonist genotypes in sudden unexpected death in infancy (SUDI); unexplained SUDI have a higher frequency of allele 2.

    Science.gov (United States)

    Highet, Amanda R; Berry, Anne M; Goldwater, Paul N

    2010-01-01

    This investigation was designed to explore the role of IL-1RN genotype in unexplained infant deaths (including sudden infant death syndrome (SIDS)), non-infectious infant deaths, and infectious infant deaths, and to investigate whether IL-1RN genotype is related to the finding of organisms in normally sterile sites in infant deaths. IL-1RN 89bp variable number of tandem repeat polymorphism genotype was determined using polymerase chain reaction for 49 cases of unexplained sudden unexpected death in infancy (uSUDI), 13 cases of infectious sudden unexpected death in infancy, 10 cases of non-infectious sudden unexpected death in infancy, and 103 live control infants. IL-1RN genotype was then compared with the presence of bacteria in normally sterile sites in infant deaths. An association was found between the homozygous A2 allele and uSUDI (P = 0.007; 95% confidence interval 1.41-17.67) where carriage of the 2/2 genotype was 4.85 times more likely to increase risk of uSUDI compared with the predominant 1/1 genotype. The role of infection in uSUDI and SIDS may be via an immune response pathway where IL-1RN A2 affects interleukin (IL)-1 regulation. These results are consistent with previous research where polymorphic genotypes conferring more severe proinflammatory responses are found more frequently in uSUDI/SIDS infants than in controls.

  2. The Arabidopsis flagellin receptor FLS2 mediates the perception of Xanthomonas Ax21 secreted peptides.

    Science.gov (United States)

    Danna, Cristian H; Millet, Yves A; Koller, Teresa; Han, Sang-Wook; Bent, Andrew F; Ronald, Pamela C; Ausubel, Frederick M

    2011-05-31

    Detection of microbes by plants relies in part on an array of pattern-recognition receptors that recognize conserved microbial signatures, so-called "microbe-associated molecular patterns." The Arabidopsis thaliana receptor-like kinase FLS2 is the pattern-recognition receptor for bacterial flagellin. Similarly to FLS2, the rice transmembrane protein XA21 is the receptor for the sulfated form of the Xanthomonas oryzae pv. oryzae secreted protein Ax21. Here we show that Ax21-derived peptides activate Arabidopsis immunity, triggering responses similar to those elicited by flagellin, including an oxidative burst, induction of defense-response genes, and enhanced resistance to bacterial pathogens. To identify Arabidopsis Xa21 functional homologs, we used a reverse genetics approach to screen T-DNA insertion mutants corresponding to all 47 of the Arabidopsis genes encoding non-RD kinases belonging to the interleukin-1 receptor-associated kinase (IRAK) family. Surprisingly, among all of these mutant lines, only fls2 mutants exhibited a significant loss of response to Ax21-derived peptides. Ax21 peptides also failed to activate defense-related responses in an fls2-24 mutant that does not bind Flg22. Moreover, a Flg22Δ2 variant of Flg22 that binds to FLS2 but does not activate FLS2-mediated signaling suppressed Ax21-derived peptide signaling, indicating mutually exclusive perception of Flg22 or Ax21 peptides by FLS2. The data indicate that FLS2 functions beyond flagellin perception to detect other microbe-associated molecular patterns.

  3. Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex

    DEFF Research Database (Denmark)

    Frobøse, Helle; Rønn, Sif Groth; Heding, Peter E

    2006-01-01

    -activated kinase 1, TNF receptor-associated factor (TRAF)6, and TGFbeta-activated kinase (TAK)1, but not when the MAP3K MAPK/ERK kinase kinase-1 is used instead of TAK1, indicating that the target for SOCS-3 is the TRAF6/TAK1 signaling complex. By coimmunoprecipitation, it was shown that SOCS-3 inhibited...... the association between TRAF6 and TAK1 and that SOCS-3 coimmunoprecipitated with TAK1 and TRAF6. Furthermore, SOCS-3 inhibited the IL-1-induced catalytic activity of TAK1. Because ubiquitination of TRAF6 is required for activation of TAK1, we analyzed the role of SOCS-3 on TRAF6 ubiquitination and found that SOCS......-3 inhibited ubiquitin modification of TRAF6. These results indicate that SOCS-3 inhibits IL-1 signal transduction by inhibiting ubiquitination of TRAF6, thus preventing association and activation of TAK1....

  4. The peroxisome proliferator response element of the gene encoding the peroxisomal beta-oxidation enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase is a target for constitutive androstane receptor beta/9-cis-retinoic acid receptor-mediated transactivation.

    Science.gov (United States)

    Kassam, A; Winrow, C J; Fernandez-Rachubinski, F; Capone, J P; Rachubinski, R A

    2000-02-11

    The genes encoding the first two enzymes of the peroxisomal beta-oxidation pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), contain upstream cis-acting regulatory regions termed peroxisome proliferator response elements (PPRE). Transcription of these genes is mediated through the binding of peroxisome proliferator-activated receptor alpha (PPARalpha), which binds to a PPRE as a heterodimer with the 9-cis-retinoic acid receptor (RXRalpha). Here we demonstrate that the HD-PPRE is also a target for the constitutive androstane receptor beta (CARbeta). In vitro binding analysis showed that CARbeta bound the HD-PPRE, but not the AOx-PPRE, as a heterodimer with RXRalpha. Binding of CARbeta/RXRalpha to the HD-PPRE occurred via determinants that overlap partially with those required for PPARalpha/RXRalpha binding. In vivo, CARbeta/RXRalpha activated transcription from an HD-PPRE luciferase reporter construct. Interestingly, CARbeta was shown to also modulate PPARalpha/RXRalpha-mediated transactivation in a response element-specific manner. In the presence of the peroxisome proliferator, Wy-14,643, CARbeta had no effect on PPARalpha/RXRalpha-mediated transactivation from the HD-PPRE but antagonized transactivation from the AOx-PPRE in both the presence and the absence of proliferator. Our results illustrate that transcription of the AOx and HD genes is differentially regulated by CARbeta and that the HD gene is a specific target for regulation by CARbeta. Overall, this study proposes a novel role for CARbeta in the regulation of peroxisomal beta-oxidation.

