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Sample records for early interferon induction

  1. DMPD: Type I interferon [corrected] gene induction by the interferon regulatory factorfamily of transcription factors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16979567 Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...ng) (.svg) (.html) (.csml) Show Type I interferon [corrected] gene induction by the interferon regulatory factorfamily...orrected] gene induction by the interferon regulatory factorfamily of transcription factors. Authors Honda K

  2. Interferon Induction by RNA Viruses and Antagonism by Viral Pathogens

    Directory of Open Access Journals (Sweden)

    Yuchen Nan

    2014-12-01

    Full Text Available Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR. Host PRR for RNA viruses include Toll-like receptors (TLR and retinoic acid-inducible gene I (RIG-I like receptors (RLR. Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses.

  3. Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Song, Wuqi [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); Department of Microbiology, Harbin Medical University (China); Kao, Wenping [The Key Laboratory of Pathogenic Biology, Heilongjiang Higher Education Institutions (China); Department of Microbiology, Harbin Medical University (China); Zhai, Aixia [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); Qian, Jun; Li, Yujun [The Key Laboratory of Pathogenic Biology, Heilongjiang Higher Education Institutions (China); Zhang, Qingmeng [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); Zhao, Hong; Hu, Yunlong; Li, Hui [Department of Microbiology, Harbin Medical University (China); Zhang, Fengmin, E-mail: fengminzhang@ems.hrbmu.edu.cn [The Heilongjiang Key Laboratory of Immunity and Infection, Heilongjiang (China); The Key Laboratory of Pathogenic Biology, Heilongjiang Higher Education Institutions (China); Department of Microbiology, Harbin Medical University (China)

    2013-09-06

    Highlights: •IRF7 nuclear localisation was inhibited by BDV persistently infected. •BDV N protein resistant to IFN induction both in BDV infected OL cell and N protein plasmid transfected OL cell. •BDV N protein is related to the inhibition of IRF7 nuclear localisation. -- Abstract: The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1–IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-α/β expression in a BDV-persistently infected human oligodendroglia cell line following RNA interference-mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-β. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway.

  4. Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway.

    Science.gov (United States)

    Song, Wuqi; Kao, Wenping; Zhai, Aixia; Qian, Jun; Li, Yujun; Zhang, Qingmeng; Zhao, Hong; Hu, Yunlong; Li, Hui; Zhang, Fengmin

    2013-09-06

    The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1-IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-α/β expression in a BDV-persistently infected human oligodendroglia cell line following RNA interference-mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-β. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. DMPD: TLR3: interferon induction by double-stranded RNA including poly(I:C). [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18262679 TLR3: interferon induction by double-stranded RNA including poly(I:C). Mat...l) Show TLR3: interferon induction by double-stranded RNA including poly(I:C). PubmedID 18262679 Title TLR3: interferon induction

  6. Interferon induction by viruses. XV. Biological characteristics of interferon induction-suppressing particles of vesicular stomatitis virus

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    Marcus, P.I.; Sekellick, M.J.

    1987-06-01

    A single interferon (IFN) induction-suppressing particle (ISP) of vesicular stomatitis virus (VSV) blocked completely the yield of IFN in a cell otherwise programmed to produce IFN. With mouse L cells as hosts, one lethal hit of UV radiation (D37 = 52.5 ergs/mm2) to the VSV genome sufficed to inactivate ISP activity; however, with ''aged'' primary chick embryo cells as hosts, it took 198 lethal hits (D37 = 10,395 ergs/mm2). ISP expression in chick cells did not require virus replication or amplified RNA synthesis, but did involve functional virion-associated L protein. ISP in chick cells also were capable of inhibiting, in a multiplicity-dependent manner, the plaquing efficiency of two viruses that require cellular polymerase II (pol II) for replication, e.g., pseudorabies and influenza. The refractory state to IFN inducibility that resulted from infection of chick cells with ISP (VSV tsO5 (UV = 100 hits)) was still extant after 6 days. In contrast, the plaquing efficiency of pseudorabies virus returned to control levels by 5 h after ISP infection. Chick cells infected with UV ISP remained viable, served as hosts for the replication of other viruses, and could be subcultured. Models are presented to account for these contrasting effects. The involvement of viral plus-strand leader RNA as an inhibitor of cellular pol II-dependent RNA synthesis, and the multifunctional activities of the virion-associated L protein, are discussed as possible molecules involved in the action of ISP in chick cells.

  7. Inhibition of interferon induction and action by the nairovirus Nairobi sheep disease virus/Ganjam virus.

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    Barbara Holzer

    Full Text Available The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV. NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus. We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU.

  8. Irf3 polymorphism alters induction of interferon beta in response to Listeria monocytogenes infection.

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    Oleg Garifulin

    2007-09-01

    Full Text Available Genetic makeup of the host plays a significant role in the course and outcome of infection. Inbred strains of mice display a wide range of sensitivities to Listeria monocytogenes infection and thus serve as a good model for analysis of the effect of genetic polymorphism. The outcome of L. monocytogenes infection in mice is influenced by the ability of this bacterium to induce expression of interferon beta mRNA, encoded in mouse by the Ifnb1 (interferon beta 1, fibroblast gene. Mouse strains that lack components of the IFN beta signaling pathway are substantially more resistant to infection. We found that macrophages from the ByJ substrain of the common C57BL/6 inbred strain of mice are impaired in their ability to induce Ifnb1 expression in response to bacterial and viral infections. We mapped the locus that controls differential expression of Ifnb1 to a region on Chromosome 7 that includes interferon regulatory factor 3 (Irf3, which encodes a transcription factor responsible for early induction of Ifnb1 expression. In C57BL/6ByJ mice, Irf3 mRNA was inefficiently spliced, with a significant proportion of the transcripts retaining intron 5. Analysis of the Irf3 locus identified a single base-pair polymorphism and revealed that intron 5 of Irf3 is spliced by the atypical U12-type spliceosome. We found that the polymorphism disrupts a U12-type branchpoint and has a profound effect on the efficiency of splicing of Irf3. We demonstrate that a naturally occurring change in the splicing control element has a dramatic effect on the resistance to L. monocytogenes infection. Thus, the C57BL/6ByJ mouse strain serves as an example of how a mammalian host can counter bacterial virulence strategies by introducing subtle alteration of noncoding sequences.

  9. Induction pegylated interferon alfa-2b in combination with ribavirin in patients with genotypes 1 and 4 chronic hepatitis C: a prospective, randomized, multicenter, open-label study.

    Science.gov (United States)

    Brady, Daniel E; Torres, Dawn M; An, Jong W; Ward, John A; Lawitz, Eric; Harrison, Stephen A

    2010-01-01

    Standard of care (SOC) treatment for chronic hepatitis C (CHC) involves weekly pegylated (PEG) interferon plus weight-based ribavirin with resultant sustained virologic response (SVR) rates at or near 50% for genotypes 1 and 4 virus. Induction therapy with higher doses of PEG interferon may improve first-phase viral kinetics and thus improve the overall SVR in genotypes 1 and 4 patients. This multicenter, randomized, open-label trial enrolled treatment-naive genotypes 1- and 4-infected CHC patients to either initial induction therapy versus SOC. The induction group received PEG interferon alfa-2b 3.0 mcg/kg/wk for 12 weeks followed by PEG interferon alfa-2b 1.5 mcg/kg/wk for 36 weeks and 13 +/- 2 mg/kg ribavirin daily for 48 weeks. SOC patients received PEG interferon alfa-2b 1.5 mcg/kg weekly for 48 weeks and 13 +/- 2 mg/kg ribavirin daily for 48 weeks. The primary end point was SVR. There were 610 patients enrolled throughout the United States. Complete early virologic response was 62.6% versus 57.7% in induction versus SOC (NS). Overall SVR was 32% in induction versus 29% in SOC group (NS). Dose reduction of either PEG interferon (24.1% vs 23.8%) or ribavirin (26.8% vs 25.1%) was similar between the 2 groups. There was a trend toward a significant difference when comparing the SVR in induction therapy in patients weighing more than 85 kg versus those receiving SOC (38% vs 28%; P = .08). Induction therapy does not enhance complete early virologic response or SVR rates in a predominantly genotype 1 CHC population compared with SOC therapy. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  10. Interferon Regulatory Factor 8 (IRF8) Impairs Induction of Interferon Induced with Tetratricopeptide Repeat Motif (IFIT) Gene Family Members*

    Science.gov (United States)

    White, Christine L.; Kessler, Patricia M.; Dickerman, Benjamin K.; Ozato, Keiko; Sen, Ganes C.

    2016-01-01

    The chromosomally clustered interferon-induced with tetratricopeptide repeat motif (IFIT) gene family members share structural features at the gene and protein levels. Despite these similarities, different IFIT genes have distinct inducer- and cell type-specific induction patterns. Here, we investigated the mechanism for the observed differential induction of the mouse Ifit1, Ifit2, and Ifit3 genes in B cells and demonstrated that the repressive effect of the transcription factor interferon regulatory factor 8 (IRF8), which is highly expressed in B cells, played an essential role in this regulation. Although IRF8 could impair induction of all three IFIT genes following stimulation of retinoic acid-inducible gene I (RIG-I), it could selectively impair the induction of the Ifit1 gene following IFN stimulation. The above properties could be imparted to IRF8-non-expressing cells by ectopic expression of the protein. Induction of reporter genes, driven by truncated Ifit1 promoters, identified the regions that mediate the repression, and a chromatin immunoprecipitation assay revealed that more IRF8 bound to the IFN-stimulated response element of the Ifit1 gene than to those of the Ifit2 and the Ifit3 genes. Mutational analyses of IRF8 showed that its ability to bind DNA, interact with other proteins, and undergo sumoylation were all necessary to selectively repress Ifit1 gene induction in response to IFN. Our study revealed a new role for IRFs in differentially regulating the induction patterns of closely related IFN-stimulated genes that are located adjacent to one another in the mouse genome. PMID:27137933

  11. Induction of alpha interferon by human immunodeficiency virus type 1 in human monocyte-macrophage cultures.

    OpenAIRE

    Szebeni, J; Dieffenbach, C; Wahl, S M; Venkateshan, C N; Yeh, A; Popovic, M.; Gartner, S; Wahl, L M; Peterfy, M; Friedman, R. M.

    1991-01-01

    The induction of interferon (IFN) by human immunodeficiency virus type 1 (HIV-1) in primary, nonstimulated monocyte-macrophage cultures was studied. HIV-1 infection, as confirmed by p24 antigen levels in the cell supernatant, led to the production of alpha interferon (IFN-alpha) over 7 to 21 days following infection. In two of seven experiments, the IFN detected was acid labile. Coupled reverse transcription-polymerase chain reaction analysis confirmed the induction of IFN-alpha mRNA in cells...

  12. Hepatitis A and hepatitis C viruses: divergent infection outcomes marked by similarities in induction and evasion of interferon responses.

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    Qu, Lin; Lemon, Stanley M

    2010-11-01

    Hepatitis A and hepatitis C viruses (HAV and HCV) are both positive-strand ribonucleic acid (RNA) viruses with hepatotropic lifestyles. Despite several important differences, they share many biological and molecular features and similar genome replication schemes. Despite this, HAV infections are usually effectively controlled by the host with elimination of the virus, whereas HCV most often is able to establish lifelong persistent infection. The mechanisms underlying this difference are unknown. The cellular helicases RIG-I and MDA5, and Toll-like receptor 3, are pattern recognition receptors that sense virus-derived RNAs within hepatocytes in the liver. Activation of these receptors leads to their interaction with specific adaptor proteins, mitochondrial antiviral signaling protein (MAVS) and TIR-domain-containing adapter-inducing interferon-β (TRIF), respectively, which engage downstream kinases to activate two crucial transcription factors, nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). This results in the induction of interferons (IFNs) and IFN-stimulated genes that ultimately establish an antiviral state. These signaling pathways are central to host antiviral defense and thus frequent targets for viral interference. Both HAV and HCV express proteases that target signal transduction through these pathways and that block the induction of IFNs upon sensing of viral RNA by these receptors. An understanding of the differences and similarities in the early innate immune responses to these infections is likely to provide important insights into the mechanism underlying the long-term persistence of HCV. © Thieme Medical Publishers.

  13. Expression of interferon gamma by a recombinant rabies virus strongly attenuates the pathogenicity of the virus via induction of type I interferon.

    Science.gov (United States)

    Barkhouse, Darryll A; Garcia, Samantha A; Bongiorno, Emily K; Lebrun, Aurore; Faber, Milosz; Hooper, D Craig

    2015-01-01

    Previous animal model experiments have shown a correlation between interferon gamma (IFN-γ) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-γ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-γ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNγ. Morbidity and mortality were monitored in mice infected intranasally with SPBNγ or SPBN(-) control virus to determine the degree of attenuation caused by the expression of IFN-γ. Incorporation of IFN-γ into the rabies virus genome highly attenuated the virus. SPBNγ has a 50% lethal dose (LD50) more than 100-fold greater than SPBN(-). In vitro and in vivo mouse experiments show that SPBNγ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR(-/-)) cannot control the SPBNγ infection and rapidly die. These data suggest that IFN-γ production has antiviral effects in rabies, largely due to the induction of type I interferons. Survival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-γ production in the CNS prior to the appearance of virus-neutralizing antibodies. Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-γ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-γ directly in the

  14. Mechanism of Interferon-Stimulated Gene Induction in HIV-1-Infected Macrophages.

    Science.gov (United States)

    Nasr, Najla; Alshehri, Abdullateef A; Wright, Thomas K; Shahid, Maryam; Heiner, Bonnie M; Harman, Andrew N; Botting, Rachel A; Helbig, Karla J; Beard, Michael R; Suzuki, Kazuo; Kelleher, Anthony D; Hertzog, Paul; Cunningham, Anthony L

    2017-10-15

    Viruses manipulate the complex interferon and interferon-stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells, many of which are antiviral. Here, we examine the mechanism of induction of ISGs and show this occurs in two phases. The first phase was transient (0 to 24 h postinfection [hpi]), induced mainly by extracellular vesicles and one of its component proteins, HSP90α, contained within the HIV inoculum. The second, dominant, and persistent phase (>48 hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knockdown of the RIGI adaptor, MAVS, by small interfering RNA (siRNA) and the inhibition of both the initiation and elongation of HIV transcription by short hairpin RNA (shRNA) transcriptional silencing. We further define the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1, and IRF7, also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also show that the ISGs IFIT1 to -3 inhibit HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, noncytopathic infection, while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo Elucidating the mechanisms of ISG induction may help in devising immunotherapeutic strategies to limit the size of these reservoirs.IMPORTANCE HIV, like other viruses, manipulates the antiviral interferon and interferon-stimulated gene (ISG) system to facilitate its initial infection and establishment of viral reservoirs. HIV specifically inhibits all type I and III interferons in its target cells, including macrophages, dendritic cells, and T cells

  15. Interferon induction by viruses. VIII. Vesicular stomatitis virus: (+-)DI-011 particles induce interferon in the absence of standard virions

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    Sekellick, M.J.; Marcus, P.I.

    1982-02-01

    Evidence was presented that VSV (+-)DI-011 particles, which contain a genome of covalently linked totally self-complementary RNA, were excellent inducers of interferon (IFN) - by virtue of the dsRNA presumed to form within an infected cell, and that one molecule of that dsRNA per cell sufficed to induce a quantum yield of IFN. While the IFN-inducing capacity of (+-)DI-011 particle preparations has been confirmed, some researchers contend that DIP by themselves cannot induce IFN and that induction requires the presence of coinfecting (contaminating) standard VSV PFP. Consequently, we reexamined this question and now report that under five different conditions where the function of contaminating standard virus is reduced markedly, or eliminated, there was no diminution of the interferon-inducing particle (IFP) activity in preparations of (+-)DI-011 particles. Thus, inactivation of contaminating PFP by uv radiation or heat, the elimination (during induction) of cycling infection through the use of anti-serum (in the case of mouse L cells), and the reduction of PFP by four successive velocity sedimentation-gradient purifications had no adverse affect on the IFN-inducing capacity of DI-011 in either ''aged'' primary chick embryo cells or in mouse L(Y) cells. Furthermore, dilutions of DI-011 stocks which precluded the presence of even a single PFP still induced IFN in ''aged'' chick embryo cells. In concert these data demonstrate convincingly that IFN induction by DI-011 particles does not require coinfection with standard virus. It follows that DI-011 particles are intrinsically capable of inducing IFN.

  16. Induction of interferon-alpha by glycoprotein D of herpes simplex virus : A possible role of chemokine receptors

    NARCIS (Netherlands)

    Ankel, H; Westra, DF; Welling-Wester, S; Lebon, P

    1998-01-01

    The induction of type I interferons by most RNA viruses is initiated by virus-derived double-stranded (ds)RNA. However, retro- and DNA-viruses, which do not synthesize dsRNA, must rely on different mechanisms of induction. For human immunodeficiency virus type 1 (HIV-1), recombinant glycoproteins

  17. Interferon-α abrogates tolerance induction by human tolerogenic dendritic cells.

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    Nicole Bacher

    Full Text Available BACKGROUND: Administration of interferon-α (IFN-α represents an approved adjuvant therapy as reported for malignancies like melanoma and several viral infections. In malignant diseases, tolerance processes are critically involved in tumor progression. In this study, the effect of IFN-α on tolerance induction by human tolerogenic dendritic cells (DC was analyzed. We focussed on tolerogenic IL-10-modulated DC (IL-10 DC that are known to induce anergic regulatory T cells (iTregs. METHODOLOGY/PRINCIPAL FINDINGS: IFN-α promoted an enhanced maturation of IL-10 DC as demonstrated by upregulation of the differentiation marker CD83 as well as costimulatory molecules. IFN-α treatment resulted in an increased capacity of DC to stimulate T cell activation compared to control tolerogenic DC. We observed a strengthened T cell proliferation and increased IFN-γ production of CD4(+ and CD8(+ T cells stimulated by IFN-α-DC, demonstrating a restoration of the immunogenic capacity of tolerogenic DC in the presence of IFN-α. Notably, restimulation experiments revealed that IFN-α treatment of tolerogenic DC abolished the induction of T cell anergy and suppressor function of iTregs. In contrast, IFN-α neither affected the priming of iTregs nor converted iTregs into effector T cells. CONCLUSIONS/SIGNIFICANCE: IFN-α inhibits the induction of T cell tolerance by reversing the tolerogenic function of human DC.

  18. early versus delayed induction of labour

    African Journals Online (AJOL)

    preference. A recent meta-analysis has indicated that early administration of intravenous oxytocin for induction of contractions after PROM at term is associated with an increase in the likelihood of caesarean section (CS) without convincing evidence that the mother and fetus will be more effectively protected against the risks ...

  19. Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons.

    Science.gov (United States)

    Gielen, Vera; Sykes, Annemarie; Zhu, Jie; Chan, Brian; Macintyre, Jonathan; Regamey, Nicolas; Kieninger, Elisabeth; Gupta, Atul; Shoemark, Amelia; Bossley, Cara; Davies, Jane; Saglani, Sejal; Walker, Patrick; Nicholson, Sandra E; Dalpke, Alexander H; Kon, Onn-Min; Bush, Andrew; Johnston, Sebastian L; Edwards, Michael R

    2015-07-01

    Rhinovirus infections are the dominant cause of asthma exacerbations, and deficient virus induction of IFN-α/β/λ in asthmatic patients is important in asthma exacerbation pathogenesis. Mechanisms causing this interferon deficiency in asthmatic patients are unknown. We sought to investigate the expression of suppressor of cytokine signaling (SOCS) 1 in tissues from asthmatic patients and its possible role in impaired virus-induced interferon induction in these patients. We assessed SOCS1 mRNA and protein levels in vitro, bronchial biopsy specimens, and mice. The role of SOCS1 was inferred by proof-of-concept studies using overexpression with reporter genes and SOCS1-deficient mice. A nuclear role of SOCS1 was shown by using bronchial biopsy staining, overexpression of mutant SOCS1 constructs, and confocal microscopy. SOCS1 levels were also correlated with asthma-related clinical outcomes. We report induction of SOCS1 in bronchial epithelial cells (BECs) by asthma exacerbation-related cytokines and by rhinovirus infection in vitro. We found that SOCS1 was increased in vivo in bronchial epithelium and related to asthma severity. SOCS1 expression was also increased in primary BECs from asthmatic patients ex vivo and was related to interferon deficiency and increased viral replication. In primary human epithelium, mouse lung macrophages, and SOCS1-deficient mice, SOCS1 suppressed rhinovirus induction of interferons. Suppression of virus-induced interferon levels was dependent on SOCS1 nuclear translocation but independent of proteasomal degradation of transcription factors. Nuclear SOCS1 levels were also increased in BECs from asthmatic patients. We describe a novel mechanism explaining interferon deficiency in asthmatic patients through a novel nuclear function of SOCS1 and identify SOCS1 as an important therapeutic target for asthma exacerbations. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

  20. Induction of antiviral state in fish cells by Japanese flounder, Paralichthys olivaceus, interferon regulatory factor-1.

    Science.gov (United States)

    Caipang, Christopher Marlowe A; Hirono, Ikuo; Aoki, Takashi

    2005-07-01

    Interferon regulatory factor-1 (IRF-1) mediates an antiviral state in cells by regulating the expression of the interferon (IFN-alpha/beta) system. To elucidate the role of IRF-1 in fish during virus infections, we constructed a recombinant plasmid of the Japanese flounder, Paralichthys olivaceus IRF-1 (JF IRF-1) under the control of the cytomegalovirus (CMV) immediate/early enhancer promoter. The antiviral mechanism of JF IRF-1 was studied using transfection experiments in a homologous cell line. Here, we show that cell supernatants obtained from transiently transfected cells enhanced cell viability of a heterologous cell line upon incubation, reduced the titers of hirame rhabdovirus (HIRRV) and viral hemorrhagic septicemia virus (VHSV), and possessed cytokine-like activity, as shown by their ability to protect cells against virus infections. The supernatants also inhibited the replication of the rhabdoviruses during the early stages of infection as indicated by the reduction of viral titers in the presence of the supernatants obtained from the transfected cells. Further analysis showed that the cell culture supernatants contain cytokine-like substances that possess acid-labile and temperature-resistant properties. These results indicate that JF IRF-1 induces an antiviral state in cells by mediating the production of cytokine-like substances. Thus, JF IRF-1 might be useful as an adjuvant in the development of DNA vaccines against commercially important viral pathogens in Japanese flounder aquaculture.

  1. A Versatile Vector for In Vivo Monitoring of Type I Interferon Induction and Signaling.

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    Estanislao Nistal-Villan

    Full Text Available Development of reporter systems for in vivo examination of IFN-β induction or signaling of type I interferon (IFN-I pathways is of great interest in order to characterize biological responses to different inducers such as viral infections. Several reporter mice have been developed to monitor the induction of both pathways in response to different agonists. However, alternative strategies that do not require transgenic mice breeding have to date not been reported. In addition, detection of these pathways in vivo in animal species other than mice has not yet been addressed. Herein we describe a simple method based on the use of an adeno-associated viral vector (AAV8-3xIRF-ISRE-Luc containing an IFN-β induction and signaling-sensitive promoter sequence controlling the expression of the reporter gene luciferase. This vector is valid for monitoring IFN-I responses in vivo elicited by diverse stimuli in different organs. Intravenous administration of the vector in C57BL/6 mice and Syrian hamsters was able to detect activation of the IFN pathway in the liver upon systemic treatment with different pro-inflammatory agents and infection with Newcastle disease virus (NDV. In addition, intranasal instillation of AAV8-3xIRF-ISRE-Luc showed a rapid and transient IFN-I response in the respiratory tract of mice infected with the influenza A/PR8/34 virus lacking the NS1 protein. In comparison, this response was delayed and exacerbated in mice infected with influenza A/PR/8 wild type virus. In conclusion, the AAV8-3xIRF-ISRE-Luc vector offers the possibility of detecting IFN-I activation in response to different stimuli and in different animal models with no need for reporter transgenic animals.

  2. Hyporeactivity to interferon induction: characterization of a hyporeactive factor in the serum of encephalomyocarditis virus-infected mice.

    Science.gov (United States)

    Stringfellow, D A

    1975-02-01

    Mice infected with encephalomyocarditis virus develop a severe state of hyporeactivity to interferon induction. One mechanisms possibly responsibile for development of hyporesponsiveness in these animals is a circulating factor which can be detected in their serum 96 h after encephalomyocarditis virus infection (at the time of peak hyporeactivity in vivo). This report describes some of the physiocochemical characteristics of this serum hyporeactive factor (SHF). SHF is a protein with a molecular weight between 20,000 and 40,000 that was extremely labile at 56 C, losing greater than 90% of its biological activity in 8 min, but stable at 37 c for at least 4 h. Hyporeactive factor was also stable over a pH range of 2 to 11 for 48 h at 4 C. These results suggest that SHF is physicochemically similar to interferon. However, no interferon could be detected in the SHF preparation, and no loss in biological activity was observed when the serum factor was incubated with anti-interferon antibody, suggesting that they are separate substances.

  3. Infectious salmon anaemia virus replication and induction of alpha interferon in Atlantic salmon erythrocytes

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    Groman David B

    2008-02-01

    Full Text Available Abstract Background Infectious salmon anaemia (ISA virus (ISAV, which causes ISA in marine-farmed Atlantic salmon, is an orthomyxovirus belonging to the genus Isavirus, family Orthomyxoviridae. ISAV agglutinates erythrocytes of several fish species and it is generally accepted that the ISAV receptor destroying enzyme dissolves this haemagglutination except for Atlantic salmon erythrocytes. Recent work indicates that ISAV isolates that are able to elute from Atlantic salmon erythrocytes cause low mortality in challenge experiments using Atlantic salmon. Previous work on ISAV-induced haemagglutination using the highly pathogenic ISAV strain NBISA01 and the low pathogenic ISAV strain RPC/NB-04-0851, showed endocytosis of NBISA01 but not RPC/NB-04-0851. Real-time RT-PCR was used to assess the viral RNA levels in the ISAV-induced haemagglutination reaction samples, and we observed a slight increase in viral RNA transcripts by 36 hours in the haemagglutination reaction with NBISA01 virus when the experiment was terminated. However, a longer sampling interval was considered necessary to confirm ISAV replication in fish erythrocytes and to determine if the infected cells mounted any innate immune response. This study examined the possible ISAV replication and Type I interferon (IFN system gene induction in Atlantic salmon erythrocytes following ISAV haemagglutination. Results Haemagglutination assays were performed using Atlantic salmon erythrocytes and one haemagglutination unit of the two ISAV strains, NBISA01 and RPC/NB-04-0851, of differing genotypes and pathogenicities. Haemagglutination induced by the highly pathogenic NBISA01 but not the low pathogenic RPC/NB-04-0851 resulted in productive infection as evidenced by increased ISAV segment 8 transcripts and increase in the median tissue culture infectious dose (TCID50 by 5 days of incubation. Moreover, reverse transcription (RT quantitative PCR used to compare mRNA levels of key Type I IFN system

  4. Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

    DEFF Research Database (Denmark)

    Sena, Armando; Bendtzen, Klaus; Cascais, Maria J

    2010-01-01

    Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated with the d......Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated......-negative, 83 (68-107) mg/L, P = 0.03, and 76 (66-87) mg/L, P = 0.04, respectively. When adjusting for age and smoking for a one-standard deviation decrease in apoE levels, a 5.6-fold increase in the odds of becoming NAb-positive was detected: odds ratios (OR) 0.18 (95% CI 0.04-0.77), P = 0.04. When adjusting...... for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta....

  5. Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients

    DEFF Research Database (Denmark)

    Hegen, H; Millonig, A; Bertolotto, A

    2014-01-01

    BACKGROUND: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy. OBJECTIVES: To investigate whether early binding antibody (BAb) titers...

  6. Improvement of porcine interferon-α production by recombinant Pichia pastoris via induction at low methanol concentration and low temperature.

    Science.gov (United States)

    Jin, Hu; Liu, Guoqiang; Dai, Keke; Wang, Huihui; Li, Zhen; Shi, Zhongping

    2011-09-01

    Improved porcine interferon-α (pIFN-α) production by recombinant Pichia pastoris was achieved by culture conditions optimization in a 5-l bioreactor. The results indicated that the pIFN-α concentration, specific methanol consumption rate, specific activities of alcohol oxidase, formaldehyde dehydrogenase, and formate dehydrogenase could be significantly enhanced by decreasing induction temperature. The highest pIFN-α concentration (1.35 g l(-1)) was obtained by simultaneously controlling methanol concentration at 5 g l(-1) and induction temperature at 20 °C, which was about 1.6-fold higher than the maximum obtained with previous optimal methanol concentration level (about 10 g l(-1)) when inducing at 30 °C. The potential mechanisms behind low temperature and low methanol concentration effect on pIFN-α production may be ascribed to higher cell metabolic activity, more carbon flux towards pIFN-α production, and less intracellular/extracellular protease release.