  5. Mechanism of interleukin-1α transcriptional regulation of S100A9 in a human epidermal keratinocyte cell line

    Science.gov (United States)

    Bando, Mika; Zou, Xianqiong; Hiroshima, Yuka; Kataoka, Masatoshi; Ross, Karen F; Shinohara, Yasuo; Nagata, Toshihiko; Herzberg, Mark C; Kido, Jun-ichi

    2013-01-01

    S100A9 is a calcium-binding protein and subunit of antimicrobial calprotectin complex (S100A8/A9). Produced by neutrophils, monocytes/ macrophages and keratinocytes, S100A9 expression increases in response to inflammation. For example, IL-1α produced by epithelial cells acts autonomously on the same cells to induce expression of S100A8/A9 and cellular differentiation. Whereas it is well known that IL-1α and members of the IL-10 family of cytokines upregulate S100A8 and S100A9 in several cell lineages, the pathway and mechanism of IL-1α-dependent transcriptional control of S100A9 in epithelial cells is not established. Modeled using human epidermal keratinocytes (HaCaT cells), IL-1α stimulated phosphorylation of p38 MAPK and induced S100A9 expression, which was blocked by IL-1 receptor antagonist, RNAi suppression of p38, or a p38 MAPK inhibitor. Transcription of S100A9 in HaCaT cells depended on nucleotides -94 to -53 in the upstream promoter region, based upon use of deletion constructs and luciferase reporter activity. Within the responsive promoter region, IL-1α increased the binding activity of CCAAT/enhancer binding protein β (C/EBPβ). Mutated C/EBPβ binding sequences or C/EBPβ-specific siRNA inhibited the S100A9 transcriptional response. Hence, IL-1α is strongly suggested to increase S100A9 expression in a human epidermal keratinocyte cell line by signaling through the IL-1 receptor and p38 MAPK, increasing C/EBPβ-dependent transcriptional activity. PMID:23563247

  6. Repeated water avoidance stress induces visceral hypersensitivity: Role of interleukin-1, interleukin-6, and peripheral corticotropin-releasing factor.

    Science.gov (United States)

    Nozu, Tsukasa; Miyagishi, Saori; Nozu, Rintaro; Takakusaki, Kaoru; Okumura, Toshikatsu

    2017-12-01

    Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin-releasing factor (CRF), mast cells, and pro-inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue. Abdominal muscle contractions induced by colonic balloon distention, that is, visceromotor response (VMR) was detected electrophysiologically in conscious rats. WAS or sham stress as control for 1 h daily was loaded, and the threshold of VMR was determined before and at 24 h after the stress. Repeated WAS for three consecutive days reduced the threshold of VMR, but sham stress did not induce any change. Astressin, a CRF receptor antagonist (50 μg/kg) intraperitoneally (ip) at 10 min before each WAS session, prevented the visceral allodynia, but the antagonist (200 μg/kg) ip at 30 min and 15 h before measurement of the threshold after completing 3-day stress session did not modify the response. Ketotifen, a mast cell stabilizer (3 mg/kg), anakinra, an interleukin (IL)-1 receptor antagonist (20 mg/kg) or IL-6 antibody (16.6 μg/kg) ip for two times before the measurement abolished the response. Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  7. Production of interleukin-1alpha by human endometrial stromal cells is triggered during menses and dysfunctional bleeding and is induced in culture by epithelial interleukin-1alpha released upon ovarian steroids withdrawal.

    Science.gov (United States)

    Pretto, Chrystel M; Gaide Chevronnay, Héloïse P; Cornet, Patricia B; Galant, Christine; Delvaux, Denis; Courtoy, Pierre J; Marbaix, Etienne; Henriet, Patrick

    2008-10-01

    Endometrial breakdown during menstruation and dysfunctional bleeding is triggered by the abrupt expression of matrix metalloproteinases (MMPs), including interstitial collagenase (MMP-1). The paracrine induction of MMP-1 in stromal cells via epithelium-derived IL-1alpha is repressed by ovarian steroids. However, the control by estradiol (E) and progesterone (P) of endometrial IL-1alpha expression and bioactivity remains unknown. Variations of endometrial IL-1alpha mRNA and protein along the menstrual cycle and during dysfunctional bleeding were determined using RT-PCR, in situ hybridization, and immunolabeling. The mechanism of EP control was analyzed using culture of explants, laser capture microdissection, and purified cells. Data were compared with expression changes of IL-1beta and IL-1 receptor antagonist. IL-1alpha is synthesized by epithelial cells throughout the cycle but E and/or P prevents its release. In contrast, endometrial stromal cells produce IL-1alpha only at menses and during irregular bleeding in areas of tissue breakdown. Stromal expression of IL-1alpha, like that of MMP-1, is repressed by P (alone or with E) but triggered by epithelium-derived IL-1alpha released upon EP withdrawal. Our experiments in cultured endometrium suggest that IL-1alpha released by epithelial cells triggers the production of IL-1alpha by stromal cells in a paracrine amplification loop to induce MMP-1 expression during menstruation and dysfunctional bleeding. All three steps of this amplification cascade are repressed by EP.

  8. Angiotensin II modulates interleukin-1{beta}-induced inflammatory gene expression in vascular smooth muscle cells via interfering with ERK-NF-{kappa}B crosstalk

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shanqin [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Zhi, Hui [Cardiovascular Division, Department of Medicine, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Hou, Xiuyun [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Jiang, Bingbing, E-mail: bjiang1@rics.bwh.harvard.edu [Vascular Biology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (United States); Cardiovascular Division, Department of Medicine, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States)

    2011-07-08

    Highlights: {yields} We examine how angiotensin II modulates ERK-NF-{kappa}B crosstalk and gene expression. {yields} Angiotensin II suppresses IL-1{beta}-induced prolonged ERK and NF-{kappa}B activation. {yields} ERK-RSK1 signaling is required for IL-1{beta}-induced prolonged NF-{kappa}B activation. {yields} Angiotensin II modulates NF-{kappa}B responsive genes via regulating ERK-NF-{kappa}B crosstalk. {yields} ERK-NF-{kappa}B crosstalk is a novel mechanism regulating inflammatory gene expression. -- Abstract: Angiotensin II is implicated in cardiovascular diseases, which is associated with a role in increasing vascular inflammation. The present study investigated how angiotensin II modulates vascular inflammatory signaling and expression of inducible nitric oxide synthase (iNOS) and vascular cell adhesion molecule (VCAM)-1. In cultured rat aortic vascular smooth muscle cells (VSMCs), angiotensin II suppressed interleukin-1{beta}-induced prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and ribosomal S6 kinase (RSK)-1, and nuclear translocation of nuclear factor (NF)-{kappa}B, leading to decreased iNOS but enhanced VCAM-1 expression, associated with an up-regulation of mitogen-activated protein kinase phosphatase-1 expression. Knock-down of RSK1 selectively down regulated interleukin-1{beta}-induced iNOS expression without influencing VCAM-1 expression. In vivo experiments showed that interleukin-1{beta}, iNOS, and VCAM-1 expression were detectable in the aortic arches of both wild-type and apolipoprotein E-deficient (ApoE{sup -/-}) mice. VCAM-1 and iNOS expression were higher in ApoE{sup -/-} than in wild type mouse aortic arches. Angiotensin II infusion (3.2 mg/kg/day, for 6 days, via subcutaneous osmotic pump) in ApoE{sup -/-} mice enhanced endothelial and adventitial VCAM-1 and iNOS expression, but reduced medial smooth muscle iNOS expression associated with reduced phosphorylation of ERK and RSK-1. These results indicate that angiotensin