  7. Influence of apolipoprotein E plasma levels and tobacco smoking on the induction of neutralising antibodies to interferon-beta

    DEFF Research Database (Denmark)

    Sena, Armando; Bendtzen, Klaus; Cascais, Maria J

    2010-01-01

    Interferon-beta (IFN-beta) therapy for multiple sclerosis (MS) is associated with a potential for induction of neutralizing antibodies (NAbs). Because immune reactivity depends on changes in lipoprotein metabolism, we investigated whether plasma lipoprotein profiles could be associated...... with the development of NAbs. Thirty-one female MS patients treated with subcutaneously administered IFN-beta were included. Demographic and clinical characteristics were compared between NAbs response groups using t tests for continuous and logistic regression analysis and Fisher's exact tests for categorical data...... for apoE, smoking habit became associated with NAb induction: OR 5.6 (95% CI 1.3-87), P = 0.03. These results suggest that apoE-containing lipoprotein metabolism and, possibly, tobacco smoking may be associated with risk of NAb production in female MS patients treated with IFN-beta....

  8. Differential constitutive expression of interferon genes in early mouse embryos.

    Science.gov (United States)

    Riego, E; Pérez, A; Martínez, R; Castro, F O; Lleonart, R; de la Fuente, J

    1995-06-01

    Recent evidence suggests that several processes during mammalian embryogenesis may be regulated by IFNs or IFN-like molecules. With the use of MAPPing, the simultaneous presence of transcripts homologous to IFN-alpha, IFN-beta, IRF-1, and IRF-2 was examined in mouse embryos and in embryonal carcinoma (EC) P19 cells, which are equivalent to epiblast cells of the early postimplantation blastocysts. Transcripts for IFN-alpha, but not for IFN-beta, were detected as maternal transcripts in the ovulated oocyte and persisted over early embryogenesis. IRF-1 transcripts appeared only after the first cell cleavage in the two-cell stage embryo. IRF-2 transcripts were analyzed only in EC P19 cells and were found in both undifferentiated (D-) and differentiated (D+) cells. The IFN-alpha transcripts present in (D-) P19 cells were cloned and the partial cDNA sequences determined. Mu IFN-alpha A and a new Mu IFN-alpha species (Mu IFN-alpha 12) were isolated from (D-) P19 cells. The presence of constitutive IFN-alpha transcripts in early mouse embryos suggests a role for these molecules during embryogenesis.

  9. Plasma membrane Toll-like receptor activation increases bacterial uptake but abrogates endosomal Lactobacillus acidophilus induction of interferon

    DEFF Research Database (Denmark)

    Boye, Louise; Welsby, Iain; Lund, Lisbeth Drozd

    2016-01-01

    Lactobacillus acidophilus induces a potent interferon-β (IFN-β) response in dendritic cells (DCs) by a Toll-like receptor 2 (TLR2) -dependent mechanism, in turn leading to strong interleukin-12 (IL-12) production. In the present study, we investigated the involvement of different types...... of endocytosis in the L. acidophilus-induced IFN-β and IL-12 responses and how TLR2 or TLR4 ligation by lipopolysaccharide and Pam3/4CSK4 influenced endocytosis of L. acidophilus and the induced IFN-β and IL-12 production. Lactobacillus acidophilus was endocytosed by constitutive macropinocytosis taking place....... acidophilus enhanced the uptake of the bacteria. However, in these experimental conditions, induction of IFN-β and IL-12 was strongly inhibited. As L. acidophilus-induced IFN-β depends on endocytosis and endosomal degradation before signalling and as TLR stimulation from the plasma membrane leading...

  10. Early bichemical markers of effects: Enzyme induction, oncogene activation and markers of oxidative damage

    DEFF Research Database (Denmark)

    Poulsen, Henrik E.; Loft, Steffen

    1995-01-01

    Early bichemical marker, enzyme induction, oncogene activation, oxidative damage, low-density lipoprotein......Early bichemical marker, enzyme induction, oncogene activation, oxidative damage, low-density lipoprotein...

  11. Severe acute exacerbation of chronic hepatitis B during pegylated interferon treatment and early intervention with corticosteroid

    Directory of Open Access Journals (Sweden)

    Mao Qing

    2012-07-01

    Full Text Available Abstract Severe acute exacerbation or liver failure induced by standard interferon-α(IFN-α therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-α2a (Pegasys treatment. One patient progressed into acute-on-chronic liver failure (ACLF at the second week of Pegasys treatment. Two patients progressed into acute-on-chronic pre-liver failure (pre-ACLF at the second and eighth week of Pegasys treatment, respectively. Three patients recovered after early combined intervention with corticosteroid and lamivudine. Our data indicated that there was a risk of severe acute exacerbation among patients with chronic hepatitis B during receiving Pegasys treatment. Importantly, early combined intervention with corticosteroid and lamivudine should be introduced to prevent the disease progression and improve their prognosis once severe acute exacerbation was diagnosed.

  12. BMP regulates vegetal pole induction centres in early xenopus development.

    Science.gov (United States)

    Nachaliel, N; Re'Em-Kalma, Y; Eshed, O; Elias, S; Frank, D

    1998-10-01

    Bone morphogenetic protein (BMP) plays an important role in mesoderm patterning in Xenopus. The ectopic expression of BMP-4 protein hyperventralizes embryos, whereas embryos expressing a BMP-2/4 dominant-negative receptor (DNR) are hyperdorsalized. Mesoderm is initially induced in the marginal zone by cells in the underlying vegetal pole. While much is known about BMP's expression and role in patterning the marginal zone, little is known about its early role in regulating vegetal mesoderm induction centre formation. The role of BMP in regulating formation of vegetal mesoderm inducing centres during early Xenopus development was examined. Ectopic BMP-4 expression in vegetal pole cells inhibited dorsal mesoderm induction but increased ventral mesoderm induction when recombined with animal cap ectoderm in Nieuwkoop explants. 32-cell embryos injected with BMP-4 RNA in the most vegetal blastomere tier were not hyperdorsalized by LiCl treatment. The ectopic expression of Smad or Mix.1 proteins in the vegetal pole also inhibited dorsal mesoderm induction in explants and embryos. Expression of the BMP 2/4 DNR in the vegetal pole increased dorsal mesoderm induction and inhibited ventral mesoderm induction in explants and embryos. These results support a role for BMP signalling in regulating ventral vegetal and dorsal vegetal mesoderm induction centre formation during early Xenopus development.

  13. Processing of genome 5' termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction.

    Directory of Open Access Journals (Sweden)

    Matthias Habjan

    2008-04-01

    Full Text Available Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5' triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5' triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5' monophosphate-specific exonuclease indicates that the RIG-I-activating 5' triphosphate group was removed post-transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5' end as a strategy of viruses to evade the innate immune response.

  14. Processing of Genome 5′ Termini as a Strategy of Negative-Strand RNA Viruses to Avoid RIG-I-Dependent Interferon Induction

    Science.gov (United States)

    Habjan, Matthias; Andersson, Ida; Klingström, Jonas; Schümann, Michael; Martin, Arnold; Zimmermann, Petra; Wagner, Valentina; Pichlmair, Andreas; Schneider, Urs; Mühlberger, Elke; Mirazimi, Ali; Weber, Friedemann

    2008-01-01

    Innate immunity is critically dependent on the rapid production of interferon in response to intruding viruses. The intracellular pathogen recognition receptors RIG-I and MDA5 are essential for interferon induction by viral RNAs containing 5′ triphosphates or double-stranded structures, respectively. Viruses with a negative-stranded RNA genome are an important group of pathogens causing emerging and re-emerging diseases. We investigated the ability of genomic RNAs from substantial representatives of this virus group to induce interferon via RIG-I or MDA5. RNAs isolated from particles of Ebola virus, Nipah virus, Lassa virus, and Rift Valley fever virus strongly activated the interferon-beta promoter. Knockdown experiments demonstrated that interferon induction depended on RIG-I, but not MDA5, and phosphatase treatment revealed a requirement for the RNA 5′ triphosphate group. In contrast, genomic RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus did not trigger interferon induction. Sensitivity of these RNAs to a 5′ monophosphate-specific exonuclease indicates that the RIG-I-activating 5′ triphosphate group was removed post-transcriptionally by a viral function. Consequently, RIG-I is unable to bind the RNAs of Hantaan virus, Crimean-Congo hemorrhagic fever virus and Borna disease virus. These results establish RIG-I as a major intracellular recognition receptor for the genome of most negative-strand RNA viruses and define the cleavage of triphosphates at the RNA 5′ end as a strategy of viruses to evade the innate immune response. PMID:18446221

  15. Cross-Species Antiviral Activity of Goose Interferons against Duck Plague Virus Is Related to Its Positive Self-Feedback Regulation and Subsequent Interferon Stimulated Genes Induction

    Directory of Open Access Journals (Sweden)

    Hao Zhou

    2016-07-01

    Full Text Available Interferons are a group of antiviral cytokines acting as the first line of defense in the antiviral immunity. Here, we describe the antiviral activity of goose type I interferon (IFNα and type II interferon (IFNγ against duck plague virus (DPV. Recombinant goose IFNα and IFNγ proteins of approximately 20 kDa and 18 kDa, respectively, were expressed. Following DPV-enhanced green fluorescent protein (EGFP infection of duck embryo fibroblast cells (DEFs with IFNα and IFNγ pre-treatment, the number of viral gene copies decreased more than 100-fold, with viral titers dropping approximately 100-fold. Compared to the control, DPV-EGFP cell positivity was decreased by goose IFNα and IFNγ at 36 hpi (3.89%; 0.79% and 48 hpi (17.05%; 5.58%. In accordance with interferon-stimulated genes being the “workhorse” of IFN activity, the expression of duck myxovirus resistance (Mx and oligoadenylate synthetases-like (OASL was significantly upregulated (p < 0.001 by IFN treatment for 24 h. Interestingly, duck cells and goose cells showed a similar trend of increased ISG expression after goose IFNα and IFNγ pretreatment. Another interesting observation is that the positive feedback regulation of type I IFN and type II IFN by goose IFNα and IFNγ was confirmed in waterfowl for the first time. These results suggest that the antiviral activities of goose IFNα and IFNγ can likely be attributed to the potency with which downstream genes are induced by interferon. These findings will contribute to our understanding of the functional significance of the interferon antiviral system in aquatic birds and to the development of interferon-based prophylactic and therapeutic approaches against viral disease.

  16. Toll-Like Receptor Ligands and Interferon-γ Synergize for Induction of Antitumor M1 Macrophages.

    Science.gov (United States)

    Müller, Elisabeth; Christopoulos, Panagiotis F; Halder, Sanjib; Lunde, Anna; Beraki, Kahsai; Speth, Martin; Øynebråten, Inger; Corthay, Alexandre

    2017-01-01

    Tumor-associated macrophages may either promote or suppress tumor growth depending on their activation status. Interferon-γ (IFN-γ) has been identified as a key factor for inducing tumoricidal M1 phenotype in macrophages. However, it remains unclear whether IFN-γ is sufficient or if additional stimuli are required. Here, we tested IFN-γ and a panel of toll-like receptor (TLR) agonists for the ability to activate murine macrophages toward a tumoricidal M1 phenotype. The following TLR ligands were used: TLR1/TLR2 agonist Pam3CSK4, TLR2/TLR6 agonist lipotechoic acid, TLR3 agonist poly(I:C), TLR4 agonist lipopolysaccharide (LPS), TLR5 agonist flagellin, TLR7 agonist CL264, and TLR9 agonist CpG. We used an in vitro growth inhibition assay to measure both cytotoxic and cytostatic activity of mouse macrophages against Lewis lung carcinoma (LLC) and MOPC315 plasmacytoma tumor cells. Production of nitric oxide (NO) and cytokines by activated macrophages was quantified. We found that IFN-γ alone was not able to render macrophages tumoricidal. Similarly, macrophage activation with single TLR agonists was inefficient. In sharp contrast, IFN-γ was shown to synergize with TLR agonists for induction of macrophage tumoricidal activity and production of both NO and pro-inflammatory cytokines (TNF-α, IL-12p40, and IL-12p70). Furthermore, IFN-γ was shown to suppress macrophage IL-10 secretion induced by TLR agonists. NO production was necessary for macrophage tumoricidal activity. We conclude that two signals from the microenvironment are required for optimal induction of antitumor M1 macrophage phenotype. Combination treatment with IFN-γ and TLR agonists may offer new avenues for macrophage-based cancer immunotherapy.

  17. Toll-Like Receptor Ligands and Interferon-γ Synergize for Induction of Antitumor M1 Macrophages

    Directory of Open Access Journals (Sweden)

    Elisabeth Müller

    2017-10-01

    Full Text Available Tumor-associated macrophages may either promote or suppress tumor growth depending on their activation status. Interferon-γ (IFN-γ has been identified as a key factor for inducing tumoricidal M1 phenotype in macrophages. However, it remains unclear whether IFN-γ is sufficient or if additional stimuli are required. Here, we tested IFN-γ and a panel of toll-like receptor (TLR agonists for the ability to activate murine macrophages toward a tumoricidal M1 phenotype. The following TLR ligands were used: TLR1/TLR2 agonist Pam3CSK4, TLR2/TLR6 agonist lipotechoic acid, TLR3 agonist poly(I:C, TLR4 agonist lipopolysaccharide (LPS, TLR5 agonist flagellin, TLR7 agonist CL264, and TLR9 agonist CpG. We used an in vitro growth inhibition assay to measure both cytotoxic and cytostatic activity of mouse macrophages against Lewis lung carcinoma (LLC and MOPC315 plasmacytoma tumor cells. Production of nitric oxide (NO and cytokines by activated macrophages was quantified. We found that IFN-γ alone was not able to render macrophages tumoricidal. Similarly, macrophage activation with single TLR agonists was inefficient. In sharp contrast, IFN-γ was shown to synergize with TLR agonists for induction of macrophage tumoricidal activity and production of both NO and pro-inflammatory cytokines (TNF-α, IL-12p40, and IL-12p70. Furthermore, IFN-γ was shown to suppress macrophage IL-10 secretion induced by TLR agonists. NO production was necessary for macrophage tumoricidal activity. We conclude that two signals from the microenvironment are required for optimal induction of antitumor M1 macrophage phenotype. Combination treatment with IFN-γ and TLR agonists may offer new avenues for macrophage-based cancer immunotherapy.

  18. Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand (IFNgamma)-Independent Novel Function of IFNgammaR2 as a Bax Inhibitor

    Science.gov (United States)

    2015-08-01

    AWARD NUMBER: W81XWH-12-1-0331 TITLE: Apoptosis Induction by Targeting Interferon Gamma Receptor 2 (IFNgammaR2) in Prostate Cancer: Ligand...DATE August 2015 2. REPORT TYPE Annual 3. DATES COVERED 1Aug2014 - 31Jul2015 4. TITLE AND SUBTITLE Apoptosis Induction by Targeting Interferon...inhibitor of Bax. Bax is a key mediator of apoptosis . We found that IFNγR2 is overexpressed in prostate cancer, and we hypothesize that abnormally high

  19. Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.

    Directory of Open Access Journals (Sweden)

    Dane Parker

    2014-02-01

    Full Text Available The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S. aureus infection, particularly in the pathogenesis of pneumonia. We compared the pathogenesis of infection caused by two phylogenetically and epidemiologically distinct strains of S. aureus whose behavior in humans has been well characterized. Induction of the type I IFN cascade by strain 502A, due to a NOD2-IRF5 pathway, was the major factor in causing severe pneumonia and death in a murine model of pneumonia and was associated with autolysis and release of peptidogylcan. In contrast to USA300, 502A was readily eliminated from epithelial surfaces in vitro. Nonetheless, 502A caused significantly increased tissue damage due to the organisms that were able to invade systemically and trigger type I IFN responses, and this was ameliorated in Ifnar⁻/⁻ mice. The success of USA300 to cause invasive infection appears to depend upon its resistance to eradication from epithelial surfaces, but not production of specific toxins. Our studies illustrate the important and highly variable role of type I IFN signaling within a species and suggest that targeted immunomodulation of specific innate immune signaling cascades may be useful to prevent the excessive morbidity associated with S. aureus pneumonia.

  20. Improving Performance and Operational Stability of Porcine Interferon-α Production by Pichia pastoris with Combinational Induction Strategy of Low Temperature and Methanol/Sorbitol Co-feeding.

    Science.gov (United States)

    Gao, Min-Jie; Zhan, Xiao-Bei; Gao, Peng; Zhang, Xu; Dong, Shi-Juan; Li, Zhen; Shi, Zhong-Ping; Lin, Chi-Chung

    2015-05-01

    Various induction strategies were investigated for effective porcine interferon-α (pIFN-α) production by Pichia pastoris in a 10 L fermenter. We found that pIFN-α concentration could be significantly improved with the strategies of low-temperature induction or methanol/sorbitol co-feeding. On this basis, a combinational strategy of induction at lower temperature (20 °C) with methanol/sorbitol co-feeding has been proposed for improvement of pIFN-α production. The results reveal that maximal pIFN-α concentration and antiviral activity reach the highest level of 2.7 g/L and 1.8 × 10(7) IU/mg with the proposed induction strategy, about 1.3-2.1 folds higher than those obtained with other sub-optimal induction strategies. Metabolic analysis and online multi-variable measurement results indicate that energy metabolic enrichment is responsible for the performance enhancement of pIFN-α production, as a large amount of ATP could be simultaneously produced from both formaldehyde oxidation pathway in methanol metabolism and tricarboxylic acid (TCA) cycle in sorbitol metabolism. In addition, the proposed combinational induction strategy enables P. pastoris to be resistant to high methanol concentration (42 g/L), which conceivably occur associating with the error-prone methanol over-feeding. As a result, the proposed combinational induction strategy simultaneously increased the targeted protein concentration and operational stability leading to significant improvement of pIFN-α production.

  1. Early versus late amniotomy for labor induction: a randomized trial.

    Science.gov (United States)

    Mercer, B M; McNanley, T; O'Brien, J M; Randal, L; Sibai, B M

    1995-10-01

    Our purpose was to determine the impact of early and late amniotomy on labor induction with continuous oxytocin infusion at term. A total of 209 women admitted for labor induction were randomized to early or late amniotomy. The early amniotomy group (n = 106) had membranes ruptured as soon as it was deemed safe and feasible. The late amniotomy group (n = 103) had membrane rupture performed at > or = 5 cm dilatation. The first 103 women received a continuous oxytocin infusion with incremental adjustments at 60-minute intervals as required. The next 106 women had adjustments every 30 minutes as required. Statistical analysis was confined to concurrent groups. Early amniotomy was associated with shorter labor (13.3 vs 17.8 hours, p = 0.001), chorioamnionitis (22.6% vs 6.8%, p = 0.002), and significant fetal umbilical cord compression (12.3% vs 2.9%, p = 0.017). The benefit regarding shortening of labor was limited to women having oxytocin increments every 30 minutes as required (13.3 vs 17.8 hours, p = 0.001). Alternatively, the increase in chorioamnionitis was confined to the 60-minute group (39% vs 11%, p oxytocin infusion rate is desired, amniotomy should be performed late in labor to reduce chorioamnionitis and significant umbilical cord compression. Alternatively, if early amniotomy is necessary, oxytocin should be adjusted every 30 minutes as tolerated.

  2. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferoninduction

    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...

  3. Type I Interferon Gene Response Is Increased in Early and Established Rheumatoid Arthritis and Correlates with Autoantibody Production.

    Science.gov (United States)

    Castañeda-Delgado, Julio E; Bastián-Hernandez, Yadira; Macias-Segura, Noe; Santiago-Algarra, David; Castillo-Ortiz, Jose D; Alemán-Navarro, Ana L; Martínez-Tejada, Pedro; Enciso-Moreno, Leonor; Garcia-De Lira, Yolanda; Olguín-Calderón, Diana; Trouw, Leendert A; Ramos-Remus, Cesar; Enciso-Moreno, Jose A

    2017-01-01

    Rheumatoid arthritis (RA) is an inflammatory debilitating disease that affects the joints in the early and productive phases of an individual's life. Several cytokines have been linked to the disease pathogenesis and are known to contribute to the inflammatory state characteristic of RA. The participation of type I interferon (IFN) in the pathogenesis of the disease has been already described as well as the identity of the genes that are regulated by this molecule, which are collectively known as the type I IFN signature. These genes have several functions associated with apoptosis, transcriptional regulation, protein degradation, Th2 cell induction, B cell proliferation, etc. This article evaluated the expression of several genes of the IFN signature in different stages of disease and their correlation with the levels of anticitrullinated protein antibodies (ACPA) anticarbamylated protein (Anti-CarP) antibodies. Samples from individuals with early and established RA, high-risk individuals (ACPA+ and ACPA-), and healthy controls were recruited at "Unidad de Artritis y Rheumatismo" (Rheumatism and Arthritis Unit) in Guadalajara Jalisco Mexico. Determinations of ACPA were made with Eurodiagnostica ACPA plus kit. Anti-CarP determinations were made according to previously described protocols. RNA was isolated, and purity and integrity were determined according to RNA integrity number >6. Gene expression analysis was made by RT-qPCR using specific primers for mRNAs of the type I IFN signature. Relative gene expression was calculated according to Livak and Schmitgen. Significant differences in gene expression were identified when comparing the different groups for MXA and MXB (P < 0.05), also when comparing established RA and ACPA- in both IFIT 1 and G15. An increased expression of ISG15 was identified (P < 0.05), and a clear tendency toward increase was identified for HERC5. EPSTRI1, IFI6, and IFI35 were found to be elevated in the chronic/established RA and

  4. Interferon regulatory factor 3 (IRF-3) in Japanese flounder, Paralichthys olivaceus: sequencing, limited tissue distribution, inducible expression and induction of fish type I interferon promoter.

    Science.gov (United States)

    Hu, Guobin; Yin, Xiangyan; Lou, Huimin; Xia, Jun; Dong, Xianzhi; Zhang, Jianyie; Liu, Qiuming

    2011-02-01

    Two cDNAs with different 3'-untranslated region (UTR) encoding an interferon regulatory factor 3 (IRF-3) were cloned from head kidney of Japanese flounder, Paralichthys olivaceus, by reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) methods. Sequence analysis reveals that they were generated by alternative polyadenylation. The predicted protein consists of 467 amino acid residues which shares the highest identity of 50.7-57.6% to fish IRF-3 and possesses a DNA-binding domain (DBD), an IRF association domain (IAD) and a serine-rich domain (SRD) of vertebrate IRF-3. The presence of these domains along with phylogenetic analysis places it into the IRF-3 group of the IRF-3 subfamily. RT-PCR analysis revealed that flounder IRF-3 was expressed constitutively in limited tissue types including head kidney, spleen, kidney, heart, gill, intestine and liver. A quantitative real time PCR assay was employed to monitor expression of IRF-3, type I interferon (IFN) and Mx in flounder head kidney and gill. All three genes were up-regulated by polyinosinic:polycytidylic acid (polyI:C) and lymphocystis disease virus (LCDV) with an earlier but slight and less persistent increase in transcription levels seen for the IRF-3. Finally, flounder IRF-3 was proved to induce fish type I IFN promoter in FG9307 cells, a flounder gill cell line, by a luciferase assay. These results provide insights into the roles of fish IRF-3 in the antiviral immunity. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Early stage and long term treatment of multiple sclerosis with interferon

    Directory of Open Access Journals (Sweden)

    Angela Applebee

    2009-05-01

    Full Text Available Angela Applebee, Hillel PanitchDepartment of Neurology, University of Vermont College of Medicine, and Neurology Service, Fletcher Allen Health Care, Burlington, VT, USAAbstract: Multiple sclerosis (MS affects young adults during the most productive years of their lives, and until recently many neurologists were limited to treating symptoms and attacks without any ability to alter the disease course. The 1990s ushered in an era of possibility with the approval of three interferon-beta (IFNβ therapies for the treatment of MS. Though the mechanism of action of these agents is not completely understood, it is clear they reduce magnetic resonance imaging (MRI activity as well as improve clinical outcomes. The principal randomized, blinded, multicenter trials of IFNβ all point to the need for early treatment soon after the diagnosis of MS is made. Efficacy has also been shown in patients treated after a first demyelinating event. Data on IFNβ in the treatment of secondary progressive MS (SPMS is not impressive, although it shows some benefit in SPMS patients who continue to experience MRI activity and clinical relapses, signifying a continued inflammatory component to their disease. There has been no proven efficacy of IFNβ in the treatment of primary progressive MS (PPMS. The IFNβ therapies are generally well tolerated with a favorable side effect profile. Despite benefits in MRI and clinical measures such as relapse rates and Expanded Disability Status Scale progression, patients continue to exhibit clinical progression and radiological atrophy, pointing to confounding factors and perhaps multiple etiologies of a disease that is not yet fully understood. In addition, the subject of neutralizing antibodies has recently assumed importance. The significance of these on treatment efficacy is uncertain, and until a universally accepted reliable assay is adopted, the decision to change treatment continues to rely on the clinical interpretation of

  6. Interferon stimulated genes as peripheral diagnostic markers of early pregnancy in sheep: a critical assessment.

    Science.gov (United States)

    Mauffré, V; Grimard, B; Eozenou, C; Inghels, S; Silva, L; Giraud-Delville, C; Capo, D; Sandra, O; Constant, F

    2016-11-01

    We investigated the diagnostic reliability of pregnancy detection using changes in interferon stimulated gene (ISG) messenger RNA (mRNA) levels in circulating immune cells in ewes. Two different groups of ewes (an experimental group, experiment 1 and a farm group, experiment 2) were oestrus-synchronized and blood sampled on day 14 (D0=day of insemination in control animals, experiment 1) and day 15 (experiment 2). Real-time PCR were performed to evaluate the abundance of different ISG mRNAs. In the experimental group, peripheral blood mononuclear cells of 29 ewes born and bred in experimental facilities were isolated using a Percoll gradient method. Gene expression for Chemokine (C-X-C motif) ligand 10 (CXCL10), Myxovirus (influenza virus) resistance 1 (MX1) and Signal transducer and activator of transcription 1 (STAT1) mRNA were, respectively, 8.3-fold, 6.1-fold and 2.7-fold higher (P0.10) in CXCL10, STAT1, MX1, Myxovirus (influenza virus) resistance 2 (MX2) and ISG15 ubiquitin-like modifier (ISG15) mRNA expression were found between pregnant and non-pregnant ewes. The ROC curves and the hierarchical classification generated from the real-time PCR data failed to discriminate between pregnant and non-pregnant animals. In this group of animals, our results show a strong variability in ISG expression patterns: 17% of animals identified as non-pregnant by the five tests were in fact pregnant, only 52% of pregnant animals had at least two positive results (two genes above threshold), whereas up to five positive results (five genes above threshold) were needed to avoid misclassification. In conclusion, this study illustrates the high variability in ISG expression levels in immune circulating cells during early pregnancy and, therefore, highlights the limits of using ISG expression levels in blood samples, collected on PAXgene® tubes on farms, for early pregnancy detection in sheep.

  7. Antiviral activity and host gene induction by tamarin and marmoset interferon-alpha and interferon-gamma in the GBV-B primary hepatocyte culture model.

    Science.gov (United States)

    Chavez, Deborah; Guerra, Bernadette; Lanford, Robert E

    2009-08-01

    GBV-B induces hepatitis in tamarins and marmosets and is a surrogate model for HCV infections. Here, we cloned and characterized the antiviral activity of tamarin and marmoset interferon (IFN)alpha and IFN gamma. Potent antiviral activity was observed for tamarin and marmoset IFN alpha in primary hepatocyte cultures infected with GBV-B. The antiviral activity was greater in cultures exposed to IFN alpha prior to GBV-B infection, suggesting that either GBV-B was capable of inhibition of the antiviral activity of exogenous IFN alpha or that the preexisting endogenous IFN response to the virus reduced efficacy to exogenous IFN alpha. IFN gamma also exhibited antiviral activity in GBV-B infected hepatocytes. The transcriptional response to IFN alpha in marmoset hepatocytes was characterized using human genome microarrays. Since the GBV-B hepatocyte culture model possesses a functional innate immune response, it will provide opportunities to explore the nature of the antiviral response to a virus closely related to HCV.

  8. Enhancement of delayed-type hypersensitivity and induction of interferon by the lipophilic agents DDA and CP-20,961

    NARCIS (Netherlands)

    Kraaijeveld, C.A.; Snippe, H.; Harmsen, T.; Benaissa-Trouw, B.

    1982-01-01

    The lipophilic amines dimethyl dioctadecyl ammonium bromide (DDA) and N,N-dioctadecyl-N′, N′-bis(2-hydroxyethyl)propanediamine (CP-20,961) are compared on their capacities to induce interferon, nonspecific protection to viral infection, and enhancement of delayed-type hypersensitivity (DH). DDA, a

  9. Methanol/sorbitol co-feeding induction enhanced porcine interferon-α production by P. pastoris associated with energy metabolism shift.