  9. The hypothalamic peptides, beta-endorphin, neuropeptide K and interleukin-1 beta, and the opiate morphine, enhance the excitatory amino acid-induced LH release under the influence of gonadal steroids.

    Science.gov (United States)

    Bonavera, J J; Sahu, A; Kalra, S P; Kalra, P S

    1994-10-01

    Several hypothalamic neuropeptides and amino acids are known to inhibit or excite pituitary luteinizing hormone (LH) release, but the precise interplay between these 2 classes of signals in episodic LH discharge is not known. In this study, we have evaluated the interaction between neuropeptides shown previously to inhibit LH release in castrated rats and the excitatory amino acid agonist, N-methyl-D-aspartate (NMDA), on LH release in intact male rats. Rats received a permanent intracerebroventricular (i.c.v.) cannula and 9-12 days later an intrajugular cannula for frequent blood sampling. The next day, rats received i.c.v. either saline (SAL, 3 microliters, controls) or a neuropeptide: the opioid beta-endorphin (beta-END; 2.9 nmol), the tachykinin neuropeptide K (NPK, 2.5 nmol) or the cytokine interleukin-1 beta (IL-1 beta, 5.9 pmol) in SAL. The LH response to 2 consecutive i.v. injections of NMDA (5 mg/kg) at 30 min intervals was evaluated. In control rats, each NMDA injection evoked a significant release of LH at 10 min. Quite unexpectedly, the three peptides, instead of exerting an inhibitory effect, enhanced the LH response to NMDA. The peak plasma LH levels after each NMDA injection and the cumulative LH responses were significantly higher in peptide-treated than in control rats. This peculiar ability of the peptides that inhibit LH release in castrated rats, to potentiate the NMDA-induced LH release in the presence of gonadal steroids was further validated in female rats treated with an opiate receptor agonist, morphine (MOR) which is also known to suppress LH release in ovariectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro.

    Science.gov (United States)

    Redondo-Castro, Elena; Cunningham, Catriona; Miller, Jonjo; Martuscelli, Licia; Aoulad-Ali, Sarah; Rothwell, Nancy J; Kielty, Cay M; Allan, Stuart M; Pinteaux, Emmanuel

    2017-04-17

    Inflammation is a key contributor to central nervous system (CNS) injury such as stroke, and is a major target for therapeutic intervention. Effective treatments for CNS injuries are limited and applicable to only a minority of patients. Stem cell-based therapies are increasingly considered for the treatment of CNS disease, because they can be used as in-situ regulators of inflammation, and improve tissue repair and recovery. One promising option is the use of bone marrow-derived mesenchymal stem cells (MSCs), which can secrete anti-inflammatory and trophic factors, can migrate towards inflamed and injured sites or can be implanted locally. Here we tested the hypothesis that pre-treatment with inflammatory cytokines can prime MSCs towards an anti-inflammatory and pro-trophic phenotype in vitro. Human MSCs from three different donors were cultured in vitro and treated with inflammatory mediators as follows: interleukin (IL)-1α, IL-1β, tumour necrosis factor alpha (TNF-α) or interferon-γ. After 24 h of treatment, cell supernatants were analysed by ELISA for expression of granulocyte-colony stimulating factor (G-CSF), IL-10, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), IL-1 receptor antagonist (IL-1Ra) and vascular endothelial growth factor (VEGF). To confirm the anti-inflammatory potential of MSCs, immortalised mouse microglial BV2 cells were treated with bacterial lipopolysaccharide (LPS) and exposed to conditioned media (CM) of naïve or IL-1-primed MSCs, and levels of secreted microglial-derived inflammatory mediators including TNF-α, IL-10, G-CSF and IL-6 were measured by ELISA. Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased secretion of G-CSF, which was blocked by IL-1Ra. Furthermore, LPS-treated BV2 cells secreted less inflammatory and apoptotic markers, and showed increased secretion of the

  11. Interleukin-1{beta} regulates cell proliferation and activity of extracellular matrix remodelling enzymes in cultured primary pig heart cells

    Energy Technology Data Exchange (ETDEWEB)

    Zitta, Karina; Brandt, Berenice [Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel (Germany); Wuensch, Annegret [Institute of Molecular Animal Breeding and Biotechnology, Ludwig Maximilians University, Munich (Germany); Meybohm, Patrick; Bein, Berthold; Steinfath, Markus; Scholz, Jens [Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel (Germany); Albrecht, Martin, E-mail: Albrecht@anaesthesie.uni-kiel.de [Department of Anesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel (Germany)

    2010-09-03

    Research highlights: {yields} Levels of IL-1{beta} are increased in the pig myocardium after infarction. {yields} Cultured pig heart cells possess IL-1 receptors. {yields} IL-1{beta} increases cell proliferation of pig heart cells in-vitro. {yields} IL-1{beta} increases MMP-2 and MMP-9 activity in pig heart cells in-vitro. {yields} IL-1{beta} may be important for tissue remodelling events after myocardial infarction. -- Abstract: After myocardial infarction, elevated levels of interleukins (ILs) are found within the myocardial tissue and IL-1{beta} is considered to play a major role in tissue remodelling events throughout the body. In the study presented, we have established a cell culture model of primary pig heart cells to evaluate the effects of different concentrations of IL-1{beta} on cell proliferation as well as expression and activity of enzymes typically involved in tissue remodelling. Primary pig heart cell cultures were derived from three different animals and stimulated with recombinant pig IL-1{beta}. RNA expression was detected by RT-PCR, protein levels were evaluated by Western blotting, activity of matrix metalloproteinases (MMPs) was quantified by gelatine zymography and cell proliferation was measured using colorimetric MTS assays. Pig heart cells express receptors for IL-1 and application of IL-1{beta} resulted in a dose-dependent increase of cell proliferation (P < 0.05 vs. control; 100 ng/ml; 24 h). Gene expression of caspase-3 was increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h), and pro-caspase-3 but not active caspase was detected in lysates of pig heart cells by Western blotting. MMP-2 gene expression as well as enzymatic activities of MMP-2 and MMP-9 were increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h for gene expression, 48 and 72 h for enzymatic activities of MMP-2 and MMP-9, respectively). Our in vitro data suggest that IL-1{beta} plays a major role in the events of tissue remodelling in the heart. Combined