    Science.gov (United States)

    Gao, Min-Jie; Li, Zhen; Yu, Rui-Song; Wu, Jian-Rong; Zheng, Zhi-Yong; Shi, Zhong-Ping; Zhan, Xiao-Bei; Lin, Chi-Chung

    2012-09-01

    The production of porcine interferon-α (pIFN-α) by Pichia pastoris was largely enhanced when adopting sorbitol/methanol co-feeding induction strategy at 30 °C in a 10-L fermentor. Analysis of energy regeneration pattern and carbon metabolism revealed that major energy metabolism energizing pIFN-α synthesis shifted from formaldehyde dissimilatory energy metabolism pathway to TCA cycle under the methanol/sorbitol co-feeding induction strategy. The sorbitol/methanol co-feeding induction strategy weakened formaldehyde dissimilatory pathway and repressed the accumulation of toxic metabolite-formaldehyde, reduced theoretical oxygen consumption rate and oxygen supply requirement, and increased energy/methanol utilization efficiency so that more methanol could be effectively used for pIFN-α synthesis. As a result, pIFN-α antiviral activity reached a highest level of 1.8 × 10(7) IU/mL which was about 10- to 200-folds of those obtained under pure methanol induction at 20 and 30 °C, respectively.

  10. Literature Review on Induction and Mentoring Related to Early Career Teacher Attrition and Retention

    Science.gov (United States)

    Long, Julie S.; McKenzie-Robblee, Sue; Schaefer, Lee; Steeves, Pam; Wnuk, Sheri; Pinnegar, Eliza; Clandinin, D. Jean

    2012-01-01

    Early career teacher attrition is a matter of economic, social, and educational concern in many countries. Usually induction programs, including mentoring, are seen to alleviate the problem of early career teacher attrition. Mentoring/induction programs as a solution to what is defined as the problem of early career teacher attrition and retention…

  11. RIG-I mediates the co-induction of tumor necrosis factor and type I interferon elicited by myxoma virus in primary human macrophages.

    Directory of Open Access Journals (Sweden)

    Fuan Wang

    2008-07-01

    Full Text Available The sensing of pathogen infection and subsequent triggering of innate immunity are key to controlling zoonotic infections. Myxoma virus (MV is a cytoplasmic DNA poxvirus that in nature infects only rabbits. Our previous studies have shown that MV infection of primary mouse cells is restricted by virus-induced type I interferon (IFN. However, little is known about the innate sensor(s involved in activating signaling pathways leading to cellular defense responses in primary human immune cells. Here, we show that the complete restriction of MV infection in the primary human fibroblasts requires both tumor necrosis factor (TNF and type I IFN. We also demonstrate that MV infection of primary human macrophages (pHMs activates the cytoplasmic RNA sensor called retinoic acid inducible gene I (RIG-I, which coordinately induces the production of both TNF and type I IFN. Of note, RIG-I sensing of MV infection in pHMs initiates a sustained TNF induction through the sequential involvement of the downstream IFN-regulatory factors 3 and 7 (IRF3 and IRF7. Thus, RIG-I-mediated co-induction of TNF and type I IFN by virus-infected pHMs represents a novel innate defense mechanism to restrict viral infection in human cells. These results also reveal a new regulatory mechanism for TNF induction following viral infection.

  12. Chronic hepatitis C patients with a post-treatment virological relapse re-treated with an induction dose of 18 MU interferon-alpha in combination with ribavirin and amantadine: a two-arm randomized pilot study

    NARCIS (Netherlands)

    Weegink, C. J.; Sentjens, R. E.; Beld, M. G.; Dijkgraaf, M. G. W.; Reesink, H. W.

    2003-01-01

    Thirty-seven chronic hepatitis C patients with virological relapse (VR) after previous interferon-alpha (IFN) or IFN/ribavirin (Riba) therapy, were re-treated. Patients were randomized for either IFN/Riba and amantadine (Ama) including a 2-week initial high IFN induction course (18 MU IFN daily)

  13. Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Khorooshi, Reza; Mørch, Marlene Thorsen; Holm, Thomas Hellesøe

    2015-01-01

    The Type I interferons (IFN), beta (IFN-β) and the alpha family (IFN-α), act through a common receptor and have anti-inflammatory effects. IFN-β is used to treat multiple sclerosis (MS) and is effective against experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice with EAE......-endogenous Type I IFN influences EAE. Using IFN-β reporter mice, we showed that direct administration of polyinosinic-polycytidylic acid (poly I:C), a potent inducer of IFN-β, into the cerebrospinal fluid induced increased leukocyte numbers and transient upregulation of IFN-β in CD45/CD11b-positive cells located...... in the meninges and choroid plexus, as well as enhanced IFN-β expression by parenchymal microglial cells. Intrathecal injection of poly I:C to mice showing first symptoms of EAE substantially increased the normal disease-associated expression of IFN-α, IFN-β, interferon regulatory factor-7 and IL-10 in CNS...

  14. Deciphering of the Human Interferon-Regulated Proteome by Mass Spectrometry-Based Quantitative Analysis Reveals Extent and Dynamics of Protein Induction and Repression.

    Science.gov (United States)

    Megger, Dominik A; Philipp, Jos; Le-Trilling, Vu Thuy Khanh; Sitek, Barbara; Trilling, Mirko

    2017-01-01

    Interferons (IFNs) are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative, and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the gene expression profile of cells. Due to characteristics such as rapid gene induction and signaling, IFNs also represent prototypical model systems for various aspects of biomedical research (e.g., signal transduction). In regard to the signaling and activated promoters, IFNs can be subdivided into two groups. Here, alterations of the cellular proteome of human cells treated with IFNα and IFNγ were elucidated in a time-resolved manner by quantitative proteome analysis. The majority of protein regulations were strongly IFN type and time dependent. In addition to the expected upregulation of IFN-responsive proteins, an astonishing number of proteins became profoundly repressed especially by IFNγ. Thus, our comprehensive analysis revealed important insights into the human IFN-regulated proteome and its dynamics of protein induction and repression. Interestingly, the new class of IFN-repressed genes comprises known host factors for highly relevant pathogens such as HIV, dengue virus, and hepatitis C virus.

  15. Deciphering of the Human Interferon-Regulated Proteome by Mass Spectrometry-Based Quantitative Analysis Reveals Extent and Dynamics of Protein Induction and Repression

    Directory of Open Access Journals (Sweden)

    Dominik A. Megger

    2017-09-01

    Full Text Available Interferons (IFNs are pleotropic cytokines secreted upon encounter of pathogens and tumors. Applying their antipathogenic, antiproliferative, and immune stimulatory capacities, recombinant IFNs are frequently prescribed as drugs to treat different diseases. IFNs act by changing the gene expression profile of cells. Due to characteristics such as rapid gene induction and signaling, IFNs also represent prototypical model systems for various aspects of biomedical research (e.g., signal transduction. In regard to the signaling and activated promoters, IFNs can be subdivided into two groups. Here, alterations of the cellular proteome of human cells treated with IFNα and IFNγ were elucidated in a time-resolved manner by quantitative proteome analysis. The majority of protein regulations were strongly IFN type and time dependent. In addition to the expected upregulation of IFN-responsive proteins, an astonishing number of proteins became profoundly repressed especially by IFNγ. Thus, our comprehensive analysis revealed important insights into the human IFN-regulated proteome and its dynamics of protein induction and repression. Interestingly, the new class of IFN-repressed genes comprises known host factors for highly relevant pathogens such as HIV, dengue virus, and hepatitis C virus.

  16. Alpha/beta interferon receptor signaling amplifies early proinflammatory cytokine production in the lung during respiratory syncytial virus infection.

    Science.gov (United States)

    Goritzka, Michelle; Durant, Lydia R; Pereira, Catherine; Salek-Ardakani, Samira; Openshaw, Peter J M; Johansson, Cecilia

    2014-06-01

    Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1(-/-)) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1(-/-) mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1(-/-) mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production. The initial response to viral infection is characterized by the production of interferons (IFNs). One group of IFNs, the type I IFNs, are produced early upon virus infection and signal through the IFN-α/β receptor (IFNAR) to induce proteins important for limiting viral replication and directing immune responses. Here we examined the importance of type I IFNs in early responses to respiratory syncytial virus (RSV). Our

  17. Change in the responsiveness of interferon-stimulated genes during early pregnancy in cows with Borna virus-1 infection.

    Science.gov (United States)

    Takino, Tadashi; Okamura, Taku; Ando, Tatsuya; Hagiwara, Katsuro

    2016-11-14

    Borna disease virus is a neurotropic pathogen and infects the central nervous system. This virus infected a variety of animal species including cows. The most of cows infected with Borna disease virus 1 (BoDV-1) exhibit subclinical infection without any neurological symptoms throughout their lifetime. We previously reported on the low conception rates in-seropositive cows. Interferon-τ (IFN-τ) plays an important role in stable fertilization, and is produced from the fetal side following embryo growth at 15-40 days of pregnancy. IFN-τ induces the expression of interferon-stimulated gene (ISG) 15 and Mx2 in peripheral blood mononuclear cells (PBMCs). To understand the embryo growth and maternal reaction during early pregnancy in cows with BoDV-1 infection, we aimed to assess the gene expression of ISG15 and Mx2 from PBMCs in BoDV-1-seropositive cows. None of the cows showed any clinical and neurological symptoms. Among the cows that conceived, the expressions of the ISG15 and Mx2 genes were greater in the BoDV-1-seropositive cows than in the BoDV-1-seronegative cows; the difference was significant between the cows that conceived and those that did not (P < 0.05). The expression of ISG15 and Mx2 genes during early pregnancy significantly increased in the BoDV-1-seropositive cows and may be important for the maintenance of stable pregnancy in BoDV-1-infected cows. In contrast, the gene expression levels of ISG15 and Mx2 did not significantly increase during early pregnancy in BoDV-1-seronegative cows. Thus, BoDV-1 infection may lead to instability in the maintenance of early pregnancy by interfering with INF-τ production.

  18. Alpha interferon inhibits early stages of the human immunodeficiency virus type 1 replication cycle.

    OpenAIRE

    Shirazi, Y; Pitha, P M

    1992-01-01

    In this study, we have analyzed the effect of human alpha interferon (IFN-alpha) on a single replication cycle of human immunodeficiency virus type 1 (HIV-1) infection in the lymphocytic cell line CEM-174, which is highly sensitive to the antiviral effects of IFN. Pretreatment of cells with 50 to 500 U of recombinant human IFN-alpha per ml resulted in a marked reduction in viral RNA and protein synthesis. The effect of IFN-alpha was dose dependent and was amplified in multiple infection cycle...

  19. Interferon-inducible protein 10 (IP-10) is associated with viremia of early HIV-1 infection in Korean patients.

    Science.gov (United States)

    Lee, SoYong; Chung, Yoon-Seok; Yoon, Cheol-Hee; Shin, YoungHyun; Kim, SeungHyun; Choi, Byeong-Sun; Kim, Sung Soon

    2015-05-01

    Cytokines/chemokines play key roles in modulating disease progression in human immunodeficiency virus (HIV) infection. Although it is known that early HIV-1 infection is associated with increased production of proinflammatory cytokines, the relationship between cytokine levels and HIV-1 pathogenesis is not clear. The concentrations of 18 cytokines/chemokines in 30 HIV-1 negative and 208 HIV-1 positive plasma samples from Korean patients were measured by the Luminex system. Early HIV-1 infection was classified according to the Fiebig stage (FS) based on the characteristics of the patients infected with HIV-1. Concentrations of interleukin-12 (IL-12), interferon-inducible protein-10 (IP-10), macrophage inflammatory protein-1α (MIP-1α) and regulated upon activation, normal T cells expressed and secreted (RANTES) were increased significantly during the early stage of HIV-1 infection (FS II-IV) compared with the HIV-1-negative group. Of these cytokines, an elevated level of IP-10 was the only factor to be correlated positively with a higher viral load during the early stages of HIV-1 infection (FS II-IV) in Koreans (R = 0.52, P IP-10 may be an indicator for HIV-1 viremia and associated closely with viral replication in patients with early HIV-1 infection. © 2015 Wiley Periodicals, Inc.

  20. Review of interferon beta-1b in the treatment of early and relapsing multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Damiano Paolicelli

    2009-07-01

    Full Text Available Damiano Paolicelli, Vita Direnzo, Maria TrojanoDepartment of Neurological and Psychiatric Sciences, University of Bari, Bari, ItalyAbstract: Multiple sclerosis (MS is the most common autoimmune illness of the central nervous system. For many years the inflammatory manifestations of MS were treated using only corticosteroids. Since the 1990s the results of several clinical trials with immunomodulatory agents have changed the therapeutic approach to this disease. Interferon beta (IFNβ-1b represents the pioneer of those therapies. There is growing evidence from clinical trials on relapsing-remitting MS and clinically isolated syndromes suggestive of MS that IFNβ-1b reduces the frequency and severity of relapses and the development of new and active brain lesions as assessed by magnetic resonance imaging. Long-term data suggest a persistent efficacy of IFNβ-1b on disease activity and a positive effect in slowing disability worsening. Furthermore a reduction of relapse rate and a slight positive effect on the progression were demonstrated when IFNβ-1b was administered to still-active secondary progressive MS. IFNβ-1b therapy is well tolerated and relatively free of long-term side effects. In spite of the emergence of new agents for the treatment of MS, IFNβ-1b still remains a first-line therapy with a fundamental role in all stages of the disease.Keywords: interferon beta-1b, relapsing-remitting multiple sclerosis, clinically isolated syndromes, efficacy, safety, neutralizing antibodies

  1. Induction of miR-155 after Brain Injury Promotes Type 1 Interferon and has a Neuroprotective Effect

    Directory of Open Access Journals (Sweden)

    Emily B. Harrison

    2017-07-01

    Full Text Available Traumatic brain injury (TBI produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH. Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization with DAPI in MAP2 positive neurons. In miR-155 knock out (KO mice expression of type I interferons IFNα and IFNβ, as well as IFN regulatory factor 1 and IFN-induced chemokine CXCL10 was decreased after TBI relative to wild type (WT mice. Unexpectedly, miR-155 KO mice had increased levels of microglial marker Iba1 and increased neuronal degeneration as measured by fluoro-jade C (FJC staining, suggesting a neuroprotective role for miR-155 in the context of TBI. This work demonstrates a role for miR-155 in regulation of the IFN response and neurodegeneration in the aftermath of TBI. While the presence of neuronal nuclear miRNAs has been described previously, their importance in disease states is relatively unknown. Here, we show evidence of dynamic regulation and pathological function of a nuclear miRNA in TBI.

  2. Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human lens epithelial cells: apoptosis through the formation of 3-hydroxykynurenine.

    Science.gov (United States)

    Mailankot, Maneesh; Nagaraj, Ram H

    2010-09-01

    Interferon-gamma (IFN-gamma) is known to cause apoptosis of lens epithelial cells and cataract formation, but the molecular mechanisms underlying these effects are unknown. IFN-gamma induces the expression of indoleamine 2,3-dioxygenase (IDO) and thereby enhances the production of kynurenines from l-tryptophan. The present study was designed to investigate the role of IDO and kynurenines in the IFN-gamma-mediated apoptosis of lens epithelial cells and to determine the signaling pathways involved. IFN-gamma stimulated the synthesis of IDO and activated the JAK-STAT1 signaling pathway in human lens epithelial cells (HLE-B3) in a dose-dependent manner. Meanwhile, fludarabine, an inhibitor of STAT1 activation, blocked IFN-gamma-mediated IDO expression. N-Formylkynurenine, kynurenine (Kyn) and 3-hydroxykynurenine (3OHKyn) were detected in cells, with 3OHKyn concentrations being higher than those of the other kynurenines. The intracellular production of kynurenines was completely blocked by 1-methyl-DL-tryptophan (MT), an inhibitor of IDO. Kyn- and 3OHKyn-modified proteins were detected in IFN-gamma-treated cells. The induction of IDO by IFN-gamma in HLE-B3 cells caused increases in intracellular ROS, cytosolic cytochrome c and caspase-3 activity, along with a decrease in protein-free thiol content. These changes were accompanied by apoptosis. At equimolar concentrations, 3OHKyn caused higher levels of apoptosis than the other kynurenines in HLE-B3 cells. MT and a kynurenine 3-hydroxylase inhibitor (Ro61-8048) effectively inhibited IFN-gamma-mediated apoptosis in HLE-B3 cells. Our results show that the induction of IDO by IFN-gamma is JAK-STAT1 pathway-dependent and that this induction causes 3OHKyn-mediated apoptosis in HLE-B3 cells. These data suggest that IDO-mediated kynurenine formation could play a role in cataract formation related to chronic inflammation. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  3. Modulation of the early immune response against viruses by a teleostean interferon regulatory factor-1 (IRF-1).

    Science.gov (United States)

    Caipang, Christopher Marlowe A; Hirono, Ikuo; Aoki, Takashi

    2009-03-01

    We investigated the role of a teleostean interferon regulatory factor-1 (IRF-1) in the regulation of the fish immune system using Japanese flounder, Paralichthys olivaceus, as a model. Fish were intramuscularly vaccinated with a recombinant plasmid expressing the Japanese flounder IRF-1 (JF IRF-1) under the control of the cytomegalovirus immediate/early enhancer (CMV) promoter and were sampled at different days post-immunization. Peripheral blood leukocytes (PBLs) obtained from the JF IRF-1-vaccinated fish during the early stages post-vaccination had significantly elevated levels of nitric oxide (NO) and higher acid phosphatase (AP) activity compared with the control groups. Moreover, supernatants of PBLs obtained from the IRF-1-vaccinated fish contained cytokine-like substances as shown by their protective effect against hirame rhabdovirus (HIRRV) and viral hemorrhagic septicemia virus (VHSV) in two cell lines, hirame natural embryo (HINAE) cell line and epithelial papillosum of cyprini (EPC) cell line. Relative expression of an anti-viral gene, Mx was highest at the 7th day post-vaccination. Co-injection of JF IRF-1 with a DNA vaccine encoding the major capsid protein (MCP) gene of red seabream iridovirus (RSIV) resulted in elevated serum neutralization antibodies but was not significantly different from that in the fish vaccinated with the DNA vaccine alone. These results suggest that the JF IRF-1 modulates the early immune response in fish and is a potential candidate as genetic adjuvant for vaccination.

  4. Induction

    DEFF Research Database (Denmark)

    Sprogøe, Jonas; Elkjaer, Bente

    2010-01-01

    The purpose of this paper is to explore how induction of newcomers can be understood as both organizational renewal and the maintenance of status quo, and to develop ways of describing this in terms of learning.......The purpose of this paper is to explore how induction of newcomers can be understood as both organizational renewal and the maintenance of status quo, and to develop ways of describing this in terms of learning....

  5. Induction pegylated interferon alfa-2a and high dose ribavirin do not increase SVR in heavy patients with HCV genotype 1 and high viral loads.

    Science.gov (United States)

    Reddy, K Rajender; Shiffman, Mitchell L; Rodriguez-Torres, Maribel; Cheinquer, Hugo; Abdurakhmanov, Djamal; Bakulin, Igor; Morozov, Viacheslav; Silva, Giovanni Faria; Geyvandova, Natalia; Stanciu, Carol; Rabbia, Michael; McKenna, Michael; Thommes, James A; Harrison, Stephen A

    2010-12-01

    Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin. This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL. Patients were randomized to 180 μg/wk peginterferon alfa-2a for 48 weeks plus 1200 mg/day ribavirin (standard of care) (group A, n = 191) or 1400/1600 mg/day ribavirin (group B, n = 189). Additional groups included 360 μg/wk peginterferon alfa-2a for 12 weeks then 180 μg/wk peginterferon alfa-2a for 36 weeks plus 1200 mg/day ribavirin (group C, n = 382) or 1400/1600 mg/day ribavirin (group D, n = 383). Follow-up lasted 24 weeks after treatment. Sustained virologic response rates (HCV RNA level alfa-2a regimens (A + B vs C + D: odds ratio [OR], 1.08; 95% confidence interval [CI], 0.83-1.39; P = .584) or pooled ribavirin regimens (A + C vs B + D: OR, 1.00; 95% CI, 0.79-1.28; P = .974). In patients infected with HCV genotype 1 who are difficult to treat (high viral load, body weight ≥85 kg), a 12-week induction regimen of peginterferon alfa-2a and/or higher-dose ribavirin is not more effective than the standard regimen. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  6. Plasma interferon-gamma-inducible protein-10 levels are associated with early, but not sustained virological response during treatment of acute or early chronic HCV infection.

    Directory of Open Access Journals (Sweden)

    Jordan J Feld

    Full Text Available BACKGROUND: High plasma levels of interferon-gamma inducible protein-10 (IP-10 have been shown to be associated with impaired treatment response in chronic hepatitis C virus (HCV infection. Whether IP-10 levels predict treatment in acute HCV infection is unknown. METHODS: Patients with acute or early chronic HCV infection from the Australian Trial in Acute Hepatitis C (ATAHC cohort were evaluated. Baseline and on-treatment plasma IP-10 levels were measured by ELISA. IL28B genotype was determined by sequencing. RESULTS: Overall, 74 HCV mono-infected and 35 HIV/HCV co-infected patients were treated in ATAHC, of whom 89 were adherent to therapy and were included for analysis. IP-10 levels correlated with HCV RNA levels at baseline (r = 0.48, P600 pg/mL achieved RVR. There was no association with IP-10 levels and early virological response (EVR or sustained virological response (SVR. CONCLUSIONS: Baseline IP-10 levels are associated with early viral kinetics but not ultimate treatment outcome in acute HCV infection. Given previous data showing that patients with high baseline IP-10 are unlikely to spontaneously clear acute HCV infection, they should be prioritized for early antiviral therapy.

  7. Identification and Characterization of Stimulator of Interferon Genes As a Robust Adjuvant Target for Early Life Immunization

    Directory of Open Access Journals (Sweden)

    Francesco Borriello

    2017-12-01

    Full Text Available Immunization is key to preventing infectious diseases, a leading cause of death early in life. However, due to age-specific immunity, vaccines often demonstrate reduced efficacy in newborns and young infants as compared to adults. Here, we combined in vitro and in vivo approaches to identify adjuvant candidates for early life immunization. We employed newborn and adult bone marrow-derived dendritic cells (BMDCs to perform a screening of pattern recognition receptor agonists and found that the stimulator of interferon genes ligand 2′3′-cGAMP (hereafter cGAMP induces a comparable expression of surface maturation markers in newborn and adult BMDCs. Then, we utilized the trivalent recombinant hemagglutinin (rHA influenza vaccine, Flublok, as a model antigen to investigate the role of cGAMP in adult and early life immunization. cGAMP adjuvantation alone could increase rHA-specific antibody titers in adult but not newborn mice. Remarkably, as compared to alum or cGAMP alone, immunization with cGAMP formulated with alum (Alhydrogel enhanced newborn rHA-specific IgG2a/c titers ~400-fold, an antibody subclass associated with the development of IFNγ-driven type 1 immunity in vivo and endowed with higher effector functions, by 42 days of life. Highlighting the amenability for successful vaccine formulation and delivery, we next confirmed that cGAMP adsorbs onto alum in vitro. Accordingly, immunization early in life with (cGAMP+alum promoted IFNγ production by CD4+ T cells and increased the proportions and absolute numbers of CD4+ CXCR5+ PD-1+ T follicular helper and germinal center (GC GL-7+ CD138+ B cells, suggesting an enhancement of the GC reaction. Adjuvantation effects were apparently specific for IgG2a/c isotype switching without effect on antibody affinity maturation, as there was no effect on rHA-specific IgG avidity. Overall, our studies suggest that cGAMP when formulated with alum may represent an effective adjuvantation system to foster

  8. Early amniotomy after vaginal misoprostol for induction of labor: a randomized clinical trial.

    Science.gov (United States)

    Makarem, Mohamed H; Zahran, Kamal M; Abdellah, Mohamad S; Karen, Mohamed A

    2013-08-01

    To test the effectiveness and safety of early amniotomy after vaginal misoprostol for the induction of labor. A randomized clinical trial that included 320 women with medical or obstetric indication for labor induction. They were randomly assigned into two equal groups, amniotomy group and control group. Each participant received vaginal misoprostol 50 μg every 6 h for induction of labor. In amniotomy group, amniotomy was done in the early active phase of labor while in the control group, the membranes were left to rupture spontaneously or as judged by the senior resident in the duty. More subjects in the amniotomy group achieved vaginal delivery within 24 h than in the control group [117 (73.13 %) vs. 105 (65.63 %)]. Subjects in the amniotomy group reported shorter induction to delivery interval (09.72 ± 4.61 h vs. 13.61 ± 5.61, P = .002), and better neonatal outcome compared to the control group. There were no statistically significant differences between both group with regard to number of doses of misoprostol, need for oxytocin, Cesarean Section indication and maternal side effects. Early amniotomy after vaginal misoprostol for labor induction is associated with higher successful vaginal delivery rate, shorter labor duration and better neonatal outcome.

  9. Pattern formation in a pentameral animal: induction of early adult rudiment development in sea urchins.

    Science.gov (United States)

    Minsuk, Sharon B; Raff, Rudolf A

    2002-07-15

    We investigated adult rudiment induction in the direct-developing sea urchin Heliocidaris erythrogramma microsurgically. After removal of the archenteron (which includes presumptive coelomic mesoderm as well as presumptive endoderm) from late gastrulae, larval ectoderm develops properly but obvious rudiments (tube feet, nervous system, and adult skeleton) fail to form, indicating that coelomic mesoderm, endoderm, or both are required for induction of adult development. Recombination of ectoderm and archenteron rescues development. Implanted endoderm alone or left coelom alone each regenerate the full complement of archenteron derivatives; thus, they are uninformative as to the relative inductive potential of the two regions. However, in isolated ectoderm, more limited regeneration gives rise to larvae containing no archenteron derivatives at all, endoderm only, or both endoderm and left coelom. Adult nervous system begins to develop only in the latter, indicating that left coelom is required for the inductive signal. Isolated ectoderm develops a vestibule (the precursor of adult ectoderm) and correctly regulates vestibular expression of the ectodermal territory marker HeET-1, indicating that the early phase of vestibule development occurs autonomously; only later development requires the inductive signal. Another ectodermal marker, HeARS, is regulated properly in the larval ectoderm region, but not in the vestibule. HeARS regulation thus represents an early response to the inducing signal. We compare HeARS expression in H. erythrogramma with that in indirect developers and discuss its implications for modularity in the evolution of developmental mode. 2002 Elsevier Science (USA).

  10. Production of Interferon α by Human Immunodeficiency Virus Type 1 in Human Plasmacytoid Dendritic Cells Is Dependent on Induction of Autophagy

    OpenAIRE

    Zhou, Dejiang; Kang, Kyung Hee; Spector, Stephen A.

    2012-01-01

    Background. The mechanisms responsible for interferon α (IFN-α) production by plasmacytoid dendritic cells (pDCs) during human immunodeficiency virus type 1 (HIV-1) infection are unknown. This research examined the roles of Toll-like receptor 7 (TLR7) and autophagy in IFN-α production by pDCs during HIV-1 infection.

  11. Early induction of labor in high-risk intrahepatic cholestasis of pregnancy: what are the costs?

    Science.gov (United States)

    Friberg, Anne Katrine; Zingmark, Vera; Lyndrup, Jens

    2016-10-01

    Induction of labor among pregnant women with high levels of total bile acid (TBA) is common among clinicians. We examined, if women with intrahepatic cholestasis of pregnancy (ICP) and TBA ≥ 40 μmol/l have a higher risk of maternal-fetal complications, when labor is induced at 37 weeks of gestation, compared with induction of labor at term in women with low-risk ICP. Retrospective cohort study of 16,185 women delivering at Roskilde University Hospital in the period 2006-2011. Women with high-risk ICP (TBA ≥ 40 μmol/l) had labor induced at 37 weeks of gestation; women with low-risk ICP (TBA high-risk ICP 0.4 % (95 % CI 0.27-0.46 %). No difference was found in mode of delivery, length of induction of labor nor in neonatal outcomes, except for an expected difference in birthweight. In high-risk ICP, ALT was not raised in 10.3 % (95 % CI 2.5-18.2 %). Early induction of labor at 37 weeks of gestation seems justified in high-risk ICP, as, except for abbreviating gestational age by 9 days with 296 g smaller babies, induction of labor was not followed by detectable maternal-fetal disadvantages and is favored by an expected major reduction in ICP stillbirth risk.

  12. Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis.

    Science.gov (United States)

    Laperchia, Claudia; Tesoriero, Chiara; Seke-Etet, Paul F; La Verde, Valentina; Colavito, Valeria; Grassi-Zucconi, Gigliola; Rodgers, Jean; Montague, Paul; Kennedy, Peter G E; Bentivoglio, Marina

    2017-08-01

    Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease. The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness. The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis.

  13. Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.

    Science.gov (United States)

    Freeman, J; Baglino, S; Friborg, J; Kraft, Z; Gray, T; Hill, M; McPhee, F; Hillson, J; Lopez-Talavera, J C; Wind-Rotolo, M

    2014-06-01

    Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa. © 2014 John Wiley & Sons Ltd.