  12. Interleukin-1beta regulates cell proliferation and activity of extracellular matrix remodelling enzymes in cultured primary pig heart cells.

    Science.gov (United States)

    Zitta, Karina; Brandt, Berenice; Wuensch, Annegret; Meybohm, Patrick; Bein, Berthold; Steinfath, Markus; Scholz, Jens; Albrecht, Martin

    2010-09-03

    After myocardial infarction, elevated levels of interleukins (ILs) are found within the myocardial tissue and IL-1beta is considered to play a major role in tissue remodelling events throughout the body. In the study presented, we have established a cell culture model of primary pig heart cells to evaluate the effects of different concentrations of IL-1beta on cell proliferation as well as expression and activity of enzymes typically involved in tissue remodelling. Primary pig heart cell cultures were derived from three different animals and stimulated with recombinant pig IL-1beta. RNA expression was detected by RT-PCR, protein levels were evaluated by Western blotting, activity of matrix metalloproteinases (MMPs) was quantified by gelatine zymography and cell proliferation was measured using colorimetric MTS assays. Pig heart cells express receptors for IL-1 and application of IL-1beta resulted in a dose-dependent increase of cell proliferation (Ppig heart cells by Western blotting. MMP-2 gene expression as well as enzymatic activities of MMP-2 and MMP-9 were increased by IL-1beta (Pheart. Combined with our recently published in vivo data (Meybohm et al., PLoS One, 2009), the results presented here strongly suggest IL-1beta as a key molecule guiding tissue remodelling events after myocardial infarction. Copyright 2010 Elsevier Inc. All rights reserved.

  13. Maternal and Cord Blood Levels of Serum Amyloid A, C-Reactive Protein, Tumor Necrosis Factor-α, Interleukin -1β, and Interleukin-8 During and After Delivery

    Directory of Open Access Journals (Sweden)

    Luciane Marzzullo Cicarelli

    2005-01-01

    after delivery and try to correlate these proteins with tumor necrosis factor-α, interleukin -1β, and interleukin-8. Acute-phase proteins and cytokines were measured by ELISA in 24 healthy pregnant women undergoing vaginal delivery or Cesarean section. Cord blood samples in addition to maternal blood were collected. SAA and CRP reached the maximum maternal serum levels 24 hours after delivery, while cytokines remained constant over time. SAA and CRP were significantly higher in maternal serum than in newborn's (P<.001 at the moment of delivery. SAA and CRP, regardless of the type of delivery, reproduce the common pattern observed in most inflammatory conditions. Proinflammatory cytokine serum levels do not mirror the increase in SAA and CRP levels.

  14. [THE EFFECTS OF CHRO- NIC ADMINISTRATION OF MODERATE DOSE OF PROINFLAMMATORY CYTOKINE INTERLEUKIN-1β ON RAT INVESTIGATIVE BEHAVIOR AND SPATIAL MEMORY].

    Science.gov (United States)

    Kalemenev, S V; Sizov, V V; Ischenko, A M; Zubareva, O E

    2015-05-01

    The aim of this study was to discover the effects of chronic intraperitoneal administration of proinflammatory cytokine interleukin-1β (IL-1β) on rat investigative behavior and spatial memory. Rats were injected with a moderate pyrogenic dose of IL-1β (0.5 mkg/kg) daily during 14 days (7 days before tests and 7 testing days). The behavior was examined in 23.5 hours after the previous injection of cytokine. The test battery included: "The open field" (within 3 consecutive days), "The exploration of novel objects", and "The Morris water maze". The animals treated with IL-1β differed from the control animals in an essential decrease of locomotor activity, slight increase of anxiety and suppression of exploratory behavior. The impairment of spatial memory was not revealed.

  15. Clinical significance of interleukin-1 genotype in smoking patients as a predictor of peri-implantitis: A case-control study

    Science.gov (United States)

    García-Delaney, Cristina; Sánchez-Garcés, Maria-Ángeles; Sánchez-Torres, Alba; Gay-Escoda, Cosme

    2015-01-01

    Background Interleukin-1 (IL-1) is a proinflammatory cytokine that plays an important role in the pathogenesis of periodontitis, and so it might be useful to detect high-risk cases of peri-implantitis. It has been reported that IL-1 polymorphisms and smoking habit have a synergic effect, increasing the incidence of peri-implantitis. The aim of the present study was to evaluate the relationship between IL-1 gene polymorphisms and peri-implantitis in smoking patients. Material and Methods A case-control study was performed in 27 patients with peri-implantitis and 27 patients with healthy implants. All patients included were smokers. IL-1A-C889T, IL-1B+C3953T and IL-1RN+T2018C were identified by polymerase chain reaction (PCR) amplification in order to establish a relation between these variables and the presence of peri-implantitis. A bivariate analysis was performed and odds-ratio (OR) were calculated. Results The incidence of peri-implantitis was significantly higher in patients with previous history of periodontitis (p=0.024; OR=10.9). Both groups were similar regarding IL-1A-C889T, IL-1B+C3953T and IL-1RN+T2018C genotypes. No increased risk in heavy smokers with IL-1 polymorphism was found. Conclusions IL-1 genotypes do not seem to be good predictors of peri-implantitis in the great majority of smoking patients. Furthermore, no synergic effect was found between IL-1 genotypes and heavy smokers. Patients with a previous history of periodontitis were more prone to peri-implantitis. Key words:Peri-implantitis, interleukin-1 genotype positive, case-control study, smoking. PMID:26449434

  16. Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals.