  14. Early versus late amniotomy for labour induction: a randomized controlled trial.

    Science.gov (United States)

    Gagnon-Gervais, Karine; Bujold, Emmanuel; Iglesias, Marie-Hélène; Duperron, Louise; Masse, André; Mayrand, Marie-Hélène; Sansregret, Andrée; Fraser, William; Audibert, François

    2012-11-01

    To evaluate the impact of early vs. late amniotomy on delivery mode in women undergoing induction of labor. 143 women admitted for induction were randomized to early amniotomy (EA, concomitant with the beginning of oxytocin infusion; n = 71) or to late amniotomy (LA, four hours after the beginning of oxytocin; n = 72). Randomization was stratified by parity. The primary outcome was the rate of cesarean. Secondary outcomes were duration of labor and intrapartum fever. The cesarean rate was similar between groups (18% vs. 17% among nulliparous; and 3% vs. 0% among parous women, in EA and LA group, respectively). However, EA was associated with shorter oxytocin-to-delivery interval (12 vs. 15 h) and a non-significant decrease in intrapartum fever (3% vs. 25%) than LA in nulliparous women (p = 0.05). For women undergoing oxytocin induction, early amniotomy is associated with shorter labor in nulliparous women with no effect on the risk of cesarean section in both nulliparous and multiparous women.

  15. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

    DEFF Research Database (Denmark)

    Kappos, Ludwig; Freedman, Mark S; Polman, Chris H

    2009-01-01

    with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. METHODS: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon...... beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after....... No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. INTERPRETATION: Effects on the rate of conversion to CDMS and the favourable long-term safety...

  16. Tuber induction and initiation during production and early field growth of transplants from in vitro-derived potato plants

    NARCIS (Netherlands)

    Lommen, W.J.M.; Struik, P.C.

    2006-01-01

    In transplants from in vitro-derived plantlets from very early potato (Solanum tuberosum) cultivars, a lower degree of tuber induction at the time of field planting is thought to increase tuber production. Leaf-bud cuttings were used to assess the progress to tuber induction in in vitro-derived

  17. Daily interferon induction regimen using different manufactured interferons (alpha-2a or alpha-2b in combination with ribavirin for treatment of chronic hepatitis C: a prospective randomized study Esquema de indução diário com interferon alfa 2-a ou alfa 2-b em combinação com ribavirina para tratamento da hepatite crônica C: estudo prospectivo randomizado

    Directory of Open Access Journals (Sweden)

    Eduardo Lorens Braga

    2006-12-01

    Full Text Available BACKGROUD: Studies on hepatitis C virus kinetics showed that serum levels of interferon fall 48 h after drug administration, when viral load is increasing again. Previously to the availability of pegylated interferon, daily induction therapy with standard interferon was under evaluation. AIMS: To evaluate the safety and efficacy of interferon alpha daily induction regimen in combination with ribavirin. PATIENTS AND METHODS: A randomized trial including 93 patients with chronic hepatitis C was carried out. On satisfying all eligibility criteria, patients were randomly allocated to two different treatment groups: 44 individuals in treatment arm A: IFN 3 MU thrice weekly + ribavirin 1.0-1.2 g daily for 48 weeks (IFN TIW and 49 individuals in treatment arm B: IFN 3 MU daily + ribavirin 1.0-1.2 g daily for 12 weeks followed by IFN 3 MU thrice weekly + ribavirin 1.0-1.2 g daily, until completion of 48 weeks of therapy (IFN QD. HCV genotyping was obtained in 85 subjects. A negative HCV-RNA 6 months after cessation of therapy was considered a sustained virological response RESULTS: Eighty three patients completed treatment, five dropped out (one from IFN TIW and four from IFN QD and in five patients therapy was discontinued due to medical request (two from IFN TIW and three from IFN QD. There was no statistically significant difference between groups with respect to therapy interruption. The frequency of cirrhosis was 29%, similar in both groups. In the "intention to treat" analysis the overall sustained virological response was 39.8%. There was no significant difference in sustained virological response rate between both treatment strategies (36.4% IFN TIW vs 42.9% IFN QD. In the 83 patients who finished the trial, sustained virological response was 44.6%. Among subjects with HCV genotype-1, the sustained virological response was 42% (40.9% IFN TIW vs 42.9% IFN QD and among patients with HCV genotype 2 or 3, the sustained virological response was 55

  18. A floral induction system for the study of early Arabidopsis flower development.

    Science.gov (United States)

    O'Maoiléidigh, Diarmuid Seosamh; Wellmer, Frank

    2014-01-01

    Assessing the molecular changes that occur over the course of flower development is hampered by difficulties in isolating sufficient amounts of floral tissue at specific developmental stages. This is especially problematic when investigating molecular events at very early stages of Arabidopsis flower development, as the floral buds are minute and are initiated sequentially such that a single flower on an inflorescence is at a given developmental stage. Moreover, young floral buds are hidden by older buds, which present an additional challenge for dissection. To circumvent these issues, a floral induction system that allows the simultaneous induction of a large number of flowers on the inflorescence of a single plant was generated. To allow the plant community to avail of the full benefits of this system, we address some common problems that can be encountered when growing these plants and collecting floral buds for analysis.

  19. The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes.

    Science.gov (United States)

    de Jong, Tamarah D; Lübbers, Joyce; Turk, Samina; Vosslamber, Saskia; Mantel, Elise; Bontkes, Hetty J; van der Laken, Conny J; Bijlsma, Johannes W; van Schaardenburg, Dirkjan; Verweij, Cornelis L

    2016-07-13

    The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature's functional consequences. The aim of this study was to investigate the contribution of peripheral leukocyte subsets to the IFN signature in early arthritis. Blood was collected from 26 patients with early arthritis and lysed directly or separated into peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs). PBMCs were sorted into CD4(+) T cells, CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes by flow cytometry. Messenger RNA expression of three interferon response genes (IRGs RSAD2, IFI44L, and MX1) and type I interferon receptors (IFNAR1 and IFNAR2) was determined in whole blood and blood cell subsets by quantitative polymerase chain reaction. IRG expression was averaged to calculate an IFN score for each sample. Patients were designated "IFN(high)" (n = 8) or "IFN(low)" (n = 18) on the basis of an IFN score cutoff in whole peripheral blood from healthy control subjects. The difference in IFN score between IFN(high) and IFN(low) patients was remarkably large for the PMN fraction (mean 25-fold) compared with the other subsets (mean 6- to 9-fold), indicating that PMNs are the main inducers of IRGs. Moreover, the relative contribution of the PMN fraction to the whole-blood IFN score was threefold higher than expected from its abundance in blood (p = 0.008), whereas it was three- to sixfold lower for the other subsets (p ≤ 0.063), implying that the PMNs are most sensitive to IFN signaling. Concordantly, IFNAR1 and IFNAR2 were upregulated compared with healthy controls selectively in patient PMNs (p ≤ 0.0077) but not in PBMCs. PMNs are the main contributors to the whole-blood type I IFN signature in patients with early arthritis, which seems due to

  20. Induction of natural killer cell activity of thoracic duct lymphocytes by polyinosinic-polycytidylic acid (poly(I:C)) or interferon.

    Science.gov (United States)

    Fresa, K L; Korngold, R; Murasko, D M

    1985-04-01

    Natural killer (NK) cell activity of thoracic duct lymphocytes (TDL) was examined in normal mice and in mice treated with polyinosinic-polycytidylic acid (poly(I:C) and interferon (IFN). TDL from mice treated with phosphate-buffered saline (PBS) expressed little or no NK cell activity against YAC-1 target cells at effector-to-target ratios of up to 200:1, even after in vitro treatment with murine L-cell IFN. In contrast, TDL from poly(I:C)- or IFN-treated mice expressed significant NK activity, which correlated with the significantly higher NK activity of splenocytes from these mice compared to the NK activity of splenocytes from PBS-treated mice. These data indicate that although TDL from normal mice express no detectable NK cell activity, NK cell activity can be induced in TDL by in vivo treatment with poly(I:C) or IFN.

  1. Induction of GADD34 is necessary for dsRNA-dependent interferon-β production and participates in the control of Chikungunya virus infection.

    Directory of Open Access Journals (Sweden)

    Giovanna Clavarino

    Full Text Available Nucleic acid sensing by cells is a key feature of antiviral responses, which generally result in type-I Interferon production and tissue protection. However, detection of double-stranded RNAs in virus-infected cells promotes two concomitant and apparently conflicting events. The dsRNA-dependent protein kinase (PKR phosphorylates translation initiation factor 2-alpha (eIF2α and inhibits protein synthesis, whereas cytosolic DExD/H box RNA helicases induce expression of type I-IFN and other cytokines. We demonstrate that the phosphatase-1 cofactor, growth arrest and DNA damage-inducible protein 34 (GADD34/Ppp1r15a, an important component of the unfolded protein response (UPR, is absolutely required for type I-IFN and IL-6 production by mouse embryonic fibroblasts (MEFs in response to dsRNA. GADD34 expression in MEFs is dependent on PKR activation, linking cytosolic microbial sensing with the ATF4 branch of the UPR. The importance of this link for anti-viral immunity is underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection.

  2. Induction of cell-mediated immunity during early stages of infection with intracellular protozoa

    Directory of Open Access Journals (Sweden)

    Gazzinelli R.T.

    1998-01-01

    Full Text Available Toxoplasma gondii and Trypanosoma cruzi are intracellular parasites which, as part of their life cycle, induce a potent cell-mediated immunity (CMI maintained by Th1 lymphocytes and IFN-g. In both cases, induction of a strong CMI is thought to protect the host against rapid parasite multiplication and consequent pathology and lethality during the acute phase of infection. However, the parasitic infection is not eliminated by the immune system and the vertebrate host serves as a parasite reservoir. In contrast, Leishmania sp, which is a slow growing parasite, appears to evade induction of CMI during early stages of infection as a strategy for surviving in a hostile environment (i.e., inside the macrophages which are their obligatory niche in the vertebrate host. Recent reports show that the initiation of IL-12 synthesis by macrophages during these parasitic infections is a key event in regulating CMI and disease outcome. The studies reviewed here indicate that activation/inhibition of distinct signaling pathways and certain macrophage functions by intracellular protozoa are important events in inducing/modulating the immune response of their vertebrate hosts, allowing parasite and host survival and therefore maintaining parasite life cycles.

  3. Predictors of Early Discontinuation of Pegylated Interferon for Reasons Other Than Lack of Efficacy in United States Veterans With Chronic Hepatitis C.

    Science.gov (United States)

    LaFleur, Joanne; Hoop, Robert; Korner, Eli; DuVall, Scott; Morgan, Timothy; Pandya, Prashant; Han, Jian; Knippenberg, Kristin; Nelson, Richard E

    2015-01-01

    During the dual-therapy era, many patients with chronic hepatitis C discontinued therapy for reasons other than lack of efficacy (non-LOE). We determined whether selected patient characteristics predicted non-LOE discontinuation using national databases of U.S. veterans with Genotypes 1-4. We identified U.S. veterans in the Veterans Health Administration system in 2004-2009 who had hepatitis C-confirming RNA laboratory results and initiated therapy with pegylated interferon and ribavirin. We used a rule to classify patients who discontinued pegylated interferon early, based on pharmacy refill and viral response data. Multivariate Cox regression was used to identify predictors of non-LOE discontinuation. Of 321,238 patients with a hepatitis C International Classification of Diseases, Ninth Revision, code, 15,297 (4.8%) met all inclusion criteria. Non-LOE discontinuers comprised 30.3% of patients. For Genotypes 1-4, the predictors (adjusted hazard ratio) of greatest magnitude were comorbidities of myocardial infarction/congestive heart failure (1.36), renal disease (1.34), and platelets 100/mm or more (1.38). For Genotypes 2 and 3, predictors of greatest magnitude were Black race (1.30), myocardial infarction/congestive heart failure (1.84), albumin 3.5 mg/dl or more (1.65), sleep aid use (1.32), and poor persistence with antidepressants (1.31) and antihypertensive agents (1.37). Our study suggests that many host factors may have contributed to non-LOE dual-therapy discontinuation in veterans and may possibly predict non-LOE discontinuation in triple therapy.

  4. Eldelumab [anti-interferon-γ-inducible protein-10 antibody] Induction Therapy for Active Crohn's Disease: a Randomised, Double-blind, Placebo-controlled Phase IIa Study.

    Science.gov (United States)

    Sandborn, William J; Rutgeerts, Paul; Colombel, Jean-Frédéric; Ghosh, Subrata; Petryka, Robert; Sands, Bruce E; Mitra, Pranab; Luo, Allison

    2017-07-01

    This 11-week Phase IIa induction study evaluated the efficacy and safety of eldelumab in patients with active Crohn's disease. Adults with Crohn's Disease Activity Index 220-450 were randomised 1:1:1 to placebo or eldelumab 10 or 20 mg/kg intravenously on Days 1 and 8, and alternate weeks thereafter. All patients underwent ileocolonoscopy at baseline. Patients with active inflammation according to the Simplified Endoscopic Score for Crohn's Disease criteria [the originally planned endoscopy cohort] underwent another ileocolonoscopy at Week 11 at the investigator's discretion. All ileocolonoscopies were centrally read. The primary objective was identification of the eldelumab target exposure for induction of remission [absolute Crohn's Disease Activity Index score Crohn's Disease Activity Index], remission, and endoscopic improvements were also assessed. A total of 121 patients were randomised. The eldelumab exposure-remission relationship was not significant at Week 11. Numerically higher remission and response rates were reported with eldelumab 20 mg/kg [29.3% and 41.5%, respectively] and 10 mg/kg [22.5% and 47.5%] versus placebo [20.0% and 35.0%]. A higher proportion of patients with a baseline Simplified Endoscopic Score for Crohn's Disease > 2 who received eldelumab achieved a 50% improvement in score and greater reductions from baseline endoscopy scores overall versus placebo. Adverse events were comparable across treatment groups. No exposure-remission relationship was seen with eldelumab. Eldelumab induction treatment demonstrated trends towards clinical and endoscopic efficacy. Safety was consistent with that reported previously. ClinicalTrials.gov identifier: NCT01466374.

  5. Interferon Gamma in Leishmaniasis

    Science.gov (United States)

    Kima, Peter E.; Soong, Lynn

    2013-01-01

    Leishmaniasis is a complex disease that is caused by parasites of the Leishmania genus. Leishmania are further classified into several complexes, each of which can engage in distinct interactions with mammalian hosts resulting in differing disease presentations. It is therefore not unexpected that host immune responses to Leishmania are variable. The induction of interferon gamma (IFN-γ) and response to it in these infections has received considerable attention. In this review, we summarize our current understanding of some of the host responses during Leishmania infections that are regulated by IFN-γ. In addition, studies that explore the nature of parasite-derived molecular mediators that might affect the host response to IFN-γ are also discussed. PMID:23801993

  6. Morphology and Quantitative Monitoring of Gene Expression Patterns during Floral Induction and Early Flower Development in Dendrocalamus latiflorus

    OpenAIRE

    Wang, Xiaoyan; Zhang, Xuemei; Zhao, Lei; Guo, Zhenhua

    2014-01-01

    The mechanism of floral transition in bamboo remains unclear. Dendrocalamus latiflorus (Bambusease, Bambusoideae, Poaceae) is an economically and ecologically important clumping bamboo in tropical and subtropical areas. We evaluated morphological characteristics and gene expression profiling to study floral induction and early flower development in D. latiflorus. The detailed morphological studies on vegetative buds and floral organography were completed using paraffin sectioning and scanning...

  7. Functional limitations of plasmacytoid dendritic cells limit type I interferon, T cell responses and virus control in early life.

    Directory of Open Access Journals (Sweden)

    Elodie Belnoue

    Full Text Available Infant mortality from viral infection remains a major global health concern: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. Similarly, the WE strain of lymphocytic choriomeningitis virus (LCMV-WE causes acute self-limiting infection in adult mice but follows a protracted course in infant animals, in which LCMV-specific CD8⁺ T cells fail to expand and control infection. By disrupting type I IFNs signaling in adult mice or providing IFN-α supplementation to infant mice, we show here that the impaired early life T cell responses and viral control result from limited early type I IFN responses. We postulated that plasmacytoid dendritic cells (pDC, which have been identified as one major source of immediate-early IFN-I, may not exert adult-like function in vivo in the early life microenvironment. We tested this hypothesis by studying pDC functions in vivo during LCMV infection and identified a coordinated downregulation of infant pDC maturation, activation and function: despite an adult-like in vitro activation capacity of infant pDCs, the expression of the E2-2 pDC master regulator (and of critical downstream antiviral genes such as MyD88, TLR7/TLR9, NF-κB, IRF7 and IRF8 is downregulated in vivo at baseline and during LCMV infection. A similar pattern was observed in response to ssRNA polyU, a model ligand of the TLR7 viral sensor. This suggests that the limited T cell-mediated defense against early life viral infections is largely attributable to / regulated by infant pDC responses and provides incentives for novel strategies to supplement or stimulate immediate-early IFN-α responses.

  8. Interferon-alpha mediates restriction of human immunodeficiency virus type-1 replication in primary human macrophages at an early stage of replication.

    Directory of Open Access Journals (Sweden)

    Kelly M Cheney

    2010-10-01

    Full Text Available Type I interferons (IFNα and β are induced directly in response to viral infection, resulting in an antiviral state for the cell. In vitro studies have shown that IFNα is a potent inhibitor of viral replication; however, its role in HIV-1 infection is incompletely understood. In this study we describe the ability of IFNα to restrict HIV-1 infection in primary human macrophages in contrast to peripheral blood mononuclear cells and monocyte-derived dendritic cells. Inhibition to HIV-1 replication in cells pretreated with IFNα occurred at an early stage in the virus life cycle. Late viral events such as budding and subsequent rounds of infection were not affected by IFNα treatment. Analysis of early and late HIV-1 reverse transcripts and integrated proviral DNA confirmed an early post entry role for IFNα. First strand cDNA synthesis was slightly reduced but late and integrated products were severely depleted, suggesting that initiation or the nucleic acid intermediates of reverse transcription are targeted. The depletion of integrated provirus is disproportionally greater than that of viral cDNA synthesis suggesting the possibility of a least an additional later target. A role for either cellular protein APOBEC3G or tetherin in this IFNα mediated restriction has been excluded. Vpu, previously shown by others to rescue a viral budding restriction by tetherin, could not overcome this IFNα induced effect. Determining both the viral determinants and cellular proteins involved may lead to novel therapeutic approaches. Our results add to the understanding of HIV-1 restriction by IFNα.

  9. Trisomy 21 consistently activates the interferon response

    Science.gov (United States)

    Sullivan, Kelly D; Lewis, Hannah C; Hill, Amanda A; Pandey, Ahwan; Jackson, Leisa P; Cabral, Joseph M; Smith, Keith P; Liggett, L Alexander; Gomez, Eliana B; Galbraith, Matthew D; DeGregori, James; Espinosa, Joaquín M

    2016-01-01

    Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits. DOI: http://dx.doi.org/10.7554/eLife.16220.001 PMID:27472900

  10. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

    DEFF Research Database (Denmark)

    Kappos, Ludwig; Freedman, Mark S; Polman, Chris H

    2009-01-01

    BACKGROUND: The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment...... beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after...... randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes...

  11. Interferon-γ Inhibits Ebola Virus Infection.

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    Bethany A Rhein

    Full Text Available Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

  12. Recent advances in the anti-HCV mechanisms of interferon

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    Menghao Huang

    2014-08-01

    Full Text Available Interferon (IFN in combination with ribavirin has been the standard of care (SOC for chronic hepatitis C for the past few decades. Although the current SOC lacks the desired efficacy, and 4 new direct-acting antiviral agents have been recently approved, interferons are still likely to remain the cornerstone of therapy for some time. Moreover, as an important cytokine system of innate immunity, host interferon signaling provides a powerful antiviral response. Nevertheless, the mechanisms by which HCV infection controls interferon production, and how interferons, in turn, trigger anti-HCV activities as well as control the outcome of HCV infection remain to be clarified. In this report, we review current progress in understanding the mechanisms of IFN against HCV, and also summarize the knowledge of induction of interferon signaling by HCV infection.

  13. Early versus delayed amniotomy during labor induction with oxytocin in women with Bishop's score of ≥6: a randomized trial.

    Science.gov (United States)

    Bala, Anju; Bagga, Rashmi; Kalra, Jasvinder; Dutta, Sourabh

    2017-08-09

    To study the effect of "early amniotomy" {initiating induction of labor (IOL) with amniotomy followed by oxytocin} versus "late amniotomy" (initiating IOL with oxytocin followed by amniotomy 4-8 h later) in induced labor. One hundred and fifty women with Bishop's score of ≥6 undergoing IOL were randomized into "early amniotomy" and "delayed amniotomy". Early amniotomy resulted in a reduced induction-delivery interval (IDI) (7.35 versus 11.66 h with delayed amniotomy, p = .000) but higher the caesarean section (CS) rate was observed (10.7 versus 2.7% with delayed amniotomy, p = .049). With early amniotomy, the proportion of women delivering within 12 h was higher (86.7 versus 60%, p = .000) and the maximum oxytocin concentration used was lower (30.05 versus 39.68 mU/min, p = .001) as compared to delayed amniotomy. The neonatal outcomes were similar in the two groups. Early amniotomy detected meconium prior to initiating uterine contractions with oxytocin in three women who underwent CS for meconium. Initiating IOL with amniotomy in women with a favorable cervix was efficacious in expediting delivery, but it resulted in a higher CS rate. The higher CS rate was partly due to CS for meconium detected as a result of early amniotomy. Clinical Trials Registry (CTRI), India: Registration number CTRI/2015/01/005418.

  14. CpG Type A Induction of an Early Protective Environment in Experimental Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    James Crooks

    2017-01-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS, and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immunity is clearly pivotal in the pathogenesis of EAE, with an essential role of CD4+ T cells, little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs, typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs. In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type A ODN (CpG-A, known to induce high amounts of IFN-α in pDCs, significantly reduced disease severity in EAE, relative to controls (12.63±1.86 versus 23.49±1.46, resp.; p=0.001. Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+ CD4+ T cells. CpG-A likewise reduced the levels of IL-17 and IFN-γ in the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A-treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms.

  15. Cost-effectiveness of early initiation of fingolimod versus delayed initiation after 1 year of intramuscular interferon beta-1a in patients with multiple sclerosis.

    Science.gov (United States)

    Agashivala, Neetu; Kim, Edward

    2012-07-01

    Fingolimod is a once-daily orally administered disease-modifying therapy (DMT) indicated for treatment of relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical relapses and delay accumulation of physical disability. In the randomized, double-blind, phase 3 TRANSFORMS trial, 0.5 mg/d oral fingolimod substantially reduced relapse frequency when compared with IM interferon-β1a (IFN-β1a) at 12-months. In a 12-month, double-blind, extension phase of the TRANSFORMS study, patients assigned to receive fingolimod continued to receive the same dosage, whereas patients who originally received IM IFN-β1a were randomized to receive either 0.5 or 1.25 mg/d fingolimod. To investigate the cost-effectiveness of initiating fingolimod therapy early versus after 1 year of IFN-β1a therapy using TRANSFORMS study extension data. A Microsoft Excel-based model was used to calculate the cost per relapse avoided for 2 years with continuous treatment with fingolimod compared with first-year treatment with IM IFN-β1a and second-year treatment with fingolimod. One-way sensitivity analyses were conducted on key input variables to assess their effect on cost per relapse avoided. The 2-year relapse rate in the early fingolimod arm was 0.23, and in the delayed fingolimod arm was 0.53. The cost per relapse avoided was $83,125 in the early fingolimod arm versus $103,624 in the delayed fingolimod arm. Results of the sensitivity analyses showed an effect of drug acquisition cost and number of relapses in patients who received no treatment. Continuous treatment with fingolimod for 2 years resulted in a lower cost per relapse avoided compared with treatment with IM IFN-β1a for the first year and then switching to fingolimod therapy. Thus, delaying fingolimod therapy does not seem to be cost effective. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

  16. E2F/Rb Family Proteins Mediate Interferon Induced Repression of Adenovirus Immediate Early Transcription to Promote Persistent Viral Infection.

    Directory of Open Access Journals (Sweden)

    Yueting Zheng

    2016-01-01

    Full Text Available Interferons (IFNs are cytokines that have pleiotropic effects and play important roles in innate and adaptive immunity. IFNs have broad antiviral properties and function by different mechanisms. IFNs fail to inhibit wild-type Adenovirus (Ad replication in established cancer cell lines. In this study, we analyzed the effects of IFNs on Ad replication in normal human cells. Our data demonstrate that both IFNα and IFNγ blocked wild-type Ad5 replication in primary human bronchial epithelial cells (NHBEC and TERT-immortalized normal human diploid fibroblasts (HDF-TERT. IFNs inhibited the replication of divergent adenoviruses. The inhibition of Ad5 replication by IFNα and IFNγ is the consequence of repression of transcription of the E1A immediate early gene product. Both IFNα and IFNγ impede the association of the transactivator GABP with the E1A enhancer region during the early phase of infection. The repression of E1A expression by IFNs requires a conserved E2F binding site in the E1A enhancer, and IFNs increased the enrichment of the E2F-associated pocket proteins, Rb and p107, at the E1A enhancer in vivo. PD0332991 (Pabociclib, a specific CDK4/6 inhibitor, dephosphoryles pocket proteins to promote their interaction with E2Fs and inhibited wild-type Ad5 replication dependent on the conserved E2F binding site. Consistent with this result, expression of the small E1A oncoprotein, which abrogates E2F/pocket protein interactions, rescued Ad replication in the presence of IFNα or IFNγ. Finally, we established a persistent Ad infection model in vitro and demonstrated that IFNγ suppresses productive Ad replication in a manner dependent on the E2F binding site in the E1A enhancer. This is the first study that probes the molecular basis of persistent adenovirus infection and reveals a novel mechanism by which adenoviruses utilize IFN signaling to suppress lytic virus replication and to promote persistent infection.

  17. Predictors of vaginal delivery in medically indicated early preterm induction of labor.

    Science.gov (United States)

    Sievert, Rachel A; Kuper, Spencer G; Jauk, Victoria C; Parrish, Melissa; Biggio, Joseph R; Harper, Lorie M

    2017-09-01

    When delivery is indicated prior to 34 weeks, many providers perform a cesarean delivery rather than induce labor based on perceptions of a high failure rate. Given the morbidity of cesarean delivery, an accurate estimate of the success rate and factors associated with success in preterm induction of labor is important in management decisions. We sought to develop a prediction model for successful induction of labor in preterm patients using factors known at the time the decision is made to deliver. A retrospective cohort study of all live singletons undergoing an indicated induction of labor between 23 and 34 0/7 weeks from 2011 through 2015. Pregnancies with major fetal anomalies or no intrapartum fetal monitoring were excluded. Successful induction of labor was defined as vaginal delivery. The cohort was randomly split into a training cohort to develop a prediction model for vaginal delivery and a validation cohort to test the model. Factors significantly associated with vaginal delivery were identified using univariate analyses, and candidate factors were used in the multivariate logistic regression model. Only factors known at the start of the induction of labor were used in the model. Receiver-operating characteristic curves were created to estimate the predictive value of the model. Sensitivity and specificity of the model were assessed. Of 331 patients who underwent induction of labor, 208 (62.8%) delivered vaginally and 123 (37.1%) by cesarean delivery. Of the factors significantly associated with cesarean delivery, the final model included gestational age, simplified Bishop score, suspected intrauterine growth retardation, chronic hypertension, and body mass index. In the training cohort, the model correctly classified 72.3% of subjects with a sensitivity (cesarean delivery predicted/cesarean delivery performed) of 56.7% and a specificity (vaginal delivery predicted/vaginal delivery performed) of 84.1%. When applied to the validation cohort, 73.9% of

  18. [Alpha-interferon and mental disorders].

    Science.gov (United States)

    Debien, C; De Chouly De Lenclave, M B; Foutrein, P; Bailly, D

    2001-01-01

    The interferon alpha stands as a reference both in oncology and virology. But its efficiency is limited by frequent somatic as well as neuropsychic side effects. As a matter of fact, the reduction or the ending of a chemotherapy treatment come chiefly from the psychiatric complications caused by the use of interferon. For about 30% of patients, various psychic disorders are noticed: personality disorders, mood disorders, anxiety states, suicidal tendencies, manic and psychotic symptoms. We thus propose a review which shall be completed by a discussion on wether the interferon is responsible or not of the appearance of the described mental disorders. We shall conclude with a synthesis of the proposed practical management when confronted with such disorders. Psychiatric complications under interferon-Alpha. The appearance of psychiatric complications caused by interferon has been the subject of many publications. They have also raised the question of the toxicity mechanism which is still misunderstood today. This toxicity appears to be dose-dependent with variations depending on the daily dose given, the mode of administration, the combination with other chemotherapy treatments, the concomitance with a cerebral radiotherapy or a medical history of psychiatric disorders. Most of these effects occur after three weeks of treatment but non specific neuropsychic symptoms can be observed earlier. Non specific symptoms. They appear early but are difficult to detect, though they bring together a whole lot of clinical signs: asthenia, irritability, psychomotor slowdown, depressive mood or even a real "subsyndromic" depressive syndrome, anorexia, decline of the libido, concentration and attention problems, dizzy spells and headaches. Some authors have described intense and fluctuating of personality, mixing anxiety, irritability and disorder of drive control. Depression. Depression is the most frequently found psychiatric pathology in studies but the real frequency of clear

  19. The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes

    NARCIS (Netherlands)

    de Jong, Tamarah D.; Lübbers, Joyce; Turk, Samina; Vosslamber, Saskia; Mantel, Elise; Bontkes, Hetty J.; van der Laken, Conny J.; Bijlsma, Johannes W.; van Schaardenburg, Dirkjan; Verweij, Cornelis L.

    2016-01-01

    The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing to this IFN signature could provide insight into the signature's functional consequences. The aim of

  20. Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication

    NARCIS (Netherlands)

    Niedelman, Wendy; Sprokholt, Joris K.; Clough, Barbara; Frickel, Eva-Maria; Saeij, Jeroen P. J.

    2013-01-01

    The intracellular protozoan parasite Toxoplasma gondii is a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate

  1. English as a Foreign Language Instructors’ Induction: Early Practices of Language Teachers Teaching at Tertiary Level

    Directory of Open Access Journals (Sweden)

    Mustafa Öztürk

    2012-02-01

    Full Text Available This study aimed to investigate the nature of the induction process of English as a foreign language (EFL teachers teaching at tertiary level through individual interviews. In order to gather intended data, fifteen novice instructors teaching at four different public universities in Ankara were interviewed on a basis of two criteria: (a having 1 to 3 years of teaching experience, and (b teaching at higher education level. The data gathered from the interviews were transcribed, coded, and categorized under themes in a qualitative research tradition. Subsequently the Şndings were interpreted. The findings were organized around research questions and there appeared four main themes: (1 nature of induction process; (2 common concerns of novice teachers; (3 possible adaptation challenges; and (4 practices to overcome difŞculties. The results revealed that pre-service education, especially of the graduates of nonEducation Faculties, did not adequately respond to the needs of the novice teachers in induction period. Considering this insufŞcient preparation and unsatisfactory pedagogical formation processes, an effective teacher education program as well as a contributing teacher induction program was claimed to be adopted by higher education institutions

  2. English as a Foreign Language Instructors’ Induction: Early Practices of Language Teachers Teaching at Tertiary Level

    Directory of Open Access Journals (Sweden)

    Mustafa Öztürk

    2012-04-01

    Full Text Available This study aimed to investigate the nature of the induction process of English as a foreign language (EFL teachers teaching at tertiary level through individual interviews. In order to gather intended data, fifteen novice instructors teaching at four different public universities in Ankara were interviewed on a basis of two criteria: (a having 1 to 3 years of teaching experience, and (b teaching at higher education level. The data gathered from the interviews were transcribed, coded, and categorized under themes in a qualitative research tradition. Subsequently the findings were interpreted. The findings were organized around research questions and there appeared four main themes: (1 nature of induction process; (2 common concerns of novice teachers; (3 possible adaptation challenges; and (4 practices to overcome difficulties. The results revealed that pre-service education, especially of the graduates of non-Education Faculties, did not adequately respond to the needs of the novice teachers in induction period. Considering this insufficient preparation and unsatisfactory pedagogical formation processes, an effective teacher education program as well as a contributing teacher induction program was claimed to be adopted by higher education institutions.

  3. Metabolic induction and early responses of mouse blastocyst developmental programming following maternal low protein diet affecting life-long health.

    Science.gov (United States)

    Eckert, Judith J; Porter, Richard; Watkins, Adam J; Burt, Elizabeth; Brooks, Suzanne; Leese, Henry J; Humpherson, Peter G; Cameron, Iain T; Fleming, Tom P

    2012-01-01

    Previously, we have shown that a maternal low protein diet, fed exclusively during the preimplantation period of mouse development (Emb-LPD), is sufficient to induce by the blastocyst stage a compensatory growth phenotype in late gestation and postnatally, correlating with increased risk of adult onset cardiovascular disease and behavioural dysfunction. Here, we examine mechanisms of induction of maternal Emb-LPD programming and early compensatory responses by the embryo. Emb-LPD induced changes in maternal serum metabolites at the time of blastocyst formation (E3.5), notably reduced insulin and increased glucose, together with reduced levels of free amino acids (AAs) including branched chain AAs leucine, isoleucine and valine. Emb-LPD also caused reduction in the branched chain AAs within uterine fluid at the blastocyst stage. These maternal changes coincided with an altered content of blastocyst AAs and reduced mTORC1 signalling within blastocysts evident in reduced phosphorylation of effector S6 ribosomal protein and its ratio to total S6 protein but no change in effector 4E-BP1 phosphorylated and total pools. These changes were accompanied by increased proliferation of blastocyst trophectoderm and total cells and subsequent increased spreading of trophoblast cells in blastocyst outgrowths. We propose that induction of metabolic programming following Emb-LPD is achieved through mTORC1signalling which acts as a sensor for preimplantation embryos to detect maternal nutrient levels via branched chain AAs and/or insulin availability. Moreover, this induction step associates with changes in extra-embryonic trophectoderm behaviour occurring as early compensatory responses leading to later nutrient recovery.

  4. Unraveling the complexities of the interferon response during SARS-CoV infection

    OpenAIRE

    Lang, Anna; Baas, Tracey; Smits, Saskia L.; Katze, Michael G.; Osterhaus, Albert DME; Haagmans, Bart L.

    2009-01-01

    Viruses employ different strategies to circumvent the antiviral actions of the innate immune response. SARS coronavirus (SARS-CoV), a virus that causes severe lung damage, encodes an array of proteins able to inhibit induction and signaling of type-I interferons. However, recent studies have demonstrated that interferons are produced during SARS-CoV infection in humans and macaques. Furthermore, nuclear translocation of activated STAT1 and a range of interferon-stimulated genes could be demon...

  5. Early raise of BDNF in hippocampus suggests induction of posttranscriptional mechanisms by antidepressants

    Directory of Open Access Journals (Sweden)

    Barlati Sergio

    2009-05-01

    Full Text Available Abstract Background The neurotrophin BDNF has been implicated in the regulation of neuroplasticity, gene expression, and synaptic function in the adult brain, as well as in the pathophysiology of neuropsychiatric disorders and the mechanism of action of antidepressants. Antidepressant treatments have been shown to increase the expression of BDNF mRNA, although the changes measured were found to be different depending on various factors. A few studies only have measured levels of BDNF protein after antidepressant treatments, and poor correlation was found between mRNA and protein changes. We studied the time course of expression of BDNF mRNA and protein during drug treatments, in order to elucidate the temporal profile of regulation of this effector and whether mRNA and protein levels correlate. Rat groups were treated for 1, 2 or 3 weeks with fluoxetine or reboxetine; in additional groups drug treatment was followed by a washout week (3+1. Total BDNF mRNA was measured by Real Time PCR, pro- and mature BDNF proteins were measured by Western blot. Results We found that mature BDNF protein is induced more rapidly than mRNA, by both drugs in hippocampus (weeks 1–2 and by reboxetine in prefrontal/frontal cortex (week 1. The temporal profile of BDNF protein expression was largely inconsistent with that of mRNA, which followed the protein induction and reached a peak at week 3. Conclusion These results suggest that BDNF protein is rapidly elevated by antidepressant treatments by posttranscriptional mechanisms, and that induction of BDNF mRNA is a slower process.

  6. Characterization of the early molecular changes in the glomeruli of Cd151-/-mice highlights induction of mindin and MMP-10.

    Science.gov (United States)

    Naudin, Crystal; Smith, Brian; Bond, Danielle R; Dun, Matthew D; Scott, Rodney J; Ashman, Leonie K; Weidenhofer, Judith; Roselli, Séverine

    2017-11-22

    In humans and FVB/N mice, loss of functional tetraspanin CD151 is associated with glomerular disease characterised by early onset proteinuria and ultrastructural thickening and splitting of the glomerular basement membrane (GBM). To gain insight into the molecular mechanisms associated with disease development, we characterised the glomerular gene expression profile at an early stage of disease progression in FVB/N Cd151 -/- mice compared to Cd151 +/+ controls. This study identified 72 up-regulated and 183 down-regulated genes in FVB/N Cd151 -/- compared to Cd151 +/+ glomeruli (p < 0.05). Further analysis highlighted induction of the matrix metalloprotease MMP-10 and the extracellular matrix protein mindin (encoded by Spon2) in the diseased FVB/N Cd151 -/- GBM that did not occur in the C57BL/6 diseased-resistant strain. Interestingly, mindin was also detected in urinary samples of FVB/N Cd151 -/- mice, underlining its potential value as a biomarker for glomerular diseases associated with GBM alterations. Gene set enrichment and pathway analysis of the microarray dataset showed enrichment in axon guidance and actin cytoskeleton signalling pathways as well as activation of inflammatory pathways. Given the known function of mindin, its early expression in the diseased GBM could represent a trigger of both further podocyte cytoskeletal changes and inflammation, thereby playing a key role in the mechanisms of disease progression.

  7. Neonatal dexamethasone administration causes progressive renal damage due to induction of an early inflammatory response

    NARCIS (Netherlands)

    Liu, Yan; van Goor, Harry; Havinga, Rick; Baller, Julius F. W.; Bloks, Vincent W.; van der Leij, Feike R.; Sauer, Pieter J. J.; Kuipers, Folkert; Navis, Gerjan; de Borst, Martin H.

    Glucocorticoids (GCs) are widely used to prevent chronic lung disease in immature newborns. Emerging evidence indicates that GC exposure in early life may interfere with kidney function and is associated with hypertension in later life. In this study, we have investigated the effect of neonatal

  8. The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism.

    Science.gov (United States)

    Parker, William; Hornik, Chi Dang; Bilbo, Staci; Holzknecht, Zoie E; Gentry, Lauren; Rao, Rasika; Lin, Shu S; Herbert, Martha R; Nevison, Cynthia D

    2017-04-01

    The wide range of factors associated with the induction of autism is invariably linked with either inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and young children may be much more strongly associated with autism than its use during pregnancy, perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during early development. Thus, one explanation for the increased prevalence of autism is that increased exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in babies and small children. This view mandates extreme urgency in probing the long-term effects of acetaminophen use in babies and the possibility that many cases of infantile autism may actually be induced by acetaminophen exposure shortly after birth.

  9. Improvement of porcine cloning efficiency by trichostain A through early-stage induction of embryo apoptosis.

    Science.gov (United States)

    Ji, Qianqian; Zhu, Kongju; Liu, Zhiguo; Song, Zhenwei; Huang, Yuankai; Zhao, Haijing; Chen, Yaosheng; He, Zuyong; Mo, Delin; Cong, Peiqing

    2013-03-15

    Trichostain A (TSA), an inhibitor of histone deacetylases, improved developmental competence of SCNT embryos in many species, apparently by improved epigenetic reprogramming. The objective of the present study was to determine the effects of TSA-induced apoptosis in cloned porcine embryos. At various developmental stages, a comet assay and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining were used to detect apoptosis, and real-time polymerase chain reaction was used to assess expression of genes related to apoptosis and pluripotency. In this study, TSA significantly induced apoptosis (in a dose-dependent manner) at the one-, two-, and four-cell stages. However, in blastocyst stage embryos, TSA decreased the apoptotic index (P < 0.05). Expression levels of Caspase 3 were higher in TSA-treated versus control embryos at the two-cell stage (not statistically significant). The expression ratio of antiapoptotic Bcl-xl gene to proapoptotic Bax gene, an indicator of antiapoptotic potential, was higher in TSA-treated groups at the one-, two-, and four-cell and blastocyst stages. Furthermore, expression levels of pluripotency-related genes, namely, Oct4 and Nanog, were elevated at the morula stage (P < 0.05) in TSA treatment groups. We concluded that inducing apoptosis might be a mechanism by which TSA promotes development of reconstructed embryos. At the initial stage of apoptosis induction, abnormal cells were removed, thereby enhancing proliferation of healthy cells and improving embryo quality. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Interferon-induced depression: prevalence and management.

    Science.gov (United States)

    Scalori, A; Pozzi, M; Bellia, V; Apale, P; Santamaria, G; Bordoni, T; Redaelli, A; Avolio, A; Parravicini, P; Pioltelli, P; Roffi, L

    2005-02-01

    Interferon-induced depression ranges from 0 to 50%. Interferon schedule and a history of psychiatric illnesses are not enough to predict who will develop symptoms and who will not. To assess the prevalence of depression during interferon therapy; to test whether Minnesota Multiphasic Personality Inventory is useful in clinical practice for the early identification of patients at risk of depression; whether and how the depression can be cured. One hundred and eighty-five patients treated with interferon and ribavirin for chronic hepatitis C. Before therapy, all patients underwent a Minnesota Multiphasic Personality Inventory and a clinical examination, specifically for the identification of depressive symptoms. Thirty-one patients developed a psychiatric disorder, 11 of them requiring treatment with anti-depressant drugs. Among the 18 patients with Minnesota Multiphasic Personality Inventory positive tests, 16 developed a psychiatric disorder, 8 of them a severe disorder (sensitivity of 0.58; 0.73 for severe disorders). Among the 154 who did not develop psychiatric side effects, 152 had a negative Minnesota Multiphasic Personality Inventory (specificity: 0.99). Severe psychiatric disorders were successfully treated with anti-depressant drugs. Psychiatric side effects are easy to see during interferon therapy. A psychiatric evaluation should be considered on all patients before treatment. If depression develops, it should be treated aggressively, and selective serotonin re-uptake inhibitors are the anti-depressants of choice.

  11. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yu-Ching [Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan (China); Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Ho, Heng-Chien; Lee, Miau-Rong [Department of Biochemistry, China Medical University, Taichung 404, Taiwan (China); Lai, Kuang-Chi [Department of Surgery, China Medical University Beigang Hospital, Yunlin 651, Taiwan (China); School of Medicine, China Medical University, Taichung 404, Taiwan (China); Yeh, Chung-Min; Lin, Yueh-Min [Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan (China); Ho, Tin-Yun [School of Chinese Medicine, China Medical University, Taichung 404, Taiwan (China); Hsiang, Chien-Yun, E-mail: cyhsiang@mail.cmu.edu.tw [Department of Microbiology, China Medical University, Taichung 404, Taiwan (China); Chung, Jing-Gung, E-mail: jgchung@mail.cmu.edu.tw [Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China)

    2012-07-15

    The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9–18 fold) of induction in the microarray data, and its early induction was observed in a 2 h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

  12. Early MRI results and odds of attaining 'no evidence of disease activity' status in MS patients treated with interferon β-1a in the EVIDENCE study.

    Science.gov (United States)

    Coyle, Patricia K; Reder, Anthony T; Freedman, Mark S; Fang, Juanzhi; Dangond, Fernando

    2017-08-15

    'No evidence of disease activity' (NEDA) is increasingly used as a treatment target with disease-modifying drugs for relapsing multiple sclerosis. This post-hoc analysis of the randomised EVIDENCE trial compared interferon beta-1a injected subcutaneously three times weekly (IFN β-1a SC tiw) with interferon β-1a injected intramuscularly once weekly (IFN β-1a IM qw) on NEDA and clinical activity-free (CAF) status. The influence of the frequency of magnetic resonance imaging (MRI) scanning on NEDA and the effect of baseline T1 gadolinium-enhancing (Gd+) lesions on NEDA and CAF were also investigated. More patients in the IFN β-1a SC tiw group achieved NEDA compared with the IFN β-1a IM qw group, although rates were lower when monthly MRI scans through 24weeks were included (35.0% vs. 21.6%, respectively; p<0.001) versus the 24-week scan alone (59.5% vs. 41.2%; p<0.001). Absence of baseline Gd+ lesions predicted NEDA through Week 72 in the IFN β-1a IM qw group (p=0.022), and CAF through Week 48 in patients receiving IFN β-1a SC tiw (p=0.024). IFN β-1a SC tiw was associated with significantly higher rate of NEDA status compared with IFN β-1a IM qw. Baseline Gd+ lesions augured less frequent CAF or NEDA status. Inclusion of more MRI scans in the analysis reduced rates of NEDA status. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Early induction of Na(+)-dependent uridine uptake in the regenerating rat liver.

    Science.gov (United States)

    Ruiz-Montasell, B; Martinez-Mas, J V; Enrich, C; Casado, F J; Felipe, A; Pastor-Anglada, M

    1993-01-18

    Na(+)-dependent uridine transport into liver plasma membrane vesicles from partially hepatectomized and sham-operated rats was studied. Preparations purified 6 h after 70% hepatectomy exhibited an increased Vmax of uridine uptake (3.7 vs. 1.4 pmol/mg prot/3 s) without any change in Km (6 microM). Incubation of the vesicles in the presence of monensin decreased uridine uptake although the differences between both experimental groups remained identical. It is concluded that uridine transport is induced early after partial hepatectomy by a mechanism which does not involve changes in the transmembrane Na+ gradient. This is the first evidence in favor of modulation of nucleoside transport into liver cells.

  14. Luteal P4 synthesis in early pregnant gilts after induction of estrus with PMSG/hCG.

    Science.gov (United States)

    Blitek, Agnieszka; Szymanska, Magdalena; Pieczywek, Marta; Morawska-Pucinska, Ewa

    2016-03-01

    The present study was designed to examine whether an estrus induction with gonadotropins could affect luteal P4 synthesis in early pregnant gilts. Sixteen prepubertal gilts received 750IU of PMSG and 500IU of hCG 72h later. Prepubertal gilts in the control group (n=17) were observed daily for estrus behavior. All gilts were inseminated in their first estrus. Corpora lutea (CLs) were collected on days 10, 12 and 15 of pregnancy and analyzed for (1) the mRNA and protein expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 family 11 subfamily A polypeptide 1 (CYP11A1), and 3β-hydroxysteroid dehydrogenase (3βHSD); (2) the tissue concentration of P4; and (3) the mRNA expression of luteinizing hormone receptor (LHR) and estrogen receptors (ESR1 and ESR2). Additionally, P4 concentration was analyzed in blood serum of all animals. PMSG/hCG injections to induce estrus decreased mRNA expression of StAR, CYP11A1 and 3βHSD on day 10 and CYP11A1 on day 12 of pregnancy compared with the control group, while CYP11A1 and 3βHSD proteins were down-regulated on day 10 in the hormonally-treated gilts. Concentrations of P4 in luteal tissue and blood serum were also lower in animals after gonadotropin-induced estrus. In contrast, LHR and ESR1 mRNA expression was greater in PMSG/hCG-treated than control gilts on day 15 of gestation. In conclusion, induction of estrus with a PMSG/hCG protocol in prepubertal gilts impaired expression of the luteal P4 synthesis system. Low P4 content may, in turn, induce local mechanisms involving LHR and ESR1 expression to support CL function. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. The Roles of Parental Inductions, Moral Emotions, and Moral Cognitions in Prosocial Tendencies among Mexican American and European American Early Adolescents

    Science.gov (United States)

    Carlo, Gustavo; Knight, George P.; McGinley, Meredith; Hayes, Rachel

    2011-01-01

    This study examined the relationships between parental inductions, sympathy, prosocial moral reasoning, and prosocial behaviors. A total of 207 early adolescents who self-identified as Mexican American (girls, n = 105; mean age = 10.91 years) and 108 who identified as European American (girls, n = 54; mean age = 11.07 years) completed measures of…

  16. Interferon-gamma confers resistance to experimental allergic encephalomyelitis

    DEFF Research Database (Denmark)

    Krakowski, M; Owens, T

    1996-01-01

    In experimental allergic encephalomyelitis (EAE), T cells infiltrate the central nervous system (CNS) and induce inflammation. These CD4+ T cells secrete interferon (IFN)-gamma, levels of which correlate with disease severity, and which is proposed to play a key role in disease induction. Many...

  17. Protective role of interferon against cytotoxcicity induced by rabies ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-02-15

    Feb 15, 2010 ... and reduced cytogenetic changes suggest that protection induced by interferon against rabies virus activity could be, at ... by Alikhanian and Iijina. (1958) in their work on the induction of mutation in actinomycetes by phages. The exact mechanism of viral mutagenesis is not well known. Viruses may attack ...

  18. Interferon Gamma-1b Injection

    Science.gov (United States)

    Interferon gamma-1b injection is used to reduce the frequency and severity of serious infections in people with chronic ... severe, malignant osteopetrosis (an inherited bone disease). Interferon gamma-1b is in a class of medications called ...

  19. Reproductive strategy, spawning induction, spawning temperatures and early life history of captive sicklefin chub Macrhybopsis meeki

    Science.gov (United States)

    Albers, Janice; Wildhaber, Mark L.

    2017-01-01

    Macrhybopsis reproduction and propagule traits were studied in the laboratory using two temperature regimes and three hormone treatments to determine which methods produced the most spawns. Only sicklefin chub Macrhybopsis meeki spawned successfully although sturgeon chub Macrhybopsis gelida released unfertilized eggs. All temperature and hormone treatments produced M. meeki spawns, but two treatments had similar success rates at 44 and 43%, consisting of a constant daily temperature with no hormone added, or daily temperature fluctuations with hormone added to the water. Spawns consisted of multiple successful demersal circular swimming spawning embraces interspersed with circular swims without embraces. The most spawns observed for one female was four and on average, 327 eggs were collected after each spawn. The water-hardened eggs were semi-buoyant and non-adhesive, the first confirmation of this type of reproductive guild in the Missouri River Macrhybopsis sp. From spawn, larvae swam vertically until 123 accumulated degree days (° D) and 167° D for consumption of first food. Using average water speed and laboratory development time, the predicted drift distance for eggs and larvae could be 468–592 km in the lower Missouri River. Results from this study determined the reproductive biology and early life history of Macrhybopsis spp. and provided insight into their population dynamics in the Missouri River.

  20. Induction of contact sensitivity by cell-associated immunocomplexes requires activation of the early complement components.

    Science.gov (United States)

    Lio, D; Sireci, G; Gervasi, F; Dieli, F; Salerno, A

    1992-12-01

    Lymph node cells collected from CBA/J mice 4 days after painting the skin with picryl chloride behave like antigen presenting cells and induce contact sensitivity when injected into naive recipient mice. The immunizing capacity of these '4-day' cells is due to T cells which carry on their membrane hapten-IgM immunocomplexes. Incubation of the cells with complement from mouse strains that express high C4 serum levels (C4H), abolishes their immunizing capacity. This effect is related to the activation of the early components of the classical complement pathway, as supported by experiments using C3 and C4-depleted or C5 and C6-genetically deficient mouse sera. The detection of different amounts of C3b and C4b on the surface of 4-day T cells after incubation with C4L and C4H sera supports the possibility that membrane bound activated complement components could modify the immunizing capacity of these cells. Results herein reported suggest that membrane-bound C3b and C4b are not per se inhibitory but interfere with the residual complement activating capacity of 4-day T cells. The role of complement activation by 4-day T cells is pivotal as complement depletion of recipient mice by cobra venom factor (CVF) inhibits the immunizing capacity of untreated 4-day T cells, while 4-day T cells treated with complement in vitro and injected together with C4a anaphylatoxin are able to immunize recipient mice.

  1. Interferon Alfa-2b Injection

    Science.gov (United States)

    Interferon alfa-2b injection is used to treat a number of conditions.Interferon alfa-2b injection is used alone or in combination ... Hodgkin's lymphoma (NHL; a slow-growing blood cancer). Interferon alfa-2b is in a class of medications called ...

  2. Morphology and Quantitative Monitoring of Gene Expression Patterns during Floral Induction and Early Flower Development in Dendrocalamus latiflorus

    Directory of Open Access Journals (Sweden)

    Xiaoyan Wang

    2014-07-01

    Full Text Available The mechanism of floral transition in bamboo remains unclear. Dendrocalamus latiflorus (Bambusease, Bambusoideae, Poaceae is an economically and ecologically important clumping bamboo in tropical and subtropical areas. We evaluated morphological characteristics and gene expression profiling to study floral induction and early flower development in D. latiflorus. The detailed morphological studies on vegetative buds and floral organography were completed using paraffin sectioning and scanning electron microscopy. The 3 mm floral buds commence the development of stamen primordia and pistil primordium. Furthermore, homologs of floral transition-related genes, including AP1, TFL1, RFL, PpMADS1, PpMADS2, SPL9, FT, ID1, FCA, and EMF2, were detected and quantified by reverse transcriptase PCR and real-time PCR in vegetative and floral buds, respectively. Distinct expression profiles of ten putative floral initiation homologues that corresponded to the developmental stages defined by bud length were obtained and genes were characterized. Six of the genes (including DlTFL1, DlRFL, DlMADS2, DlID1, DlFCA, DlEMF2 showed statistically significant changes in expression during floral transition. DlAP1 demonstrated a sustained downward trend and could serve as a good molecular marker during floral transition in D. latiflorus. The combined analysis provided key candidate markers to track the transition from the vegetative to reproductive phase.

  3. Morphology and quantitative monitoring of gene expression patterns during floral induction and early flower development in Dendrocalamus latiflorus.

    Science.gov (United States)

    Wang, Xiaoyan; Zhang, Xuemei; Zhao, Lei; Guo, Zhenhua

    2014-07-07

    The mechanism of floral transition in bamboo remains unclear. Dendrocalamus latiflorus (Bambusease, Bambusoideae, Poaceae) is an economically and ecologically important clumping bamboo in tropical and subtropical areas. We evaluated morphological characteristics and gene expression profiling to study floral induction and early flower development in D. latiflorus. The detailed morphological studies on vegetative buds and floral organography were completed using paraffin sectioning and scanning electron microscopy. The 3 mm floral buds commence the development of stamen primordia and pistil primordium. Furthermore, homologs of floral transition-related genes, including AP1, TFL1, RFL, PpMADS1, PpMADS2, SPL9, FT, ID1, FCA, and EMF2, were detected and quantified by reverse transcriptase PCR and real-time PCR in vegetative and floral buds, respectively. Distinct expression profiles of ten putative floral initiation homologues that corresponded to the developmental stages defined by bud length were obtained and genes were characterized. Six of the genes (including DlTFL1, DlRFL, DlMADS2, DlID1, DlFCA, DlEMF2) showed statistically significant changes in expression during floral transition. DlAP1 demonstrated a sustained downward trend and could serve as a good molecular marker during floral transition in D. latiflorus. The combined analysis provided key candidate markers to track the transition from the vegetative to reproductive phase.

  4. Dual roles of palladin protein in in vitro myogenesis: inhibition of early induction but promotion of myotube maturation.

    Directory of Open Access Journals (Sweden)

    Ngoc-Uyen-Nhi Nguyen

    Full Text Available Palladin is a microfilament-associated phosphoprotein whose function in skeletal muscle has rarely been studied. Therefore, we investigate whether myogenesis is influenced by the depletion of palladin expression known to interfere with the actin cytoskeleton dynamic required for skeletal muscle differentiation. The inhibition of palladin in C2C12 myoblasts leads to precocious myogenic differentiation with a concomitant reduction in cell apoptosis. This premature myogenesis is caused, in part, by an accelerated induction of p21, myogenin, and myosin heavy chain, suggesting that palladin acts as a negative regulator in early differentiation phases. Paradoxically, palladin-knockdown myoblasts are unable to differentiate terminally, despite their ability to perform some initial steps of differentiation. Cells with attenuated palladin expression form thinner myotubes with fewer myonuclei compared to those of the control. It is noteworthy that a negative regulator of myogenesis, myostatin, is activated in palladin-deficient myotubes, suggesting the palladin-mediated impairment of late-stage myogenesis. Additionally, overexpression of 140-kDa palladin inhibits myoblast differentiation while 200-kDa and 90-kDa palladin-overexpressed cells display an enhanced differentiation rate. Together, our data suggest that palladin might have both positive and negative roles in maintaining the proper skeletal myogenic differentiation in vitro.

  5. Differential impact of interferon regulatory factor 7 in the initiation of the type I interferon response in the LCMV infected CNS versus the periphery

    DEFF Research Database (Denmark)

    Christensen, Jeanette Erbo; Fenger, Christina; Issazadeh-Navikas, Shohreh

    2012-01-01

    Interferon (IFN) regulatory factors (IRFs) are a family of transcription factors involved in regulating type I IFN genes and other genes participating in the early antiviral host response. To better understand the mechanisms involved in virus-induced central nervous system (CNS) inflammation, we...... studied the influence of IRF1, -3, -7, and -9 on the transcriptional activity of key genes encoding antiviral host factors in the CNS of mice infected with lymphocytic choriomeningitis virus (LCMV). A key finding is that neither IRF3 nor IRF7 is absolutely required for induction of a type I IFN response...... in the LCMV-infected CNS, whereas concurrent elimination of both factors markedly reduces the virus-induced host response. This is unlike the situation in the periphery, where deficiency of IRF7 almost eliminates the LCMV-induced production of the type I IFNs. This difference is seemingly related to the local...

  6. Down-regulation of interferon-gamma-induced class II expression on human glioma cells by recombinant interferon-beta: effects of dosage treatment schedule.

    Science.gov (United States)

    Joseph, J; Knobler, R L; D'Imperio, C; Lublin, F D

    1988-11-01

    We have examined the influence of human recombinant interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) on class II antigen expression on cultured glioblastoma multiforme cells by flow cytometry. Class II molecules were not constitutively expressed on these cells, nor induced by IFN-beta. IFN-gamma increased class II expression in a dose-dependent fashion. We demonstrate that IFN-beta is either antagonistic or synergistic with IFN-gamma in class II induction depending upon dose and schedule of administration. Both interferons at 100 IU/ml reduce class II expression by 18%, compared to IFN-gamma alone. Pretreatment with IFN-beta for 72 h, followed by both interferons yielded a 90% reduction. In contrast, lower concentrations (10 IU/ml) of both interferons were synergistic.