    Directory of Open Access Journals (Sweden)

    David R Bonsall

    Full Text Available Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson's Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β. We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively, all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel

  17. Dental Calculus Stimulates Interleukin-1β Secretion by Activating NLRP3 Inflammasome in Human and Mouse Phagocytes.

    Science.gov (United States)

    Montenegro Raudales, Jorge Luis; Yoshimura, Atsutoshi; Sm, Ziauddin; Kaneko, Takashi; Ozaki, Yukio; Ukai, Takashi; Miyazaki, Toshihiro; Latz, Eicke; Hara, Yoshitaka

    2016-01-01

    Dental calculus is a mineralized deposit associated with periodontitis. The bacterial components contained in dental calculus can be recognized by host immune sensors, such as Toll-like receptors (TLRs), and induce transcription of proinflammatory cytokines, such as IL-1β. Studies have shown that cellular uptake of crystalline particles may trigger NLRP3 inflammasome activation, leading to the cleavage of the IL-1β precursor to its mature form. Phagocytosis of dental calculus in the periodontal pocket may therefore lead to the secretion of IL-1β, promoting inflammatory responses in periodontal tissues. However, the capacity of dental calculus to induce IL-1β secretion in human phagocytes has not been explored. To study this, we stimulated human polymorphonuclear leukocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) with dental calculus collected from periodontitis patients, and measured IL-1β secretion by ELISA. We found that calculus induced IL-1β secretion in both human PMNs and PBMCs. Calculus also induced IL-1β in macrophages from wild-type mice, but not in macrophages from NLRP3- and ASC-deficient mice, indicating the involvement of NLRP3 and ASC. IL-1β induction was inhibited by polymyxin B, suggesting that LPS is one of the components of calculus that induces pro-IL-1β transcription. To analyze the effect of the inorganic structure, we baked calculus at 250°C for 1 h. This baked calculus failed to induce pro-IL-1β transcription. However, it did induce IL-1β secretion in lipid A-primed cells, indicating that the crystalline structure of calculus induces inflammasome activation. Furthermore, hydroxyapatite crystals, a component of dental calculus, induced IL-1β in mouse macrophages, and baked calculus induced IL-1β in lipid A-primed human PMNs and PBMCs. These results indicate that dental calculus stimulates IL-1β secretion via NLRP3 inflammasome in human and mouse phagocytes, and that the crystalline structure has a partial role in

  18. Dental Calculus Stimulates Interleukin-1β Secretion by Activating NLRP3 Inflammasome in Human and Mouse Phagocytes.

    Directory of Open Access Journals (Sweden)

    Jorge Luis Montenegro Raudales

    Full Text Available Dental calculus is a mineralized deposit associated with periodontitis. The bacterial components contained in dental calculus can be recognized by host immune sensors, such as Toll-like receptors (TLRs, and induce transcription of proinflammatory cytokines, such as IL-1β. Studies have shown that cellular uptake of crystalline particles may trigger NLRP3 inflammasome activation, leading to the cleavage of the IL-1β precursor to its mature form. Phagocytosis of dental calculus in the periodontal pocket may therefore lead to the secretion of IL-1β, promoting inflammatory responses in periodontal tissues. However, the capacity of dental calculus to induce IL-1β secretion in human phagocytes has not been explored. To study this, we stimulated human polymorphonuclear leukocytes (PMNs and peripheral blood mononuclear cells (PBMCs with dental calculus collected from periodontitis patients, and measured IL-1β secretion by ELISA. We found that calculus induced IL-1β secretion in both human PMNs and PBMCs. Calculus also induced IL-1β in macrophages from wild-type mice, but not in macrophages from NLRP3- and ASC-deficient mice, indicating the involvement of NLRP3 and ASC. IL-1β induction was inhibited by polymyxin B, suggesting that LPS is one of the components of calculus that induces pro-IL-1β transcription. To analyze the effect of the inorganic structure, we baked calculus at 250°C for 1 h. This baked calculus failed to induce pro-IL-1β transcription. However, it did induce IL-1β secretion in lipid A-primed cells, indicating that the crystalline structure of calculus induces inflammasome activation. Furthermore, hydroxyapatite crystals, a component of dental calculus, induced IL-1β in mouse macrophages, and baked calculus induced IL-1β in lipid A-primed human PMNs and PBMCs. These results indicate that dental calculus stimulates IL-1β secretion via NLRP3 inflammasome in human and mouse phagocytes, and that the crystalline structure has a

  19. In inflammatory reactive astrocytes co-cultured with brain endothelial cells nicotine-evoked Ca(2+) transients are attenuated due to interleukin-1beta release and rearrangement of actin filaments.

    Science.gov (United States)

    Delbro, D; Westerlund, A; Björklund, U; Hansson, E

    2009-03-17

    The aim of this study was to investigate whether nicotine acetylcholine receptors (nAChRs) are expressed in a more pronounced way in astrocytes co-cultured with microvascular endothelial cells from adult rat brain, compared with monocultured astrocytes, as a sign of a more developed signal transduction system. Also investigated was whether nicotine plays a role in the control of neuroinflammatory reactivity in astrocytes. Ca(2+) imaging experiments were performed using cells loaded with the Ca(2+) indicator Fura-2/AM. Co-cultured astrocytes responded to lower concentrations of nicotine than did monocultured astrocytes, indicating that they are more sensitive to nicotine. Co-cultured astrocytes also expressed a higher selectivity for alpha7nAChR and alpha4/beta2 subunits and evoked higher Ca(2+) transients compared with monocultured astrocytes. The Ca(2+) transients referred to are activators of Ca(2+)-induced Ca(2+) release from intracellular stores, both IP(3) and ryanodine, triggered by influx through receptor channels. The nicotine-induced Ca(2+) transients were attenuated after incubation with the inflammatory mediator lipopolysaccharide (LPS), but were not attenuated after incubation with the pain-transmitting peptides substance P and calcitonin-gene-related peptide, nor with the infection and inflammation stress mediator, leptin. Furthermore, LPS-induced release of interleukin-1beta (IL-1beta) measured by enzyme-linked immunosorbent assay (ELISA) was more pronounced in co-cultured versus monocultured astrocytes. Incubation with both LPS and IL-1beta further attenuated nicotine-induced Ca(2+) response. We also found that LPS and IL-1beta induced rearrangement of the F-actin filaments, as measured with an Alexa488-conjugated phalloidin probe. The rearrangements consisted of increases in ring formations and a more dispersed appearance of the filaments. These results indicate that there is a connection between a dysfunction of nicotine Ca(2+) signaling in

  20. An encoding device and a method of encoding

    DEFF Research Database (Denmark)

    2012-01-01

    The present invention relates to an encoding device, such as an optical position encoder, for encoding input from an object, and a method for encoding input from an object, for determining a position of an object that interferes with light of the device. The encoding device comprises a light source...... in the area in the space and may interfere with the light, which interference may be encoded into a position or activation....

  1. Regulation of transcription of nucleotide-binding leucine-rich repeat-encoding genes SNC1 and RPP4 via H3K4 trimethylation.

    Science.gov (United States)

    Xia, Shitou; Cheng, Yu Ti; Huang, Shuai; Win, Joe; Soards, Avril; Jinn, Tsung-Luo; Jones, Jonathan D G; Kamoun, Sophien; Chen, She; Zhang, Yuelin; Li, Xin

    2013-07-01

    Plant nucleotide-binding leucine-rich repeat (NB-LRR) proteins serve as intracellular sensors to detect pathogen effectors and trigger immune responses. Transcription of the NB-LRR-encoding Resistance (R) genes needs to be tightly controlled to avoid inappropriate defense activation. How the expression of the NB-LRR R genes is regulated is poorly understood. The Arabidopsis (Arabidopsis thaliana) suppressor of npr1-1, constitutive 1 (snc1) mutant carries a gain-of-function mutation in a Toll/Interleukin1 receptor-like (TIR)-NB-LRR-encoding gene, resulting in the constitutive activation of plant defense responses. A snc1 suppressor screen identified modifier of snc1,9 (mos9), which partially suppresses the autoimmune phenotypes of snc1. Positional cloning revealed that MOS9 encodes a plant-specific protein of unknown function. Expression analysis showed that MOS9 is required for the full expression of TIR-NB-LRR protein-encoding RECOGNITION OF PERONOSPORA PARASITICA 4 (RPP4) and SNC1, both of which reside in the RPP4 cluster. Coimmunoprecipitation and mass spectrometry analyses revealed that MOS9 associates with the Set1 class lysine 4 of histone 3 (H3K4) methyltransferase Arabidopsis Trithorax-Related7 (ATXR7). Like MOS9, ATXR7 is also required for the full expression of SNC1 and the autoimmune phenotypes in the snc1 mutant. In atxr7 mutant plants, the expression of RPP4 is similarly reduced, and resistance against Hyaloperonospora arabidopsidis Emwa1 is compromised. Consistent with the attenuated expression of SNC1 and RPP4, trimethylated H3K4 marks are reduced around the promoters of SNC1 and RPP4 in mos9 plants. Our data suggest that MOS9 functions together with ATXR7 to regulate the expression of SNC1 and RPP4 through H3K4 methylation, which plays an important role in fine-tuning their transcription levels and functions in plant defense.

  2. Effects of treatment with a fully human anti-tumour necrosis factor alpha monoclonal antibody on the local and systemic homeostasis of interleukin 1 and TNFalpha in patients with rheumatoid arthritis.

    NARCIS (Netherlands)

    Barrera Rico, P.; Joosten, L.A.B.; Broeder, A. den; Putte, L.B.A. van de; Riel, P.L.C.M. van; Berg, W.B. van den

    2001-01-01

    OBJECTIVES: To study the short term effects of a single dose of D2E7, a fully human anti-tumour necrosis factor (TNFalpha) monoclonal antibody (mAb), on the local and systemic homeostasis of interleukin 1beta (IL1beta) and TNFalpha in patients with rheumatoid arthritis (RA). METHODS: All patients

  3. Modulation of antiviral immune responses by exogenous cytokines: effects of tumour necrosis factor-α interleukin-1 α, interleukin-2 and interferon-γ on the immunogenicity of an inactivated rabies vaccine.

    NARCIS (Netherlands)

    V.E.C.J. Schijns; I.J.Th.M. Claassen (Ivo); A.A. Vermeulen; M.C. Horzinek; A.D.M.E. Osterhaus (Albert)

    1994-01-01

    textabstractIn vivo administration of exogenous cytokines may influence elicited immune responses, and hence may change the efficacy of a vaccine. We investigated the effects of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), interleukin-2 (IL-2) and interferon-gamma

  4. Differential effects of interleukin-3 and interleukin-1 on the proliferation and interleukin-6 protein secretion of acute myeloid leukemic cells; the involvement of ERK, p38 and STAT5

    NARCIS (Netherlands)

    Birkenkamp, KU; Esselink, MT; Kruijer, W; Vellenga, E

    1999-01-01

    In the present study we examined whether the p38 and extracellular signal-regulated kinase (ERK) signal transduction pathways are involved in the interleukin-3 (IL-3)- or interleukin-1 (IL-1)-mediated proliferation and cytokine production of acute myeloid leukemic (ARIL) cells. The IL-3- and

  5. Interleukin-1β-Targeted Vaccine Improves Glucose Control and β-Cell Function in a Diabetic KK-Ay Mouse Model.

    Directory of Open Access Journals (Sweden)

    Jun Zha

    Full Text Available Interleukin-1β (IL-1β has been implicated as a key proinflammatory cytokine involved in the pancreatic islet inflammation of type 2 diabetes mellitus (T2DM. Excess IL-1β impairs islet function by inducing insulin resistance and β-cell apoptosis. Therefore, specifically reducing IL-1β activity provides a therapeutic improvement for T2DM by sustaining the inhibition of IL-1β-mediated islet inflammation. In this study, we developed an IL-1β-targeted epitope peptide vaccine adjuvanted with polylactic acid microparticles (1βEPP and applied it to a diabetic KK-Ay mouse model. Results showed that the 1βEPP elicited high antibody responses, which neutralized the biological activity of IL-1β, and induced barely detectable inflammatory activity. 1βEPP immunization reduced body weight gain, protected KK-Ay mice from hyperglycemia, improved glucose tolerance and insulin sensitivity, and decreased the serum levels of free fatty acids, total cholesterol and triglyceride. Moreover, 1βEPP restored β-cell mass; inhibited β-cell apoptosis; decreased the expression of IL-1β; and interrupted NF-κB activation by reducing IKKβ and pRelA levels. These studies indicated that the IL-1β-targeted vaccine may be a promising immunotherapeutic for T2DM treatment.