  7. Raised interferon-β, type 3 interferon and interferon-stimulated genes - evidence of innate immune activation in neutrophilic asthma.

    Science.gov (United States)

    da Silva, J; Hilzendeger, C; Moermans, C; Schleich, F; Henket, M; Kebadze, T; Mallia, P; Edwards, M R; Johnston, S L; Louis, R

    2017-03-01

    Interferons play an important role in innate immunity. Previous studies report deficiency in virus induction of interferon (IFN)-α, IFN-β and IFN-λ in bronchial epithelial and bronchial lavage cells in atopic asthmatics. It is now recognized that asthma is a heterogeneous disease comprising different inflammatory phenotypes, some of which may involve innate immune activation in the absence of overt infection. The aim of this study was to investigate whether the severity of asthma or a specific cellular sputum pattern may be linked to evidence of innate immune activation. Here we investigate the expression of IFN-β, IFN-λ1 (IL-29), IFN-λ2/3 (IL-28A/B) and the interferon-stimulated genes (ISGs) such as myxovirus resistance 1 (Mx1), oligoadenylate synthetase (OAS) and viperin in unstimulated sputum cells in 57 asthmatics (including 16 mild, 19 moderate and 22 severe asthma patients) and compared them with 19 healthy subjects. We observed increased expression of IFN-β, IFN-λ1/IL-29, OAS and viperin in asthmatics compared with healthy subjects, while IL-28 was not expressed in any group. The overexpression was restricted to neutrophilic asthmatics (sputum neutrophils ≥ 76%), while eosinophilic asthmatics (sputum eosinophils ≥ 3%) did not differ from healthy subjects or even showed a lower expression of Mx1. No difference in interferon or ISG expression was observed according to clinical asthma severity. Neutrophilic, but not eosinophilic, asthmatics display overexpression of IFN-β, IFN-λ1/IL-29 and ISGs in their sputum cells that may reflect ongoing innate immune activation. © 2016 John Wiley & Sons Ltd.

  8. Effects of alachlor on the early development and induction of estrogen-responsive genes in Medaka, Oryzias latipes

    Energy Technology Data Exchange (ETDEWEB)

    Lee, C.; Ryu, J.; Park, S.Y.; Choi, K.; Jeon, S.H.; Na, J.G.; Rhee, D.G. [National Inst. of Environmental Research, Incheon (Korea)

    2004-09-15

    Alachlor is an acetanilide herbicide used to control annual grasses and weeds in field corn, soybeans, and peanuts. It is a selective systemic herbicide, absorbed by germinating shoots and by roots. Although the specific pathways are not exactly understood, the acetanilide herbicides apparently interfere with several physiological processes including biosynthesis of lipids, proteins and flavonoids. These herbicides are widely used in agriculture and are commonly detected in surface water and groundwater. Alachlor has a relatively low acute toxicity, however, repeated exposure has been reported to cause hepatotoxicity, irreversible uveal degeneration and tumour formation in some animals. Besides alachlor is one of the herbicides reported to have endocrine disrupting effects. 2,4-D, 2,4,5-T, amitrole and atrazine also belong to these types of herbicides. Alachlor is a strongly suspected endocrine disruptor in that it is listed by EPA and the World Wildlife Fund [WWF] as a potential endocrine disrupting chemical. Many mammalian and aquatic toxicological studies with alachlor were performed under the conditions of acute, subacute and chronic experiment. However, not many studies using fish have been carried out with the purpose of screening and testing of endocrine disrupting effects of alachlor. The purpose of this study was to determine the effects of alachlor on the early morphological development of medaka (Oryzias latipes). Embryonic growth, deformation and hatching success were determined to see the effects of this chemical. Also, we tried to measure the estrogenic activity of alachlor using the ELISA and RT-PCR methods. By using these techniques, we evaluated the induction of the estrogen-responsive genes, vitellogenin (precursor of yolk protein) and choriogenin (precursor of egg envelope protein) in male medaka exposed to alachlor.

  9. Quantitative HBV DNA levels as an early predictor of nonresponse in chronic HBe-antigen positive hepatitis B patients treated with interferon-alpha

    NARCIS (Netherlands)

    van der Eijk, A A; Niesters, H G M; Hansen, B E; Heijtink, R A; Janssen, H L A; Schalm, S W; de Man, R A

    To reduce unnecessary exposure to treatment, physicians must decide at an early stage whether continuation of treatment has a reasonable chance of success for the individual patient. The objectives of our study were to evaluate the previously described quantitative hepatitis B e antigen (HBeAg)

  10. Fine Tuning of a Type 1 Interferon Antagonist.

    Directory of Open Access Journals (Sweden)

    Victoria Urin

    Full Text Available Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.

  11. Interferon-γ-induced protein 10 in Lyme disease.

    Science.gov (United States)

    Fallahi, P; Elia, G; Bonatti, A

    2017-01-01

    Lyme disease is an infectious disease caused by bacteria of the Borrelia type, that affects about 300,000 people a year in the USA and 65,000 people a year in Europe. Borrelia infection, and Lyme disease, following occupational exposure has been frequently reported in USA, Europe and Asia. The manifestations of Lyme disease include erythema migrans (EM), arthritis, neuroborrelliosis (NB), and others. Cytokines and chemokines primarily orchestrate leukocyte recruitment to the areas of Borrelia infection, and they are critical mediators of immune and inflammatory responses, in particular of the induction of interferon (IFN)-γ and IFN-γ dependent chemokines. In EM high levels of T helper (Th) 1 cells chemoattranctants [monokine induced by IFN-γ (MIG), IFN-γ-induced protein 10 (IP- 10), and IFN-inducible T cell alpha chemoattractant (I-TAC)] have been shown. Synovial tissues and fluids of patients with Lyme Arthritis (LA) (overall with antibiotic-refractory LA) contained exceptionally high levels of Th1 chemoattractants and cytokines, particularly MIG and IFN-γ. In NB concentrations of IP-10 and I-TAC in the cerebrospinal fluid (CSF) were significantly higher, suggesting that IP-10 and I-TAC create a chemokine gradient between the CSF and serum and recruite C-X-C chemokine receptor 3-expressing memory CD4+ T-cells into the CSF of these patients. A positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction has also been shown. These results suggest that IFN-γ dependent chemokines are important biomarkers to monitor the progression and diffusion of the disease in patients with Borrelia infection; further larger studies are needed.

  12. Interferon Alpha in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Timothy B. Niewold

    2010-01-01

    Full Text Available The pleiotropic cytokine interferon alpha is involved in multiple aspects of lupus etiology and pathogenesis. Interferon alpha is important under normal circumstances for antiviral responses and immune activation. However, heightened levels of serum interferon alpha and expression of interferon response genes are common in lupus patients. Lupus-associated autoantibodies can drive the production of interferon alpha and heightened levels of interferon interfere with immune regulation. Several genes in the pathways leading to interferon production or signaling are associated with risk for lupus. Clinical and cellular manifestations of excess interferon alpha in lupus combined with the genetic risk factors associated with interferon make this cytokine a rare bridge between genetic risk and phenotypic effects. Interferon alpha influences the clinical picture of lupus and may represent a therapeutic target. This paper provides an overview of the cellular, genetic, and clinical aspects of interferon alpha in lupus.

  13. [Update on the use of interferons in clinical practice].

    Science.gov (United States)

    Lauta, V M

    1995-01-01

    Discovered by Isaac and Lindemann as a substance able to induce a biological interference among viruses and host cells, interferon appeared to include three main antigenic classes: alpha, beta and gamma. There is a large variety of actions exhibited by different types of interferon and among them it is possible to distinguish an antiviral, antineoplastic, immunomodulatory or hormonal activity. Many years ago, the antiviral action seemed to be relative to some cellular membrane disorders, but later other mechanisms were stressed. Among them, it is worth describing the transcription and transduction of antiviral proteins like the oligoadenilsinthetase and proteinphosphokinase, able to cause the viral RNA breackage. The antineoplastic action is exerted by direct and indirect mechanisms. Direct mechanisms include an antiproliferative activity and the induction to cellular differentiation whereas the indirect ones involve the enhancement on tumor cell surfaces of some tumor associated antigens included in the I class of MHC system. The immunomodulatory action is exerted by the stimulation of macrophages, T cells and Killer cells cytotoxic activity. The list of viral diseases sensitive to interferon treatment includes condiloma acuminata, herpes zoster, chronic B and C hepatitis and Kaposi sarcoma AIDS-related. High proportions of overall response rate were observed among interferon treated patients with condiloma acuminata (80-100%). The use of interferon in the treatment of herpes zoster achieved good results regarding a shorter duration of the time spent to induce the chest pains and cutaneous symptoms disappearance when compared with that relative to other antiviral drugs. Results obtained in the treatment of chronic B and C hepatitis regard the disappearance of viral replication serological markers and the improvement of histological and enzymatic pattern. The effectiveness of interferon in the therapy of Kaposi sarcoma is demonstrated by the reduction of cutaneous

  14. Interferon Induced Focal Segmental Glomerulosclerosis

    Directory of Open Access Journals (Sweden)

    Yusuf Kayar

    2016-01-01

    Full Text Available Behçet’s disease is an inflammatory disease of unknown etiology which involves recurring oral and genital aphthous ulcers and ocular lesions as well as articular, vascular, and nervous system involvement. Focal segmental glomerulosclerosis (FSGS is usually seen in viral infections, immune deficiency syndrome, sickle cell anemia, and hyperfiltration and secondary to interferon therapy. Here, we present a case of FSGS identified with kidney biopsy in a patient who had been diagnosed with Behçet’s disease and received interferon-alpha treatment for uveitis and presented with acute renal failure and nephrotic syndrome associated with interferon.

  15. Interferon regulatory factor signaling in autoimmune disease.

    Science.gov (United States)

    Matta, Bharati; Song, Su; Li, Dan; Barnes, Betsy J

    2017-10-01

    Interferon regulatory factors (IRFs) play critical roles in pathogen-induced innate immune responses and the subsequent induction of adaptive immune response. Dysregulation of IRF signaling is therefore thought to contribute to autoimmune disease pathogenesis. Indeed, numerous murine in vivo studies have documented protection from or enhanced susceptibility to particular autoimmune diseases in Irf-deficient mice. What has been lacking, however, is replication of these in vivo observations in primary immune cells from patients with autoimmune disease. These types of studies are essential as the majority of in vivo data support a protective role for IRFs in Irf-deficient mice, yet IRFs are often found to be overexpressed in patient immune cells. A significant body of work is beginning to emerge from both of these areas of study - mouse and human. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Interferon alpha for treatment of chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Hjorth-Hansen, Henrik; Bjerrum, Ole Weis

    2011-01-01

    Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-α) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-α compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions...

  17. Interferon alpha for treatment of chronic myeloid leukemia

    DEFF Research Database (Denmark)

    Simonsson, Bengt; Hjorth-Hansen, Henrik; Bjerrum, Ole Weis

    2011-01-01

    Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-a) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-a compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions...

  18. Adenovirus infection reverses the antiviral state induced by human interferon.

    Science.gov (United States)

    Feduchi, E; Carrasco, L

    1987-04-06

    HeLa cells treated with human lymphoblastoid interferon do not synthesize poliovirus proteins. The antiviral state against poliovirus is reversed if cells are previously infected with adenovirus type 5. A late gene product seems to be involved in this reversion, since no effect is observed at early stages of infection or in the presence of aphidicolin.

  19. Rhadinoviral interferon regulatory factor homologues.

    Science.gov (United States)

    Koch, Sandra; Schulz, Thomas F

    2017-07-26

    Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8 (HHV8) is a gammaherpesvirus and the etiological agent of Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman disease. The KSHV genome contains genes for a unique group of proteins with homology to cellular interferon regulatory factors, termed viral interferon regulatory factors (vIRFs). This review will give an overview over the oncogenic, antiapoptotic and immunomodulatory characteristics of KSHV and related vIRFs.

  20. Labor Induction

    Science.gov (United States)

    ... QUESTIONS FAQ154 LABOR, DELIVERY, AND POSTPARTUM CARE Labor Induction • What is labor induction? • Why is labor induced? • What is the Bishop ... oxytocin? • What are the risks associated with labor induction? • Is labor induction always effective? •Glossary What is ...

  1. Antiproliferative Properties of Type I and Type II Interferon

    Directory of Open Access Journals (Sweden)

    Joseph Bekisz

    2010-03-01

    Full Text Available The clinical possibilities of interferon (IFN became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in the USA for the treatment of a malignancy in 1986, with the approval of IFN-α2a (Hoffman-La Roche and IFN-α2b (Schering-Plough for the treatment of Hairy Cell Leukemia. In addition to this application, other approved antitumor applications for IFN-α2a are AIDS-related Kaposi’s Sarcoma and Chronic Myelogenous Leukemia (CML and other approved antitumor applications for IFN-α2b are Malignant Melanoma, Follicular Lymphoma, and AIDS-related Kapoisi’s Sarcoma. In the ensuing years, a considerable number of studies have been conducted to establish the mechanisms of the induction and action of IFN’s anti-tumor activity. These include identifying the role of Interferon Regulatory Factor 9 (IRF9 as a key factor in eliciting the antiproliferative effects of IFN-α as well as identifying genes induced by IFN that are involved in recognition of tumor cells. Recent studies also show that IFN-activated human monocytes can be used to achieve >95% eradication of select tumor cells. The signaling pathways by which IFN induces apoptosis can vary. IFN treatment induces the tumor suppressor gene p53, which plays a role in apoptosis for some tumors, but it is not essential for the apoptotic response. IFN-α also activates phosphatidylinositol 3-kinase (PI3K, which is associated with cell survival. Downstream of PI3K is the mammalian target of rapamycin (mTOR which, in conjunction with PI3K, may act in signaling induced by growth factors after IFN treatment. This paper will explore the mechanisms by which IFN acts to elicit its antiproliferative effects and more closely examine the clinical applications for the anti-tumor potential of IFN.

  2. Is a compromised interferon response an etiologic factor in Reye's syndrome?

    Science.gov (United States)

    Rozee, K. R.; Lee, S. H.; Crocker, J. F.; Digout, S.; Arcinue, E.

    1982-01-01

    Young mice injected with sublethal doses of Toximul MP8, a typical commercial polyoxyethylene ether-based emulsifier, died more frequently when infected with encephalomyocarditis virus than did control mice. Lymphocytes taken from emulsifier-injected mice responded poorly to interferon induction, unlike lymphocytes from control animals. Interferon protected control mice against viral encephalomyocarditis, but such protection was not equally demonstrable in emulsifier-injected mice. These data suggest that the enhanced lethality of encephalomyocarditis virus in emulsifier-injected mice is associated with and perhaps caused by a compromised interferon response in these animals. Since these emulsifiers are commonly found in the environment in areas where forests are sprayed with pesticides, a group of children suffering from Reye's syndrome who lived in such areas was investigated. Blood samples were obtained from five children with influenza B-associated Reye's syndrome during their acute illness and during convalescence. Lymphocytes obtained from these samples and from peripheral blood samples from healthy children (controls) were induced to synthesize interferon by exposure to Newcastle disease virus. The lymphocytes from the convalescent patients and from the controls responded well to induction. However, the lymphocytes obtained from patients and from the controls responded well to induction. However, the lymphocytes obtained from patients during the acute phase of Reye's syndrome responded very poorly and produced significantly less interferon. PMID:6176306

  3. Salidroside-Mediated Neuroprotection is Associated with Induction of Early Growth Response Genes (Egrs) Across a Wide Therapeutic Window.

    Science.gov (United States)

    Lai, Wenfang; Zheng, Zhenwei; Zhang, Xiaoqin; Wei, Yicong; Chu, Kedan; Brown, John; Hong, Guizhu; Chen, Lidian

    2015-08-01

    Salidroside exhibits anti-inflammatory, anti-oxidative, and anti-apoptotic properties. To identify whether salidroside might be a candidate for treating ischemic stroke, we investigated the effects of salidroside or vehicle, given daily for 6 days, after middle cerebral artery occlusion (MCAO) for 2 h and reperfusion for either 1 or 48 h in rats. Salidroside reduced cerebral infarct volume and significantly improved neurological scores whether started after 1 or 48 h of reperfusion. Microarray analysis showed that 20 % (133/678) of the genes down-regulated by ischemia and 1 h of reperfusion were up-regulated by salidroside, whereas 13 % (105/829) of the genes induced by ischemia-reperfusion were inhibited by salidroside, suggesting that salidroside can reverse effects of ischemia-reperfusion on gene expression. The main enriched functional categories induced by salidroside were genes related to synaptic plasticity, whereas salidroside inhibited genes related to inflammation. Induction of Egr1, Egr2, Egr4, and Arc by salidroside was confirmed by qRT-PCR and western blotting in ischemic brains treated after either 1 or 48 h of reperfusion. The potential protective role of Egr4 in salidroside-mediated neuroprotection was subsequently investigated in CoCl2-treated PC12 cells. Egr4 was dose-dependently induced by salidroside in PC12 cells, and depleting Egr4 with target-specific siRNA increased caspase-3 activity and Bax, but decreased Bcl-xl, which were reversed by salidroside. Finally, we confirmed that salidroside inhibited the Bax/Bcl-xl-related apoptosis after MCAO with reperfusion. In conclusion, salidroside is highly neuroprotective with a wide therapeutic time window after ischemia-reperfusion injury in the rat, and this partially involves induction of Egrs, leading to inhibition of Bax/Bcl-xl-related apoptosis.

  4. "Swim or Sink": State of Induction in the Deployment of Early Career Academics into Teaching at Makerere University

    Science.gov (United States)

    Ssempebwa, Jude; Teferra, Damtew; Bakkabulindi, Fred Edward K.

    2016-01-01

    Conducted as part of a multi-country study of the teaching-related experiences and expectations of early career academics (ECAs) in Africa, this study investigated the major influences on the teaching practice of ECAs at Makerere University; the mechanisms by which these academics learn to teach; the teaching-related challenges they experience;…

  5. Early p53-positive foci as indicators of tumor risk in ultraviolet-exposed hairless mice: kinetics of induction, effects of DNA repair deficiency, and p53 heterozygosity.

    Science.gov (United States)

    Rebel, H; Mosnier, L O; Berg, R J; Westerman-de Vries, A; van Steeg, H; van Kranen, H J; de Gruijl, F R

    2001-02-01

    p53 mutations appear to be early events in skin carcinogenesis induced by chronic UVB irradiation. Clusters of epidermal cells that express p53 in mutant conformation ("p53 positive foci") are easily detected by immunohistochemical staining long before the appearance of skin carcinomas or their precursor lesions. In a hairless mouse model, we determined the dose-time dependency of the induction of these p53+ foci and investigated the relationship with the induction of skin carcinomas. The density of p53+ foci may be a good direct indicator of tumor risk. Hairless SKH1 mice were exposed to either of two regimens of daily UVB (500 or 250 J/m2 broadband UV from Philips TL12 lamps; 54% UVB 280-315 nm). With the high-dose regimen, the average number of p53+ foci in a dorsal skin area (7.2 cm2) increased rapidly from 9.0 +/- 2.1 (SE) at 15 days to 470 +/- 80 (SE) at 40 days. At half that daily dose, the induction of p53+ foci was slower by a factor of 1.49 +/- 0.15, very similar to a previously observed slower induction of squamous cell carcinomas by a factor of 1.54 +/- 0.02. In a double-log plot of the average number of p53 + foci versus time, the curves for the two exposure regimens ran parallel (slope, 3.7 +/- 0.7), similar to the curves for the number of tumors versus time (slope, 6.9 +/- 0.8). The difference in slopes (3.7 versus 6.9) is in line with the contention that more rate-limiting steps are needed to develop a tumor than a p53+ focus. By the time the first tumors appear (around 7-8 weeks with the high daily dose), the dorsal skin contains >100 p53+ foci/cm2. To further validate the density of p53+ foci as a direct measure of tumor risk, we carried out experiments with transgenic mice with an enhanced susceptibility to UV carcinogenesis, homozygous Xpa knockout mice (deficient in nucleotide excision repair) and heterozygousp53 knockout mice (i.a. partially deficient in apoptosis). In both of these cancer-prone strains, the p53+ foci were induced at markedly

  6. Interferon-gamma in progression to chronic demyelination and neurological deficit following acute EAE

    DEFF Research Database (Denmark)

    Renno, T; Taupin, V; Bourbonnière, L

    1998-01-01

    The cytokine interferon-gamma (IFNgamma) is implicated in the induction of acute CNS inflammation, but it is less clear what role if any IFNgamma plays in progression to chronic demyelination and neurological deficit. To address this issue, we have expressed IFNgamma in myelinating oligodendrocyt...

  7. Interferon-alpha induces transient suppressors of cytokine signalling expression in human T cells

    DEFF Research Database (Denmark)

    Brender, C; Nielsen, M; Röpke, C

    2001-01-01

    The suppressors of cytokine signalling (SOCS) proteins comprise a newly identified family of negative feedback regulators of cytokine signalling. SOCS expression is differentially induced upon cytokine stimulation in different cell types. Here we show that interferon-alpha (IFNalpha) is a potent...... in cytokine sensitivity might be mediated via induction of SOCS expression with different kinetics in T cells....

  8. Unraveling the complexities of the interferon response during SARS-CoV infection

    NARCIS (Netherlands)

    A. de Lang (Anna); T. Baas (Tracey); S.L. Smits (Saskia); M.G. Katze (Michael); A.D.M.E. Osterhaus (Albert); B.L. Haagmans (Bart)

    2009-01-01

    textabstractViruses employ different strategies to circumvent the antiviral actions of the innate immune response. SARS coronavirus (SARS-CoV), a virus that causes severe lung damage encodes an array of proteins able to inhibit induction and signaling of type-I interferons. However, recent studies

  9. The innovative development in interferon beta treatments of relapsing-remitting multiple sclerosis

    DEFF Research Database (Denmark)

    Madsen, Claus

    2017-01-01

    The introduction of interferon beta therapies more than 20 years ago marked a milestone in the treatment of relapsing-remitting multiple sclerosis (RRMS) with a significant impact on the approach to modern multiple sclerosis (MS) care. Key learnings and perspectives from the early days of disease...... modifying therapies in MS have improved the knowledge base of MS, need for treatment, and patient care. The continuous development of interferons over the past two decades outlines a journey with increased understanding of the pharmacodynamics and pharmacokinetic mechanisms of interferons, leading...

  10. The value of {sup 18}F-FDG PET before and after induction chemotherapy for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy in oesophageal adenocarcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Rossum, Peter S.N. van [The University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX (United States); University Medical Center Utrecht, Department of Radiation Oncology, Utrecht (Netherlands); Fried, David V.; Zhang, Lifei; Court, Laurence E. [The University of Texas MD Anderson Cancer Center, Department of Radiation Physics, Houston, TX (United States); Hofstetter, Wayne L. [The University of Texas MD Anderson Cancer Center, Department of Thoracic and Cardiovascular Surgery, Houston, TX (United States); Ho, Linus [The University of Texas MD Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Houston, TX (United States); Meijer, Gert J. [University Medical Center Utrecht, Department of Radiation Oncology, Utrecht (Netherlands); Carter, Brett W. [The University of Texas MD Anderson Cancer Center, Department of Diagnostic Radiology, Houston, TX (United States); Lin, Steven H. [The University of Texas MD Anderson Cancer Center, Department of Radiation Oncology, Houston, TX (United States)

    2017-01-15

    The purpose of our study was to determine the value of {sup 18}F-FDG PET before and after induction chemotherapy in patients with oesophageal adenocarcinoma for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy (CRT). In 70 consecutive patients receiving a three-step treatment strategy of induction chemotherapy and preoperative chemoradiotherapy for oesophageal adenocarcinoma, {sup 18}F-FDG PET scans were performed before and after induction chemotherapy (before preoperative CRT). SUV{sub max}, SUV{sub mean}, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were determined at these two time points. The predictive potential of (the change in) these parameters for a poor pathologic response, progression-free survival (PFS) and overall survival (OS) was assessed. A poor pathologic response after induction chemotherapy and preoperative CRT was found in 27 patients (39 %). Patients with a poor pathologic response experienced less of a reduction in TLG after induction chemotherapy (p < 0.01). The change in TLG was predictive for a poor pathologic response at a threshold of -26 % (sensitivity 67 %, specificity 84 %, accuracy 77 %, PPV 72 %, NPV 80 %), yielding an area-under-the-curve of 0.74 in ROC analysis. Also, patients with a decrease in TLG lower than 26 % had a significantly worse PFS (p = 0.02), but not OS (p = 0.18). {sup 18}F-FDG PET appears useful to predict a poor pathologic response as well as PFS early after induction chemotherapy in patients with oesophageal adenocarcinoma undergoing a three-step treatment strategy. As such, the early {sup 18}F-FDG PET response after induction chemotherapy could aid in individualizing treatment by modification or withdrawal of subsequent preoperative CRT in poor responders. (orig.)

  11. Defining critical roles for NF-κB p65 and type I interferon in innate immunity to rhinovirus.

    Science.gov (United States)

    Bartlett, Nathan W; Slater, Louise; Glanville, Nicholas; Haas, Jennifer J; Caramori, Gaetano; Casolari, Paolo; Clarke, Deborah L; Message, Simon D; Aniscenko, Julia; Kebadze, Tatiana; Zhu, Jie; Mallia, Patrick; Mizgerd, Joseph P; Belvisi, Maria; Papi, Alberto; Kotenko, Sergei V; Johnston, Sebastian L; Edwards, Michael R

    2012-12-01

    The importance of NF-κB activation and deficient anti-viral interferon induction in the pathogenesis of rhinovirus-induced asthma exacerbations is poorly understood. We provide the first in vivo evidence in man and mouse that rhinovirus infection enhanced bronchial epithelial cell NF-κB p65 nuclear expression, NF-κB p65 DNA binding in lung tissue and NF-κB-regulated airway inflammation. In vitro inhibition of NF-κB reduced rhinovirus-induced pro-inflammatory cytokines but did not affect type I/III interferon induction. Rhinovirus-infected p65-deficient mice exhibited reduced neutrophilic inflammation, yet interferon induction, antiviral responses and virus loads were unaffected, indicating that NF-κB p65 is required for pro-inflammatory responses, but redundant in interferon induction by rhinoviruses in vivo. Conversely, IFNAR1(-/-) mice exhibited enhanced neutrophilic inflammation with impaired antiviral immunity and increased rhinovirus replication, demonstrating that interferon signalling was critical to antiviral immunity. We thus provide new mechanistic insights into rhinovirus infection and demonstrate the therapeutic potential of targeting NF-κB p65 (to suppress inflammation but preserve anti-viral immunity) and type I IFN signalling (to enhance deficient anti-viral immunity) to treat rhinovirus-induced exacerbations of airway diseases. Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

  12. Human Cytomegalovirus IE2 86 kDa Protein Induces STING Degradation and Inhibits cGAMP-Mediated IFN-β Induction

    Directory of Open Access Journals (Sweden)

    Jung-Eun Kim

    2017-09-01

    Full Text Available Stimulator of interferon genes (STING is a critical signaling molecule in the innate immune response against DNA viruses by either directly sensing intracellular DNA or functioning as an adaptor molecule to activate the type I interferon (IFN signaling pathway. We determined the functional interaction between STING and human cytomegalovirus (HCMV. A cDNA library containing 133 HCMV ORFs was screened to identify viral genes that inhibit STING-induced IFN-β promoter activation. Among the screened ORFs, UL122, which encodes the immediate-early 2 86 kDa (IE86 protein, strongly abolished STING-induced IFN-β promoter activation. Interestingly, IE86 protein facilitated the proteasome-dependent degradation of STING and inhibited 2′3′-cGAMP-mediated induction of IFNB1 and CXCL10. Taken together, this study demonstrates the existence of a post-translational regulation of STING by HCMV IE86 protein.

  13. Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms.

    Directory of Open Access Journals (Sweden)

    Marieke C Verweij

    2015-05-01

    Full Text Available Varicella zoster virus (VZV causes chickenpox in humans and, subsequently, establishes latency in the sensory ganglia from where it reactivates to cause herpes zoster. Infection of rhesus macaques with simian varicella virus (SVV recapitulates VZV pathogenesis in humans thus representing a suitable animal model for VZV infection. While the type I interferon (IFN response has been shown to affect VZV replication, the virus employs counter mechanisms to prevent the induction of anti-viral IFN stimulated genes (ISG. Here, we demonstrate that SVV inhibits type I IFN-activated signal transduction via the JAK-STAT pathway. SVV-infected rhesus fibroblasts were refractory to IFN stimulation displaying reduced protein levels of IRF9 and lacking STAT2 phosphorylation. Since previous work implicated involvement of the VZV immediate early gene product ORF63 in preventing ISG-induction we studied the role of SVV ORF63 in generating resistance to IFN treatment. Interestingly, SVV ORF63 did not affect STAT2 phosphorylation but caused IRF9 degradation in a proteasome-dependent manner, suggesting that SVV employs multiple mechanisms to counteract the effect of IFN. Control of SVV ORF63 protein levels via fusion to a dihydrofolate reductase (DHFR-degradation domain additionally confirmed its requirement for viral replication. Our results also show a prominent reduction of IRF9 and inhibition of STAT2 phosphorylation in VZV-infected cells. In addition, cells expressing VZV ORF63 blocked IFN-stimulation and displayed reduced levels of the IRF9 protein. Taken together, our data suggest that varicella ORF63 prevents ISG-induction both directly via IRF9 degradation and indirectly via transcriptional control of viral proteins that interfere with STAT2 phosphorylation. SVV and VZV thus encode multiple viral gene products that tightly control IFN-induced anti-viral responses.

  14. A murrel interferon regulatory factor-1: molecular characterization, gene expression and cell protection activity.

    Science.gov (United States)

    Arockiaraj, Jesu; Sathyamoorthi, Akila; Kumaresan, Venkatesh; Palanisamy, Rajesh; Chaurasia, Mukesh Kumar; Bhatt, Prasanth; Gnanam, Annie J; Pasupuleti, Mukesh; Arasu, Abirami

    2014-08-01

    In this study, we have reported a first murrel interferon regulatory factor-1 (designated as Murrel IRF-1) which is identified from a constructed cDNA library of striped murrel Channa striatus. The identified sequence was obtained by internal sequencing method from the library. The Murrel IRF-1 varies in size of the polypeptide from the earlier reported fish IRF-1. It contains a DNA binding domain along with a tryptophan pentad repeats, a nuclear localization signal and a transactivation domain. The homologous analysis showed that the Murrel IRF-1 had a significant sequence similarity with other known fish IRF-1 groups. The phylogenetic analysis exhibited that the Murrel IRF-1 clustered together with IRF-1 members, but the other members including IRF-2, 3, 4, 5, 6, 7, 8, 9 and 10 were clustered individually. The secondary structure of Murrel IRF-1 contains 27% α-helices (85 aa residues), 5.7% β-sheets (19 aa residues) and 67.19% random coils (210 aa residues). Furthermore, we predicted a tertiary structure of Murrel IRF-1 using I-Tasser program and analyzed the structure on PyMol surface view. The RNA structure of the Murrel IRF-1 along with its minimum free energy (-284.43 kcal/mol) was also predicted. The highest gene expression was observed in spleen and its expression was inducted with pathogenic microbes which cause epizootic ulcerative syndrome in murrels such as fungus, Aphanomyces invadans and bacteria, Aeromonas hydrophila, and poly I:C, a viral RNA analog. The results of cell protection assay suggested that the Murrel IRF-1 regulates the early defense response in C. striatus. Moreover, it showed Murrel IRF-1 as a potential candidate which can be developed as a therapeutic agent to control microbial infections in striped murrel. Overall, these results indicate the immune importance of IRF-1, however, the interferon signaling mechanism in murrels upon infection is yet to be studied at proteomic level.

  15. Immune- and miRNA-response to recombinant interferon beta-1a: a biomarker evaluation study to guide the development of novel type I interferon- based therapies.

    Science.gov (United States)

    Coenen, Martin; Hinze, Annette Viktoria; Mengel, Martin; Fuhrmann, Christine; Lüdenbach, Bastian; Zimmermann, Julian; Dykstra, Verena; Fimmers, Rolf; Viviani, Roberto; Stingl, Julia; Holdenrieder, Stefan; Müller, Marcus; Hartmann, Gunther; Coch, Christoph

    2015-09-22

    The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand. ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables. The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to

  16. DMPD: TICAM-1 and TICAM-2: toll-like receptor adapters that participate in inductionof type 1 interferons. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15618008 TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction... Mar;37(3):524-9. (.png) (.svg) (.html) (.csml) Show TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction... TICAM-2: toll-like receptor adapters that participate in inductionof type 1 interferons. Authors Seya T, Os

  17. Cycloheximide induces expression of the human interferon beta 1 gene in mouse cells transformed by bovine papillomavirus-interferon beta 1 recombinants.

    OpenAIRE

    Maroteaux, L; Chen, L.; Mitrani-Rosenbaum, S; Howley, P M; Revel, M

    1983-01-01

    Mouse cells transformed by a bovine papillomavirus recombinant vector containing the human interferon (IFN) beta 1 (IFN-beta 1) gene could be induced to produce human as well as mouse IFNs. The optimal conditions for induction of human IFN and of its mRNA in these transformants resembled those needed for mouse IFN: high concentrations of DEAE-dextran and low concentrations of polyriboinosinic acid-polyribocytidylic acid. Superinduction by inhibitors of protein synthesis which strongly stimula...

  18. Practicing induction:

    DEFF Research Database (Denmark)

    Sprogøe, Jonas; Rohde, Nicolas

    2009-01-01

    We claim that induction potentially triggers both individual and organizational learning and by drawing on practice-based theory we discuss how the interplay between individual and organization, what we call a generative dance, ignites both kinds of learning....

  19. The human respiratory syncytial virus nonstructural protein 1 regulates type I and type II interferon pathways.

    Science.gov (United States)

    Hastie, Marcus L; Headlam, Madeleine J; Patel, Nirav B; Bukreyev, Alexander A; Buchholz, Ursula J; Dave, Keyur A; Norris, Emma L; Wright, Cassandra L; Spann, Kirsten M; Collins, Peter L; Gorman, Jeffrey J

    2012-05-01

    Respiratory syncytial viruses encode a nonstructural protein (NS1) that interferes with type I and III interferon and other antiviral responses. Proteomic studies were conducted on human A549 type II alveolar epithelial cells and type I interferon-deficient Vero cells (African green monkey kidney cells) infected with wild-type and NS1-deficient clones of human respiratory syncytial virus to identify other potential pathway and molecular targets of NS1 interference. These analyses included two-dimensional differential gel electrophoresis and quantitative Western blotting. Surprisingly, NS1 was found to suppress the induction of manganese superoxide dismutase (SOD2) expression in A549 cells and to a much lesser degree Vero cells in response to infection. Because SOD2 is not directly inducible by type I interferons, it served as a marker to probe the impact of NS1 on signaling of other cytokines known to induce SOD2 expression and/or indirect effects of type I interferon signaling. Deductive analysis of results obtained from cell infection and cytokine stimulation studies indicated that interferon-γ signaling was a potential target of NS1, possibly as a result of modulation of STAT1 levels. However, this was not sufficient to explain the magnitude of the impact of NS1 on SOD2 induction in A549 cells. Vero cell infection experiments indicated that NS1 targeted a component of the type I interferon response that does not directly induce SOD2 expression but is required to induce another initiator of SOD2 expression. STAT2 was ruled out as a target of NS1 interference using quantitative Western blot analysis of infected A549 cells, but data were obtained to indicate that STAT1 was one of a number of potential targets of NS1. A label-free mass spectrometry-based quantitative approach is proposed as a means of more definitive identification of NS1 targets.

  20. Co-induction of cyclooxyenase-2 and early growth response gene (Egr-1 in spinal cord in a clinical model of persistent inflammation and hyperalgesia

    Directory of Open Access Journals (Sweden)

    Dolan Sharron

    2011-11-01

    Full Text Available Abstract Background This study characterised the effects of persistent peripheral inflammation of the foot on pain and spinal cord expression of cyclooxygenase-1 and -2 (COX-1 and COX-2 and early growth response gene 1 (Egr-1, known markers of neuronal plasticity, in a clinical model of naturally-occurring inflammatory disease and hyperalgesia in sheep ('footrot', before and after routine treatment (parenteral treatment with antibiotics and antiseptic footbathing. The temporal pattern of expression of COX-1, COX-2 and Egr-1 mRNA and protein were analysed using real-time PCR and Western blotting. Results Animals affected with persistent peripheral inflammation displayed significant hyperalgesia and lameness (a proxy indicator of spontaneous pain restricted to the inflamed limb. Hyperalgesia and lameness were significantly attenuated 1 day after treatment, and resolved further by day 7 and day 3, respectively. COX-2 but not COX-1, protein expression was up-regulated in spinal cord from lame animals on day 0, before treatment. Following treatment and attenuation of pain behaviours, levels of COX-2 returned to control levels. Significant induction of Egr-1 mRNA and protein were observed in spinal cord from lame animals. Three days after treatment, levels of Egr-1 mRNA returned to control levels, however, Egr-1 protein remained elevated. Conclusion Elevated levels of spinal COX-2 and Egr-1 protein correlate with the presence of pain and hyperalgesia, and may underlie persistent pain, although a direct causal link has still to be established. Understanding the temporal pattern of expression of key mediators in clinical pain states may lead to better strategies to manage pain.

  1. [Hepatitis C, interferon a and depression: main physiopathologic hypothesis].

    Science.gov (United States)

    Vignau, J; Karila, L; Costisella, O; Canva, V

    2005-01-01

    Imputability of thymic disorders caused by IFNalpha during the chronic Hepatitis C treatment -- hepatitis C and depression -- the infection by the hepatitis C virus (HCV) is a major public health concern since it affects 1.2% in the French population. Eighty percent of those contaminated by HCV keep bearing the virus chronically although they remain asymptomatic during many years. HCV infection is associated with psychiatric symptoms like depression. Together with other factors (eg the severity of hepatic condition), depression may induce significant impairment in quality of life. Conversely, some psychiatric conditions may increase the risk of HCV infection. In drug-addicted subjects using intravenous route, HCV contamination rate ranges from 74 to 100%. Compared with general population, a higher HCV contamination rate has also been noticed in some other subgroups of subjects (patients with alcohol abuse or dependence, with alcohol-induced hepatic disease and psychiatric inpatients). However, no valid explanation to this phenomenon has been established. Interferon alpha and depression - Interferons are a variety of cytokines naturally produced by human tissues and have also been synthesized for therapeutic purposes (treatment of a variety of cancers and viral infections). Many psychobehavioural symptoms are observed under IFNalpha treatment. Among them, mood disorders are known to occur early after entry into treatment and to be within the reach of preventive measures. The reported frequency of depression during IFNalpha treatment ranges from 0 to 37%. This variation reflects either methodological biases (eg differences in psychiatric assessment) or the heterogeneity of the population of patients accepted in therapeutic protocols. Note that the adjunction of ribavirine to IFNalpha in therapeutic protocols has not brought any changes in the depression frequency. The causal relationship between IFNalpha administration and the occurrence of mood disorders has been

  2. MDP Up-Regulates the Gene Expression of Type I Interferons in Human Aortic Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Xiumei Xie

    2012-03-01

    Full Text Available Muramyldipeptide (MDP, the minimum essential structure responsible for the immuno-adjuvant activity of peptidoglycan, is recognized by intracellular nuclear-binding oligomerization domain 2 (NOD2. Here, we obtained evidence that the treatment of human aortic endothelial cells (HAECs with MDP up-regulated the gene expression of type I interferons in a dose- and time-dependent manner. MDP also up-regulated the expression of the receptor NOD2, suggesting that MDP may induce a positive feedback response. The up-regulation of interferons was not dependent on the TNFa signaling, as HAECs did not express TNFa with the stimulation of MDP, and TNFa neutralizing antibody did not decrease the induction of IFNs induced by MDP. RT-PCR results showed that HAECs expressed the gene transcripts of interferon regulatory factor (IRF 1, 2, 3, 9. The western blot results showed that MDP induced the phosphorylation of IRF3. These results suggested that MDP induced the up-regulation of gene transcript of interferons through the activation of IRF3 signaling pathway. Meanwhile, MDP induced the gene expression of pro-inflammatory cytokines, including IL-1ß, IL-8, and MCP-1. Taken together, these results suggested that HAECs may play roles in the anti-infection immune response and in the induction of innate immunity.

  3. IFNB1/interferon-ß-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function

    DEFF Research Database (Denmark)

    Ambjørn, Malene; Ejlerskov, Patrick; Liu, Yawei

    2013-01-01

    IFNB1/interferon (IFN)-ß belongs to the type I IFNs and exerts potent antiproliferative, proapoptotic, antiangiogenic and immunemodulatory functions. Despite the beneficial effects of IFNB1 in experimental breast cancers, clinical translation has been disappointing, possibly due to induction of s...

  4. Interferon regulatory factor-1 protects from fatal neurotropic infection with vesicular stomatitis virus by specific inhibition of viral replication in neurons.

    Directory of Open Access Journals (Sweden)

    Sharmila Nair

    2014-03-01

    Full Text Available The innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN. In addition, the interferon regulatory factor (IRF-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducing overlapping subsets of IFN stimulated genes, the functional role of this alternative antiviral action of IRF-1 in context of viral infections in vivo remains unknown. Here, we report that IRF-1 is essential to counteract the neuropathology of vesicular stomatitis virus (VSV. IFN- and IRF-1-dependent antiviral responses act sequentially to create a layered antiviral protection program against VSV infections. Upon intranasal infection, VSV is cleared in the presence or absence of IRF-1 in peripheral organs, but IRF-1-/- mice continue to propagate the virus in the brain and succumb. Although rapid IFN induction leads to a decline in VSV titers early on, viral replication is re-enforced in the brains of IRF-1-/- mice. While IFN provides short-term protection, IRF-1 is induced with delayed kinetics and controls viral replication at later stages of infection. IRF-1 has no influence on viral entry but inhibits viral replication in neurons and viral spread through the CNS, which leads to fatal inflammatory responses in the CNS. These data support a temporal, non-redundant antiviral function of type I IFN and IRF-1, the latter playing a crucial role in late time points of VSV infection in the brain.

  5. Induction Brazing

    DEFF Research Database (Denmark)

    Henningsen, Poul

    Induction brazing is a fast and appropriate method for industrial joining of complex geometries and metal combinations. In all types of brazing processes it is important to heat the joint interface of the two materials to the same, high temperature. If one of the specimens is warmer than the other...... materials has large influence on the heating time and temperature distribution in induction heating. In order to ensure high and uniform temperature distribution near the interface of a joint between dissimilar materials the precise coil geometry and position is of great importance. The present report...... presents a combined numerical and experimental method for determination of appropriate/optimiged coil geometry and position in induction brazing tube-to-plate joints of different ratios between tube and plate thickness and different combinations of the materials stainless steel, brass and copper...

  6. Induction accelerators

    CERN Document Server

    Takayama, Ken

    2011-01-01

    A broad class of accelerators rests on the induction principle whereby the accelerating electrical fields are generated by time-varying magnetic fluxes. Particularly suitable for the transport of bright and high-intensity beams of electrons, protons or heavy ions in any geometry (linear or circular) the research and development of induction accelerators is a thriving subfield of accelerator physics. This text is the first comprehensive account of both the fundamentals and the state of the art about the modern conceptual design and implementation of such devices. Accordingly, the first part of the book is devoted to the essential features of and key technologies used for induction accelerators at a level suitable for postgraduate students and newcomers to the field. Subsequent chapters deal with more specialized and advanced topics.

  7. The Role of Interferon in the Management of BCG Refractory Nonmuscle Invasive Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Andres F. Correa

    2015-01-01

    Full Text Available Background. Thirty to forty percent of patients with high grade nonmuscle invasive bladder cancer (NMIBC fail to respond to intravesical therapy with bacillus Calmette-Guerin (BCG. Interferon-α2B plus BCG has been shown to be effective in a subset of patients with NMIBC BCG refractory disease. Here we present a contemporary series on the effectiveness and safety of intravesical BCG plus interferon-α2B therapy in patients with BCG refractory NMIBC. Methods. From January of 2005 to April of 2014 we retrospectively found 44 patients who underwent induction with combination IFN/BCG for the management of BCG refractory NMIBC. A chart review was performed to assess initial pathological stage/grade, pathological stage/grade at the time of induction, time to IFN/BCG failure, pathological stage/grade at failure, postfailure therapy, and current disease state. Results. Of the 44 patients who met criteria for the analysis. High risk disease was found in 88.6% of patients at induction. The 12-month and 24-month recurrence-free survival were 38.6% and 18.2%, respectively. 25 (56.8% ultimately had disease recurrence. Radical cystectomy was performed in 16 (36.4% patients. Conclusion. Combination BCG plus interferon-α2B remains a reasonably safe alternative treatment for select patients with BCG refractory disease prior to proceeding to radical cystectomy.

  8. The ebolavirus VP24 interferon antagonist

    Science.gov (United States)

    Zhang, Adrianna P.P.; Abelson, Dafna M.; Bornholdt, Zachary A.; Liu, Tong; Woods, Jr, Virgil L.; Saphire, Erica Ollmann

    2012-01-01

    Suppression during the early phases of the immune system often correlates directly with a fatal outcome for the host. The ebolaviruses, some of the most lethal viruses known, appear to cripple initial stages of the host defense network via multiple distinct paths. Two of the eight viral proteins are critical for immunosuppression. One of these proteins is VP35, which binds double-stranded RNA and antagonizes several antiviral signaling pathways.1,2 The other protein is VP24, which binds transporter molecules to prevent STAT1 translocation.3 A more recent discovery is that VP24 also binds STAT1 directly,4 suggesting that VP24 may operate in at least two separate branches of the interferon pathway. New crystal structures of VP24 derived from pathogenic and nonpathogenic ebolaviruses reveal its novel, pyramidal fold, upon which can be mapped sites required for virulence and for STAT1 binding. These structures of VP24, and new information about its direct binding to STAT1, provide avenues by which we may explore its many roles in the viral life cycle, and reasons for differences in pathogenesis among the ebolaviruses. PMID:23076242

  9. Production of interferon in respiratory syncytial virus bronchiolitis.

    OpenAIRE

    Isaacs, D

    1989-01-01

    Production of interferon alfa in vitro was significantly reduced during acute respiratory syncytial virus bronchiolitis but subsequently returned to normal. Nasopharyngeal and endotracheal interferon alfa were detected intermittently and in low concentrations. The degree of impairment of in vitro production and poor in vivo production of interferon alfa suggest the need for a therapeutic trial of nebulised or systemic interferon in acute bronchiolitis.

  10. Mediators of protection against lethal systemic vesicular stomatitis virus infection in hamsters: defective interfering particles, polyinosinate-polycytidylate, and interferon

    Energy Technology Data Exchange (ETDEWEB)

    Fultz, P.N.; Shadduck, J.A.; Kang, C.Y.; Streilein, J.W.

    1982-08-01

    Homologous defective interfering (DI) particles protected adult Syrian hamsters against lethal systemic infection with vesicular stomatitis virus (VSV) serotype Indiana. The DI particles had to be biologically active, but did not have to be administered at the same inoculation site as the infectious virus. Serum and tissue levels of VSV postinoculation were significantly lower in DI-protected animals than in unprotected controls, suggesting that true autointerference was occurring. However, some aspects of protection also must be mediated through nonspecific mechanisms, since susceptible hamsters could be protected against VSV Indiana by coinjection with heterologous DI particles prepared from VSV serotype New Jersey or by simultaneous administration of polyinosinic acid-polycytidylic acid. By measuring serum levels of putative hamster interferon (type 1), we found that animals coinjected with VSV and DI particles or polyinosinic acid-polycytidylic acid produced significant levels of interferon. Since similarly high serum levels of interferon were measured in recipients of VSV alone (animals that eventually died from infection), there appeared to be no correlation between protection against lethal disease and induced levels of serum interferon. Instead, serum interferon levels correlated positively with amounts of VSV PFU found in serum and tissues of infected animals, the lowest levels being found in serum of animals protected with homologous DI particles. The data are consistent with the hypothesis that autointerference by DI particles as well as various host defense mechanisms (possibly including induction of interferon) participates in protecting hamsters against lethal VSV infection.

  11. Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer.

    Science.gov (United States)

    Trott, Josephine F; Kim, Jeffrey; Abu Aboud, Omran; Wettersten, Hiromi; Stewart, Benjamin; Berryhill, Grace; Uzal, Francisco; Hovey, Russell C; Chen, Ching-Hsien; Anderson, Katie; Graef, Ashley; Sarver, Aaron L; Modiano, Jaime F; Weiss, Robert H

    2016-10-11

    Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFNα therapy with an IDO inhibitor should be revisited for RCC.

  12. An innate antiviral pathway acting before interferons at epithelial surfaces

    DEFF Research Database (Denmark)

    Iversen, Marie B; Reinert, Line S; Thomsen, Martin K

    2015-01-01

    Mucosal surfaces are exposed to environmental substances and represent a major portal of entry for microorganisms. The innate immune system is responsible for early defense against infections and it is believed that the interferons (IFNs) constitute the first line of defense against viruses. Here...... we identify an innate antiviral pathway that works at epithelial surfaces before the IFNs. The pathway is activated independently of known innate sensors of viral infections through a mechanism dependent on viral O-linked glycans, which induce CXCR3 chemokines and stimulate antiviral activity...

  13. Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon

    Science.gov (United States)

    Knoblach, Theresa; Grandel, Benedikt; Seiler, Jana

    2011-01-01

    Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity. PMID:21533215

  14. Immune Control of Chlamydial Growth in the Human Epithelial Cell Line RT4 Involves Multiple Mechanisms That Include Nitric Oxide Induction, Tryptophan Catabolism and Iron Deprivation

    National Research Council Canada - National Science Library

    Igietseme, Joseph U; Ananaba, Godwin A; Candal, Debra H; Lyn, Deborah; Black, Carolyn M

    1998-01-01

    The antimicrobial activity of T cell-derived cytokines, especially interferon (IFN)-γ, against intracellular pathogens, such as Chlamydia trachomatis, involves the induction of 3 major biochemical processes...

  15. Induction practice -

    DEFF Research Database (Denmark)

    Rohde, Nicolas; Sprogøe, Jonas

    2007-01-01

    of learning. We focus on and describe the interplay that takes place in particular induction events and analyze the "dance" through the lens of learning. The paper concludes with a brief discussion about the implications for practitioners and the challenges and future research prospects we have encountered....... We draw on an empirical enquiry in two organizational settings, a Danish management consulting company and a German retail bank....

  16. Thyrotoxicosis with pegylated interferon alfa-2b.

    Science.gov (United States)

    Lowndes, Sarah A; Asher, Ruth; Middleton, Mark R

    2010-11-01

    Despite adequate surgery, a diagnosis of stage III melanoma carries a high risk of relapse, and hence mortality. Interferon alfa is the only treatment that has currently been shown to alter the natural history of the disease, delaying relapse-free survival, particularly in patients with micrometastatic disease. There is also recent evidence of a prognostic advantage conferred by the development of autoimmune conditions in patients receiving adjuvant interferon therapy. We present the case of a 27-year-old woman with stage IIIa melanoma who was entered into the European Organisation for the Research and Treatment of Cancer 18991 trial of 5-year adjuvant treatment with pegylated interferon (peginterferon) alfa-2b. The patient developed thyrotoxicosis 3 months after commencing treatment, which required treatment with propylthiouracil. The degree of thyrotoxicosis corresponded closely to the dose of peginterferon alfa-2b given. However, in this patient, the hyperthyroidism resolved spontaneously after 4 years when peginterferon treatment was still ongoing. Seven years following the initial diagnosis, the patient has not had disease relapse. Hyperthyroidism is less common than hypothyroidism as a consequence of interferon therapy, and this case is atypical in that it resolved spontaneously during interferon therapy but is in accordance with the recent evidence of a positive association between interferon-associated autoimmunity and prognosis.

  17. [Attempted suicide during interferon therapy: a case report and literature review

    Science.gov (United States)

    Pardelli, R.; Vivaldi, I.; Maccanti, O.; Sani, S.; Menicagli, V.

    1998-01-01

    Occasionally, in the medical literature, attempted or successful suicides during interferon therapy are reported. We report a case of a 32-year-old man who developed a psychotic syndrome with attempted suicide at the third month of treatment. The cessation of interferon and an appropriate psychiatric therapy determined a complete remission of symptoms. A medical literature review, through several computerized searches, showed a lack of research into the subject. The main conclusion of our article emphasizes the importance of recognizing the early neuropsychiatric symptoms, that are reversible at the cessation of treatment.

  18. Effectiveness of interferon-beta and temozolomide combination therapy against temozolomide-refractory recurrent anaplastic astrocytoma

    Directory of Open Access Journals (Sweden)

    Arai Hajime

    2007-08-01

    Full Text Available Abstract Background Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ, has demonstrated promising activity against recurrent glioma, the effects last only a few months and drug resistance develops thereafter in most cases. Induction of O6-methylguanine-DNA methyltransferase (MGMT in tumors is considered to be responsible for resistance to TMZ. Interferon-beta has been reported to suppress MGMT in an experimental glioma model. Here we report a patient with TMZ-refractory anaplastic astrocytoma (AA who was treated successfully with a combination of interferon-beta and TMZ. Case presentation A patient with recurrent AA after radiation-chemotherapy and stereotactic radiotherapy was treated with TMZ. After 6 cycles, the tumor became refractory to TMZ, and the patient was treated with interferon-beta at 3 × 106 international units/body, followed by 5 consecutive days of 200 mg/m2 TMZ in cycles of 28 days. After the second cycle the tumor decreased in size by 50% (PR. The tumor showed further shrinkage after 8 months and the patient's KPS improved from 70% to 100%. The immunohistochemical study of the initial tumor specimen confirmed positive MGMT protein expression. Conclusion It is considered that interferon-beta pre-administration increased the TMZ sensitivity of the glioma, which had been refractory to TMZ monotherapy.

  19. Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: a randomized clinical trial.

    Science.gov (United States)

    Strug, Michael R; Su, Renwei; Young, James E; Dodds, William G; Shavell, Valerie I; Díaz-Gimeno, Patricia; Ruíz-Alonso, Maria; Simón, Carlos; Lessey, Bruce A; Leach, Richard E; Fazleabas, Asgerally T

    2016-07-01

    Does a single intrauterine infusion of human chorionic gonadotropin (hCG) at the time corresponding to a Day 3 embryo transfer in oocyte donors induce favorable molecular changes in the endometrium for embryo implantation? Intrauterine hCG was associated with endometrial synchronization between endometrial glands and stroma following ovarian stimulation and the induction of early decidual markers associated with stromal cell survival. The clinical potential for increasing IVF success rates using an intrauterine hCG infusion prior to embryo transfer remains unclear based on previously reported positive and non-significant findings. However, infusion of CG in the non-human primate increases the expression of pro-survival early decidual markers important for endometrial receptivity, including α-smooth muscle actin (α-SMA) and NOTCH1. Oocyte donors (n=15) were randomly assigned to receive an intrauterine infusion of 500 IU hCG (n=7) or embryo culture media vehicle (n=8) 3 days following oocyte retrieval during their donor stimulation cycle. Endometrial biopsies were performed 2 days later, followed by either RNA isolation or tissue fixation in formalin and paraffin embedding. Reverse transcription of total RNA from endometrial biopsies generated cDNA, which was used for analysis in the endometrial receptivity array (ERA; n = 5/group) or quantitative RT-PCR to determine relative expression of ESR1, PGR, C3 and NOTCH1. Tissue sections were stained with hematoxylin and eosin followed by blinded staging analysis for dating of endometrial glands and stroma. Immunostaining for ESR1, PGR, α-SMA, C3 and NOTCH1 was performed to determine their tissue localization. Intrauterine hCG infusion was associated with endometrial synchrony and reprograming of stromal development following ovarian stimulation. ESR1 and PGR were significantly elevated in the endometrium of hCG-treated patients, consistent with earlier staging. The ERA did not predict an overall positive impact of

  20. Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis c patients: a case control study

    Directory of Open Access Journals (Sweden)

    Levi-Drummer Rachel S

    2001-12-01

    Full Text Available Abstract Background High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. Methods A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15 with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9 with no dose reduction. Results Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. Conclusions These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C.

  1. Beta interferons in clinically isolated syndromes: a meta-analysis Interferons beta nas síndromes clínicas isoladas: meta-análise

    Directory of Open Access Journals (Sweden)

    Ailton Melo

    2008-03-01

    Full Text Available Beta-interferon use in definite multiple sclerosis (MS has been proven to modify clinical and magnetic resonance imaging outcome. We review and summarize the data of published double-blind, randomized clinical trials to assess, with a meta-analysis the safety and efficacy of beta-interferon on the occurrence of relapses in patients with a first clinical event suggestive of MS. After two years of follow-up, interferon beta decreased the risk of conversion to clinically definite MS 0.51[0.39-0.65], and delayed the time to diagnosis up to 367 days. Side-effects were mild and self limited. Our findings support the efficacy of early treatment with beta-interferon in reducing conversion to clinically defined MS in patients with clinically isolated syndromes.Já é suficientemente conhecido que a utilização de interferon beta modifica o prognóstico clínico e de ressonância magnética em pacientes com esclerose múltipla (EM. Revisamos e sumarizamos os dados dos ensaios clínicos, duplo-cegos, randomizados e controlados com placebos para analisar, através de meta-análise, a segurança e eficácia dos interferons-beta sobre a ocorrência de recidivas em pacientes com um primeiro evento clínico sugestivo de EM. Após dois anos de seguimento, os interferons-beta diminuíram o risco de conversão para EM clinicamente definida 0,51[0,39-0,65] e retardaram o tempo para diagnóstico em 367 dias. Os efeitos colaterais foram leves e auto limitados. Nossos dados comprovam a eficácia e segurança do interferon-beta em reduzir a conversão para EM clinicamente definida de pacientes com síndromes clínicas isoladas.