  6. A familial case of Muckle-Wells syndrome in a Russian population: The first successes of therapy with the interleukin 1 inhibitor canakinumab

    Directory of Open Access Journals (Sweden)

    S. O. Salugina

    2015-01-01

    Full Text Available Muckle-Wells syndrome (MWS is an autoinflammatory disease belonging to a group of cryopyrin-associated periodic syndromes (CAPS. It is considered to be one of the intermediately severe conditions among CAPSs and to be intermediate between the severest syndrome – Chronic I nfantile Onset Neurologic Cutneous Articular/Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID and the mildest syndrome–Familial Cold Autoinflammatory Syndrome (FCAS. MWS, like all cryopyrinopathies, is caused by a mutation in the NLRP3 (CIAS1 gene; it shows an autosomal inheritance pattern. There are reports on familial MWS cases in the foreign literature; such examples are sporadic in Russia. The given clinical observation clearly demonstrates a genetically verified familial case of MWS in a mother and her daughter in a Russian population and shows how long (occasionally during tens of years or more the complete complex of the disease may be formed. The results of treatment with the interleukin-1 inhibitor canakinumab in both patients are also given. The high good tolerability and high efficacy of the drug against the clinical manifestations of MWS and acute-phase markers are shown. 

  7. Interleukin-1 alpha (rs1800587) genetic polymorphism is associated with specific cognitive functions but not depression or loneliness in elderly males without dementia.

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    Wang, Eileen H; Hong, Chen-Jee; Yeh, Heng-Liang; Liou, Ying-Jay; Yang, Albert C; Liu, Mu-En; Tsai, Shih-Jen

    2013-11-27

    Inflammatory process is considered to be a pathway that results in neurodegeneration, and numerous plasma cytokines have been examined for their association with cognitive function and depression. Interleukin-1 alpha (IL-1A) genetic polymorphism (rs1800587) has been found to be associated with Alzheimer's disease susceptibility. The aim of this study was to investigate the effect of IL-1A rs1800587 genetic effects on cognitive functions, loneliness and depression severity in elderly males without dementia or major depression. 192 non-demented Chinese elderly male were recruited and underwent Cognitive Abilities Screening Instrument (CASI), Wechsler Digit Span Task, Geriatric Depression Scale-short form, and UCLA Loneliness Scale assessment. IL-1A rs1800587 is a C to T transition at position -889. Compared to the C/C carriers, the T allele carriers had significantly overall higher CASI score (p=0.017) after using age and total education years as co-variates. This was especially true in the four distinct domains of long-term memory (pDepression Scale-short form or UCLA Loneliness Scale. Our data supports that the T allele of IL-1A rs1800587 genetic polymorphism is associated with better cognitive function in the elderly. Further research will be needed to better understand the molecular mechanism for IL-1A genetic effects on cognitive function in the elderly. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  8. Effects of erythromycin on γ-glutamyl cysteine synthetase and interleukin-1β in hyperoxia-exposed lung tissue of premature newborn rats.

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    Cai, Cheng; Qiu, Gang; Gong, Xiaohui; Chen, Yihuan; Zhao, Huanhu

    2014-01-01

    To explore the effect of erythromycin on hyperoxia-induced lung injury. One-day-old preterm offspring Sprague-Dawley (SD) rats were randomly divided into four groups: group 1, air + sodium chloride; group 2, air + erythromycin;group 3, hyperoxia + sodium chloride; and group 4, hyperoxia + erythromycin. At one, seven, and 14 days of exposure, glutathione (GSH) and interleukin-1 beta (IL-1 beta) were detected by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA), and bicinchoninic acid (BCA) was used to detect GSH protein. γ-glutamine-cysteine synthetase (γ-GCS) mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). Compared with group 1, expressions of GSH and γ-GCS mRNA in group 3 were significantly increased at one and seven days of exposure (p Erythromycin may up-regulate the activity of γ-GCS, increasing the expression of GSH, inhibiting the levels of oxidant-mediated IL-1 beta and alleviating hyperoxia-induced lung injury via an antioxidant effect. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  9. Interleukin-1 beta induced synthesis of protein kinase C-delta and protein kinase C-epsilon in EL4 thymoma cells: possible involvement of phosphatidylinositol 3-kinase.

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    Varley, C L; Royds, J A; Brown, B L; Dobson, P R

    2001-01-01

    We present evidence here that the proinflammatory cytokine, interleukin-1 beta (IL-1 beta) stimulates a significant increase in protein kinase C (PKC)-epsilon and PKC-delta protein levels and increases PKC-epsilon, but not PKC-delta, transcripts in EL4 thymoma cells. Incubation of EL4 cells with IL-1 beta induced protein synthesis of PKC-epsilon (6-fold increase) by 7 h and had a biphasic effect on PKC-delta levels with peaks at 4 h (2-fold increase) and 24 h (4-fold increase). At the level of mRNA, PKC-epsilon, but not PKC-delta levels, were induced after incubation of EL4 cells with IL-1 beta. The signalling mechanisms utilized by IL-1 beta to induce the synthesis of these PKC isoforms were investigated. Two phosphatidylinositol (PI) 3-kinase-specific inhibitors, wortmannin and LY294002, inhibited IL-1 beta-induced synthesis of PKC-epsilon. However, the PI 3-kinase inhibitors had little effect on the IL-1 beta-induced synthesis of PKC-delta in these cells. Our results indicate that IL-1 beta induced both PKC-delta and PKC-epsilon expression over different time periods. Furthermore, our evidence suggests that IL-1 beta induction of PKC-epsilon, but not PKC-delta, may occur via the PI 3-kinase pathway. Copyright 2001 S. Karger AG, Basel

  10. Regulation of Neurotrophin-3 and Interleukin-1β and Inhibition of Spinal Glial Activation Contribute to the Analgesic Effect of Electroacupuncture in Chronic Neuropathic Pain States of Rats

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    Wenzhan Tu

    2015-01-01

    Full Text Available Growing evidence indicates that neurotrophin-3, interleukin-1β, and spinal glia are involved in neuropathic pain derived from dorsal root ganglia to spinal cord. Electroacupuncture is widely accepted to treat chronic pain, but the precise mechanism underlying the analgesic effect of EA has not been fully demonstrated. In this study, the mechanical withdrawal threshold and thermal withdrawal latency were recorded. We used immunofluorescence and western blots methods to investigate the effect of EA on the expression of NT-3 and IL-1β in DRG and spinal cord of CCI rats; we also examined the expression of spinal GFAP and OX-42 in spinal cord. In present study, the MWT and TWL of CCI group rats were lower than those in the Sham CCI group rats, but EA treatment increased the pain thresholds. Furtherly, we found that EA upregulates the expression of NT-3 in DRG and spinal cord of CCI rats, while EA downregulates the expression of IL-1β. Additionally, immunofluorescence exhibited that CCI-induced activation of microglia and astrocytes was inhibited significantly by EA treatment. These results demonstrated that the analgesic effect of EA may be achieved through promoting the neural protection of NT-3 as well as the inhibition of IL-1β production and spinal glial activity.

  11. The proinflammatory cytokines interleukin-1α and tumor necrosis factor α promote the expression and secretion of proteolytically active cathepsin S from human chondrocytes.

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    Caglič, Dejan; Repnik, Urška; Jedeszko, Christopher; Kosec, Gregor; Miniejew, Catherine; Kindermann, Maik; Vasiljeva, Olga; Turk, Vito; Wendt, K Ulrich; Sloane, Bonnie F; Goldring, Mary B; Turk, Boris

    2013-02-01

    Osteoarthritis and rheumatoid arthritis are destructive joint diseases that involve the loss of articular cartilage. Degradation of cartilage extracellular matrix is believed to occur due to imbalance between the catabolic and anabolic processes of resident chondrocytes. Previous work has suggested that various lysosomal cysteine cathepsins participate in cartilage degeneration; however, their exact roles in disease development and progression have not been elucidated. In order to study degradation processes under conditions resembling the in vivo milieu of the cartilage, we cultivated chondrocytes on a type II collagen-containing matrix. Stimulation of the cultivated chondrocytes with interleukin-1α and/or tumor necrosis factor α resulted in a time-dependent increase in cathepsin S expression and induced its secretion into the conditioned media. Using a novel bioluminescent activity-based probe, we were able to demonstrate a significant increase in proteolytic activity of cathepsin S in the conditioned media of proinflammatory cytokine-stimulated chondrocytes. For the first time, cathepsin S was demonstrated to be secreted from chondrocytes upon stimulation with the proinflammatory cytokines, and displayed proteolytic activity in culture supernatants. Its stability at neutral pH and potent proteolytic activity on extracellular matrix components mean that cathepsin S may contribute significantly to cartilage degradation and may thus be considered a potential drug target in joint diseases.

  12. Assessment of interleukin-1beta and interleukin-6 in the crevicular fluid around healthy implants, implants with peri-implantitis, and healthy teeth: a cross-sectional study.

    Science.gov (United States)

    Yaghobee, Siamak; Khorsand, Afshin; Rasouli Ghohroudi, Amir Alireza; Sanjari, Khashayar; Kadkhodazadeh, Mahdi

    2014-10-01

    This study aimed to assess and compare the levels of interleukin-1beta (IL-1β) and interleukin-6 (IL-6) in the crevicular fluid around healthy implants, implants with peri-implantitis, and healthy teeth. This study evaluated 16 dental implants in 8 patients (4 males and 4 females). These patients had at least one healthy implant and one implant with peri-implantitis next to healthy teeth. The crevicular fluid was collected using absorbent cones and transferred to the laboratory. Specimens were evaluated by ELISA for interleukin levels. Data were analyzed using repeated measures ANOVA and Bonferroni tests (Pimplants with peri-implantitis were significantly higher than around healthy implants (P=0.002); the latter was significantly higher than around healthy teeth (P=0.015). A significant difference was found in the level of IL-6 in the crevicular fluid around implants with peri-implantitis and healthy implants (P=0.049) and also between implants with peri-implantitis and healthy teeth (Pimplants with peri-implantitis, healthy implants, and healthy teeth. More studies with larger sample sizes in different populations are necessary.

  13. Comparison of Interleukin-1β Levels in Gingival Crevicular Fluid and Peri-Implant Crevicular Fluid and Its Relationship with Clinical Indexes

    Directory of Open Access Journals (Sweden)

    Mojgan Paknejad

    2013-01-01

    Full Text Available Objective: Interleukin-1 (IL-1 is one of the most important cytokines which seems to have an important role in the inflammatory process in gingival and peri-implant tissues. The aim of this split-mouth study was to investigate the relationship between the concentration of IL-1 in gingival crevicular fluid (GCF and peri-implant crevicular fluid (PICF and clinical parameters such as plaque index (PI, gingival index (GI, pocket depth (PD and bone loss (BL.Materials and Methods: In 32 patients, PICF and GCF samples of 41 implants and 41 contralateral teeth were collected and IL-1 was determined by enzyme-linked immunosorbent assay (ELISA. PI, GI, PD and BL were recorded for each of the samples.Result :The positive correlation between the level of IL-1 and PI, GI, PD and BL in both groups was observed (P<0.0001. In similar conditions, the level of IL-1 was greatly higher in PICF than GCF (75.26 pg/ and 45.71 pg/ , respectively (P=0.001.Conclusion: The findings of the present study indicated that the level of IL-1 may be an important supplement to clinical findings in measuring the health status of gingival or peri-implant tissues.

  14. Inflammatory Cytokines Interleukin-1β and Tumour Necrosis Factor-α - Novel Biomarkers for the Detection of Periodontal Diseases: a Literature Review.

    Science.gov (United States)

    Gomes, Francisco Isaac Fernandes; Aragão, Maria Gerusa Brito; Barbosa, Francisco Cesar Barroso; Bezerra, Mirna Marques; de Paulo Teixeira Pinto, Vicente; Chaves, Hellíada Vasconcelos

    2016-01-01

    The article aims to discuss the IL-1β and TNF-α potential use as salivary biomarkers of periodontal diseases pathogenesis and progression. This literature review has been registered in PROSPERO database with following number: CRD42016035729. Data investigation was performed on PubMed database as the main source of studies. The following search terms were used: "salivary biomarkers", "periodontal diseases", "TNF-alpha", "Interleukin-1 beta". Clinical trials and animal experimental models of periodontal disease were included in the discussion. In regards to inclusive dates, published studies from January 2006 to December 2015 were considered in this review along with the mentioned inclusion criteria. IL-1β and TNF-α salivary levels increased in diseased groups, they were associated with onset and disease severity, and their levels reduced in response to periodontal therapy. IL-1β and TNF-α could be promising biomarkers in the detection of periodontal diseases. The use of a salivary cytokine-based diagnosis appears to be a screening method capable of diagnosing periodontal diseases in an early fashion, establishing an era of individualized clinical