  2. Expression of bioactive porcine interferon-alpha in Lactobacillus casei.

    Science.gov (United States)

    Ma, Shi-jie; Li, Kun; Li, Xin-Sheng; Guo, Xiao-Qing; Fu, Peng-Fei; Yang, Ming-Fan; Chen, Hong-Ying

    2014-09-01

    In this study, we constructed an expression cassette containing the inducible lac promoter and the secretion signal from an S-layer protein of Lactobacillus brevis for the expression of porcine interferon-alpha (IFN-α) in Lactobacillus casei (Lb. casei). Reverse-transcriptase PCR verified the presence of porcine IFN-α mRNA in the recombinant Lb. casei. The porcine IFN-α protein expressed in the recombinant Lb. casei was identified by both Western blot analysis and ELISA. We used various pH values and induction times to optimize the yield of IFN-α, and found that induction with 0.8% lactose for 16 h under anaerobic conditions produced the highest concentrations of IFN-α. Furthermore, the activity of porcine IFN-α in the cultural supernatant was evaluated on ST cells infected with pseudorabies virus. The results revealed that porcine IFN-α inhibited virus replication in vitro. The findings of our study indicate that recombinant Lb. casei producing porcine IFN-α has great potential for use as a novel oral antiviral agent in animal healthcare.

  3. Acute inflammatory demyelinating polyneuropathy after treatment with pegylated interferon alfa-2a in a patient with chronic hepatitis C virus infection: a case report

    Directory of Open Access Journals (Sweden)

    Lahbabi Mounia

    2012-09-01

    Full Text Available Abstract Introduction The combination of polyethylene glycol (PEGylated interferon (pegylated interferon and ribavirin has been shown to be an effective treatment for chronic hepatitis C virus. In general, common side effects related to this combination therapy are mild and are well tolerated. However, peripheral neuropathy including demyelinating polyneuropathy related to PEG-interferon α2a (pegylated interferon alfa-2a is extremely rare. In the literature, only one case of acute inflammatory demyelinating polyneuropathy related to PEG-interferon α2a has been published previously. Case presentation To the best of our knowledge we present only the second case of acute inflammatory demyelinating polyneuropathy related to PEG-interferon α2a, occurring in a 63-year-old Caucasian man. He developed tingling, numbness, and weakness of his upper and lower extremities with acute neurological deficits after five weeks of a combination therapy with PEG-interferon α2a and ribavirin for chronic hepatitis C virus infection. His clinical course, neurological findings, and his electromyogram results were all consistent with acute inflammatory demyelinating polyneuropathy. Our patient recovered completely after interferon was stopped and symptomatic treatment and a further electromyogram showed a disappearance of neuropathy. Four weeks later, PEG-interferon α2a was reintroduced with a gradually increasing dose without any reappearance of neurological symptoms allowing hepatitis C seroconversion. Conclusions Recognition of this rare yet possible presentation is important for early and accurate diagnosis and treatment. This case report also suggests that the reintroduction of PEGylated interferon in patients who had presented with acute inflammatory demyelinating polyneuropathy related to interferon α may be safe, but this must be confirmed by further studies.

  4. SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon.

    Science.gov (United States)

    Totura, Allison L; Baric, Ralph S

    2012-06-01

    SARS-CoV is a pathogenic coronavirus that emerged from a zoonotic reservoir, leading to global dissemination of the virus. The association SARS-CoV with aberrant cytokine, chemokine, and Interferon Stimulated Gene (ISG) responses in patients provided evidence that SARS-CoV pathogenesis is at least partially controlled by innate immune signaling. Utilizing models for SARS-CoV infection, key components of innate immune signaling pathways have been identified as protective factors against SARS-CoV disease, including STAT1 and MyD88. Gene transcription signatures unique to SARS-CoV disease states have been identified, but host factors that regulate exacerbated disease phenotypes still remain largely undetermined. SARS-CoV encodes several proteins that modulate innate immune signaling through the antagonism of the induction of Interferon and by avoidance of ISG effector functions. Copyright © 2012. Published by Elsevier B.V.

  5. Herpes simplex virus infection is sensed by both Toll-like receptors and retinoic acid-inducible gene- like receptors, which synergize to induce type I interferon production

    DEFF Research Database (Denmark)

    Rasmussen, Simon Brandtoft; Jensen, Søren B; Nielsen, C

    2009-01-01

    interferons (IFNs) after infection with herpes simplex virus (HSV). Our work also identified RNase L as a critical component in IFN induction. Moreover, we found that TLR9 and RLRs activate distinct, as well as overlapping, intracellular signalling pathways. Thus, RLRs are important for recognition of HSV...

  6. A 2-year Trial of Intermittent Insulin Therapy versus Metformin for the Preservation of Beta-cell Function after Initial Short-term Intensive Insulin Induction in early Type 2 Diabetes.

    Science.gov (United States)

    Retnakaran, Ravi; Choi, Haysook; Ye, Chang; Kramer, Caroline K; Zinman, Bernard

    2018-01-27

    When administered in early type 2 diabetes (T2DM), short-term intensive insulin therapy (IIT) can improve reversible beta-cell dysfunction and induce subsequent remission of diabetes. However, this remission is ultimately temporary, as beta-cell function deteriorates over time after stopping IIT. Thus, to preserve beta-cell function, we hypothesized that "induction" IIT needs to be followed by a "maintenance therapy." In this context, we sought to evaluate the impact on beta-cell function over 2-years of two approaches to maintenance therapy: intermittent short-term IIT every 3-months versus daily metformin. In this trial, 24 adults with T2DM of 2.0±1.7 years duration and A1c 6.4±0.1% were randomized to 3-weeks of induction IIT (glargine, lispro) followed by either (i) repeat IIT for up to 2-weeks every 3-months or (ii) daily metformin. Participants underwent serial assessment of beta-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test every 3-months. The primary outcome of baseline-adjusted ISSI-2 at 2-years was higher in the metformin arm compared to intermittent IIT (245.0±31.7 vs 142.2±18.4, p=0.008). Baseline-adjusted A1c at 2-years (secondary outcome) was lower in the metformin arm (6.0±0.2% vs 7.3±0.2%, p=0.0006). At study completion, 66.7% of participants randomized to metformin had A1c≤6.0% compared to 8.3% of those on intermittent IIT (p=0.009). There were no differences in insulin sensitivity. Following induction IIT, metformin was superior to intermittent IIT for maintaining beta-cell function and glycemic control over 2-years. The strategy of induction and maintenance therapy to preserve beta-cell function warrants exploration in early T2DM. This article is protected by copyright. All rights reserved.

  7. Interferon alfa with or without ribavirin for chronic hepatitis C

    DEFF Research Database (Denmark)

    Kjaergard, L L; Krogsgaard, K; Gluud, C

    2001-01-01

    To assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C.......To assess the efficacy and safety of interferon alfa with or without ribavirin for treatment of chronic hepatitis C....

  8. Interferon-alfa treatment of facial infantile haemangiomas

    DEFF Research Database (Denmark)

    Fledelius, Hans C.; Illum, N.; Jensen, H.

    2001-01-01

    ophthalmology, haemangiomas of the face, infancy, Interferon alfa, eye at risk, amblyopia, induced refractive change, ultrasound imaging......ophthalmology, haemangiomas of the face, infancy, Interferon alfa, eye at risk, amblyopia, induced refractive change, ultrasound imaging...

  9. RNase L Mediates the Antiviral Effect of Interferon through a Selective Reduction in Viral RNA during Encephalomyocarditis Virus Infection

    Science.gov (United States)

    Li, Xiao-Ling; Blackford, John A.; Hassel, Bret A.

    1998-01-01

    The 2′,5′-oligoadenylate (2-5A) system is an RNA degradation pathway which plays an important role in the antipicornavirus effects of interferon (IFN). RNase L, the terminal component of the 2-5A system, is thought to mediate this antiviral activity through the degradation of viral RNA; however, the capacity of RNase L to selectively target viral RNA has not been carefully examined in intact cells. Therefore, the mechanism of RNase L-mediated antiviral activity was investigated following encephalomyocarditis virus (EMCV) infection of cell lines in which expression of transfected RNase L was induced or endogenous RNase L activity was inhibited. RNase L induction markedly enhanced the anti-EMCV activity of IFN via a reduction in EMCV RNA. Inhibition of endogenous RNase L activity inhibited this reduction in viral RNA. RNase L had no effect on IFN-mediated protection from vesicular stomatitis virus. RNase L induction reduced the rate of EMCV RNA synthesis, suggesting that RNase L may target viral RNAs involved in replication early in the virus life cycle. The RNase L-mediated reduction in viral RNA occurred in the absence of detectable effects on specific cellular mRNAs and without any global alteration in the cellular RNA profile. Extensive rRNA cleavage, indicative of high levels of 2-5A, was not observed in RNase L-induced, EMCV-infected cells; however, transfection of 2-5A into cells resulted in widespread degradation of cellular RNAs. These findings provide the first demonstration of the selective capacity of RNase L in intact cells and link this selective activity to cellular levels of 2-5A. PMID:9525594

  10. Lexicographic Path Induction

    DEFF Research Database (Denmark)

    Schürmann, Carsten; Sarnat, Jeffrey

    2009-01-01

    an induction principle that combines the comfort of structural induction with the expressive strength of transfinite induction. Using lexicographic path induction, we give a consistency proof of Martin-Löf’s intuitionistic theory of inductive definitions. The consistency of Heyting arithmetic follows directly...

  11. Interferon-α treatment in systemic mastocytosis

    DEFF Research Database (Denmark)

    Bjerrum, Ole Weis

    2011-01-01

    Patients with systemic mastocytosis are rare, constitute a heterogeneous clinical entity and some may not require treatment until long after diagnosis. However, most patients who present with disabling symptoms, organ involvement and fulfill B or C findings as outlined in the 2008 WHO...... classification need treatment. This review on interferon treatment in systemic mastocytosis documents an effect of this biological agent in some patients with mastocytosis. However, the place of interferon-α, as mono- or combination therapy, in the treatment algorithm may only be definitely established...

  12. Interferon-α treatment in systemic mastocytosis

    DEFF Research Database (Denmark)

    Bjerrum, Ole Weis

    2011-01-01

    Patients with systemic mastocytosis are rare, constitute a heterogeneous clinical entity and some may not require treatment until long after diagnosis. However, most patients who present with disabling symptoms, organ involvement and fulfill B or C findings as outlined in the 2008 WHO...... classification need treatment. This review on interferon treatment in systemic mastocytosis documents an effect of this biological agent in some patients with mastocytosis. However, the place of interferon-a, as mono- or combination therapy, in the treatment algorithm may only be definitely established...

  13. Long-term efficacy and safety of low-dose and dose-escalating interferon alfa-2a therapy in refractory Behçet uveitis.

    Science.gov (United States)

    Onal, Sumru; Kazokoglu, Haluk; Koc, Aylin; Akman, Mehmet; Bavbek, Tayfun; Direskeneli, Haner; Yavuz, Sule

    2011-03-01

    To investigate the long-term efficacy and safety of low-dose and dose-escalating therapy of interferon alfa-2a in the treatment of Behçet uveitis. This study included 37 patients with refractory Behçet panuveitis unresponsive to conventional immunosuppressive therapy. Induction interferon alfa-2a therapy was given as a daily dose of 3.0 million IU (MIU) subcutaneously for 14 days. Maintenance dose was achieved with 3.0 MIU 3 times per week given subcutaneously. The dosage was increased sequentially to 4.5, 6.0, and 9.0 MIU 3 times per week if uveitis relapses occurred. Total therapy duration was 24 months. Primary outcome measure was control of uveitis with quiescence during maintenance therapy. Ocular relapses per patient-year before and after initiation of interferon alfa-2a therapy and a corticosteroid-sparing effect were secondary outcomes. We also estimated the rate of remission after discontinuing interferon alfa-2a therapy. During maintenance therapy, interferon alfa-2a controlled uveitis in 35 patients (95%). In 15 patients (41%), a maintenance dosage of 3.0 MIU 3 times per week controlled uveitis without any relapse. The rate of uveitis relapses decreased from 3.52 per patient-year before to 0.75 per patient-year after initiating interferon alfa-2a therapy. Seventeen patients were receiving systemic corticosteroids at the time of initiation of interferon therapy. During the maintenance stage, 9 patients were able to discontinue and 8 to taper systemic corticosteroid therapy. Survival analysis estimated that the rate of remission after discontinuation of interferon alfa-2a therapy was 76% by 3 months. The rate of remission remained stable thereafter. A treatment protocol using a low-dose and dose-escalating therapy with interferon alfa-2a was able to control and achieve remission of uveitis in most patients with refractory ocular Behçet disease.

  14. Effects of triploidy induction on physiological and immunological characteristics of rainbow trout (Oncorhynchus mykiss) at early developmental stages (fertilized eggs, eyed eggs and fry).

    Science.gov (United States)

    Salimian, Shekoofeh; Keyvanshokooh, Saeed; Salati, Amir Parviz; Pasha-Zanoosi, Hossein; Babaheydari, Samad Bahrami

    2016-02-01

    The aim of this study was to compare effects of triploidy induction on basal physiological and immunological characteristics in rainbow trout at three developmental stages including fertilized eggs, eyed eggs and fry. Eggs and milt were taken from eight females and six males. The gametes were pooled to minimize the individual differences. After insemination, the eggs were incubated at 10°C for 10min. Half of the fertilized eggs were then subjected to heat shock for 10min submerged in a 28°C water bath to induce triploidy. The remainder were incubated normally and used as diploid controls. Three batches of eggs were randomly selected from each group and were incubated at 10-11°C under the same environmental conditions in hatchery troughs until the fry stage. The first-feeding offspring were also reared under the same environmental and nutritional conditions for 38 days. Triplicate samples of 30 eggs (10 eggs per trough) from each group were selected 1.5h post-fertilization and at the eyed stage. Based on red blood cell analysis, nine diploid and nine triploid fish were also selected for study. The triploidy induction success rate was 87.1%. While diploid fish had greater body weights than those in the heat-shock treatment group, weight gain (WG%) was not different between the fry of the diploid and heat-shock treatment groups. Of thyroid hormones measured, 3,5,3'-triiodo-l-thyronine (T3) was less (Peggs of the heat-shock treatment group, but thyroxine (T4) was greater in fry of the heat-shock treatment group as compared to those that were diploid. Cortisol concentration was greater in fry of the heat-shock treatment group as compared to those that were diploid suggesting that fry in the triploid state may be more susceptible to stressors. Concentrations of immune variables (lysozyme, ACH50, albumin, IgM, total protein, globulin and complement) were either comparable or greater in fry of the heat-shock treatment group suggesting that the immune system is not

  15. Type III Interferons in Hepatitis C Virus Infection.

    Science.gov (United States)

    Boisvert, Maude; Shoukry, Naglaa H

    2016-01-01

    The interferon (IFN)-λ family of type III cytokines includes the closely related interleukin (IL)-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1). They signal through the Janus kinases (JAK)-signal transducers and activators of transcription pathway and promote an antiviral state by the induction of expression of several interferon-stimulated genes (ISGs). Contrary to type I IFNs, the effect of IFN-λ cytokines is largely limited to epithelial cells due to the restricted pattern of expression of their specific receptor. Several genome-wide association studies have established a strong correlation between polymorphism in the region of IL-28B gene (encoding for IFN-λ3) and both spontaneous and therapeutic IFN-mediated clearance of hepatitis C virus (HCV) infection, but the mechanism(s) underlying this enhanced viral clearance are not fully understood. IFN-λ3 directly inhibits HCV replication, and in vitro studies suggest that polymorphism in the IFN-λ3 and its recently identified overlapping IFN-λ4 govern the pattern of ISGs induced upon HCV infection of hepatocytes. IFN-λ can also be produced by dendritic cells, and apart from its antiviral action on hepatocytes, it can regulate the inflammatory response of monocytes/macrophages, thus acting at the interface between innate and adaptive immunity. Here, we review the current state of knowledge about the role of IFN-λ cytokines in mediating and regulating the immune response during acute and chronic HCV infections.

  16. IL-12 and IL-18 Induction and Subsequent NKT Activation Effects of the Japanese Botanical Medicine Juzentaihoto

    Directory of Open Access Journals (Sweden)

    Ken Taniguchi

    2008-07-01

    Full Text Available In this study, we first measured some cytokine concentrations in the serum of patients treated with Juzentaihoto (JTT. Of the cytokines measured interleukin (IL -18 was the most prominently up-regulated cytokine in the serum of patients under long term JTT administration. We next evaluated the effects of JTT in mice, focusing especially on natural killer T (NKT cell induction. Mice fed JTT were compared to control group ones. After sacrifice, the liver was fixed, embedded and stained. Transmission electron microscope (TEM observations were performed. Although the mice receiving the herbal medicine had same appearance, their livers were infiltrated with massive mononuclear cells, some of which were aggregated to form clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of IL-12 and IL-18 in the liver of JTT treated mice. To clarify what the key molecules that induce immunological restoration with JTT might be, we next examined in vitro lymphocyte cultures. Mononuclear cells isolated and prepared from healthy volunteers were cultured with and without JTT. Within 24 hours, JTT induced the IL-12 and IL-18 production and later (72 hours induction of interferon (IFN-gamma. Oral administration of JTT may induce the expression of IL-12 in the early stage, and IL-18 in the chronic stage, followed by NKT induction. Their activation, following immunological restoration could contribute to anti-tumor effects.

  17. Interleukins, interferons, and establishment of pregnancy in pigs.

    Science.gov (United States)

    Mathew, Daniel J; Lucy, Matthew C; D Geisert, Rodney

    2016-06-01

    Early pregnancy in mammals requires complex and highly orchestrated cellular and molecular interactions between specialized cells within the endometrium and the conceptus. Proinflammatory cytokines are small signaling proteins released by leukocytes that augment innate and adaptive immune responses. They are also released by the mammalian trophectoderm as the conceptus apposes the uterine surface for implantation. On approximately day 12 of development in pigs, the conceptus undergoes a rapid morphological transformation referred to as elongation while simultaneously releasing estrogens and a novel conceptus form of interleukin-1 beta (IL1β). Following elongation, pig conceptuses express interferon gamma (IFNγ) and, in lesser amounts, interferon delta (IFNδ). Significant IFN signaling takes place within the endometrium between day 14 and 18 of pregnancy as the conceptus intimately associates with the uterine epithelium. Based on studies carried out in pigs and other mammals, the combined spacio-temporal activities of conceptus estrogens, IL1β, and IFN set in motion a series of coordinated events that promote establishment of pregnancy. This is achieved through enhancement of conceptus development, uterine receptivity, maternal-fetal hemotropic exchange, and endometrial leukocyte function. These events require activation of specific signaling pathways within the uterine luminal epithelium, glandular epithelium, and stroma. Here, we review proinflammatory cytokine expression by pig conceptuses and the hypothesized actions of these molecules during establishment of pregnancy. © 2016 Society for Reproduction and Fertility.

  18. Low concentration of PDGF-AB shows synergism with IFN-α in induction of IFN-β and -γ in MRC5 fibroblasts.

    Science.gov (United States)

    Šantak, G; Šantak, M; Forčić, D

    2013-11-01

    Platelet-derived growth factor (PDGF) is a potent mediator of fibroblast proliferation and chemotaxis. Also it has been reported as a strong suppressor of interferon (IFN) expression. IFN-α has opposite effect on fibroblast function and IFN induction. Here is our early report on the effect of low concentration of PDGF-AB alone or in combination with IFN-α on IFN mRNA production in MRC5 fibroblasts. MRC5 cells incubated with IFN-α or PDGF-AB, alone or in combination, produced significant induction of IFN-α, -β and -γ mRNA in comparison with untreated cells. The induction was dose-dependent, with higher effect in cells treated with lower concentrations of PDGF-AB. Also, low concentration of PDGF-AB showed synergism with IFN-α in IFN-β and -γ induction. Results presented here open new possibilities in multi-cytokine therapy and expand previous results on PDGF activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1.

    Science.gov (United States)

    Kurhade, Chaitanya; Zegenhagen, Loreen; Weber, Elvira; Nair, Sharmila; Michaelsen-Preusse, Kristin; Spanier, Julia; Gekara, Nelson O; Kröger, Andrea; Överby, Anna K

    2016-01-27

    Although type I interferons (IFNs)-key effectors of antiviral innate immunity are known to be induced via different pattern recognition receptors (PRRs), the cellular source and the relative contribution of different PRRs in host protection against viral infection is often unclear. IPS-1 is a downstream adaptor for retinoid-inducible gene I (RIG-I)-like receptor signaling. In this study, we investigate the relative contribution of IPS-1 in the innate immune response in the different brain regions during infection with tick-borne encephalitis virus (TBEV), a flavivirus that causes a variety of severe symptoms like hemorrhagic fevers, encephalitis, and meningitis in the human host. IPS-1 knockout mice were infected with TBEV/Langat virus (LGTV), and viral burden in the peripheral and the central nervous systems, type I IFN induction, brain infiltrating cells, and inflammatory response was analyzed. We show that IPS-1 is indispensable for controlling TBEV and LGTV infections in the peripheral and central nervous system. Our data indicate that IPS-1 regulates neuropathogenicity in mice. IFN response is differentially regulated in distinct regions of the central nervous system (CNS) influencing viral tropism, as LGTV replication was mainly restricted to olfactory bulb in wild-type (WT) mice. In contrast to the other brain regions, IFN upregulation in the olfactory bulb was dependent on IPS-1 signaling. IPS-1 regulates basal levels of antiviral interferon-stimulated genes (ISGs) like viperin and IRF-1 which contributes to the establishment of early viral replication which inhibits STAT1 activation. This diminishes the antiviral response even in the presence of high IFN-β levels. Consequently, the absence of IPS-1 causes uncontrolled virus replication, in turn resulting in apoptosis, activation of microglia and astrocytes, elevated proinflammatory response, and recruitment of inflammatory cells into the CNS. We show that LGTV replication is restricted to the olfactory

  20. Role of cellular caspases, nuclear factor-kappa B and interferon regulatory factors in Bluetongue virus infection and cell fate

    Directory of Open Access Journals (Sweden)

    Roy Polly

    2010-12-01

    Full Text Available Abstract Background Bluetongue virus (BTV infection causes haemorrhagic disease in ruminants and induces cell death. The pathogenesis in animals and in cell culture has been linked to BTV-induced apoptosis. Results In this report, we investigated BTV-induced apoptosis in cell culture in depth and show that both extrinsic (caspase-8 activation and intrinsic (caspase-9 activation pathways play roles in BTV apoptosis. Further, by using chemical inhibitors and knock-out cell lines, we show that these pathways act independently of each other in BTV infected cells. In addition to activation of caspase-8, -9 and executioner caspase-3, we also identified that BTV infection causes the activation of caspase-7, which results in the cleavage of poly (ADP-ribose polymerase (PARP. BTV-induced cell death appears to be due to apoptosis rather than necrosis, as the HMBG-1 was not translocated from the nucleus. We also examined if NF-κB response is related to BTV-induced apoptosis as in reovirus. Our data suggests that NF-κB response is not linked to the induction of apoptosis. It is controlled by the degradation of only IκBα but not IκBβ, resulting in a rapid transient response during BTV infection. This was supported using an NF-κB dependent luciferase reporter gene assay, which demonstrated early response, that appeared to be suppressed by the late stage of BTV replication. Furthermore, virus titres were higher in the presence of NF-κB inhibitor (SN50, indicating that NF-κB has a role in initiating an antiviral environment. In addition, we show that BTV infection induces the translocation of interferon regulatory factors (IRF-3 and IRF-7 into the nucleus. The induction of IRF responses, when measured by IRF dependent luciferase reporter gene assay, revealed that the IRF responses, like NF-κB response, were also at early stage of infection and mirrored the timing of NF-κB induction. Conclusion BTV triggers a wide range of caspase activities resulting

  1. Analyses of the pathways involved in early- and late-phase induction of IFN-beta during C. muridarum infection of oviduct epithelial cells.

    Directory of Open Access Journals (Sweden)

    Sishun Hu

    Full Text Available We previously reported that the IFN-β secreted by Chlamydia muridarum-infected murine oviduct epithelial cells (OE cells was mostly dependent on the TLR3 signaling pathway. To further characterize the mechanisms of IFN-β synthesis during Chlamydia infection of OE cells in vitro, we utilized specific inhibitory drugs to clarify the roles of IRF3 and NF-κB on both early- and late-phase C. muridarum infections. Our results showed that the pathways involved in the early-phase of IFN-β production were distinct from that in the late-phase of IFN-β production. Disruption of IRF3 activation using an inhibitor of TBK-1 at early-phase Chlamydia infection had a significant impact on the overall synthesis of IFN-β; however, disruption of IRF3 activation at late times during infection had no effect. Interestingly, inhibition of NF-κB early during Chlamydia infection also had a negative effect on IFN-β production; however, its impact was not significant. Our data show that the transcription factor IRF7 was induced late during Chlamydia infection, which is indicative of a positive feedback mechanism of IFN-β synthesis late during infection. In contrast, IRF7 appears to play little or no role in the early synthesis of IFN-β during Chlamydia infection. Finally, we demonstrate that antibiotics that target chlamydial DNA replication are much more effective at reducing IFN-β synthesis during infection versus antibiotics that target chlamydial transcription. These results provide evidence that early- and late-phase IFN-β production have distinct signaling pathways in Chlamydia-infected OE cells, and suggest that Chlamydia DNA replication might provide a link to the currently unknown chlamydial PAMP for TLR3.

  2. Purinergic agonist induction of metallothionein.

    Science.gov (United States)

    Xiong, X; Garrett, S H; Arizono, K; Brady, F O

    1992-10-01

    Metallothionein (MT) protein is readily induced in vivo in rat liver by adenosine and adenosine agonists (2-chloroadenosine, 5-(N-ethyl) carboxamido adenosine, and 5-chloro-5-deoxyadenosine). These presumably operate via AMP/adenosine receptors of the P1 (A2) type, which use the cAMP pathway. ATP was ineffective as an inducer for MT. 2-Chloroadenosine was the most effective inducer (7.27-fold at 11 hr). This induction was blockable by the adenosine antagonists, caffeine and theophylline. MT protein induction by 2-chloroadenosine in primary cultured rat hepatocytes was modest (1.55-fold), but this was also blocked by theophylline. MT mRNA induction was assessed using dot blot and Northern gel assays. Large inductions by 2-chloroadenosine (5.1- to 41-fold) were seen, and these were detectable as early as 2 hr in vivo. Two rat hepatoma cell lines (EC3 and 2M) were studied in vitro. Modest inductions of MT mRNA were seen: 2.10-fold for EC3 and 4.12-fold for 2M. Our studies implicate the potential role of the purinergic system in the modulation of transcription of MT genes in rat liver. The sources of adenosine in vivo that might cause induction of MT mRNA and protein are not well defined, but adenosine may be important as a signal in stress response situations involving tissue damage, such as ischemia, hypoxia, and hemorrhagic shock.

  3. Intensive induction chemotherapy followed by early high-dose therapy and hematopoietic stem cell transplantation results in improved outcome for patients with hepatosplenic T-cell lymphoma: a single institution experience.

    Science.gov (United States)

    Voss, Martin H; Lunning, Matthew A; Maragulia, Jocelyn C; Papadopoulos, Esperanza B; Goldberg, Jenna; Zelenetz, Andrew D; Horwitz, Steven M

    2013-02-01

    Hepatosplenic T-cell lymphoma is a rare form of extranodal non-Hodgkin lymphoma, first recognized as a distinct entity in the Revised European-American Lymphoma classification. Typical presentation includes lymphomatous infiltration of spleen and liver, and peripheral lymphadenopathy is rarely seen. The prognosis is almost uniformly poor, and there are no prospective studies of treatment of HSTCL. For this report, we conducted a retrospective review of all pts who underwent treatment for HSTCL at our institution. Individual chart review was performed to report clinical presentation, management, and outcome. We identified 14 pts with HSTCL managed at our center, 7 of which remain alive with median follow-up of 65.6 months. Six of 7 received alternative induction chemotherapy regimens such as ICE (ifosfamide, carboplatin, etoposide) or IVAC (ifosfamide, etoposide, high-dose cytarabine) as opposed to CHOP and all surviving pts had proceeded to undergo either autologous or allogeneic SCT. Our results suggest that use of non-CHOP induction regimen and early use of high dose therapy and SCT consolidation may translate to improved survival for pts with HSTCL. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Laboratory evaluation of commercial interferon preparations

    African Journals Online (AJOL)

    The antiviral, antiproliferative and natural killer-cell. (NKC) stimulatory activities of four commercial the- rapeutic interferon preparations were assayed in our laboratory. The antiviral and antiproliferative activities of each preparation were relatively similar, but an unexpectedly high NKC stimulatory activity was foupd in one ...

  5. Neuropsychiatric Complications Associated with Interferon - Alpha ...

    African Journals Online (AJOL)

    Adelaide and Meath Hospital, Tallaght, Ireland. Abstract. Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man.

  6. Laboratory evaluation of commercial interferon preparations

    African Journals Online (AJOL)

    Antiviral radio-immunoassay. This technique has been described in greater detail else- where. 7 The test is based on the quantitation by radio-immuno- assay of the reduction of growth of challenge Sindbis virus due to the protection of cells by the interferon samples. Briefly, confluent monolayers of Vero cells were grown in.

  7. Interferons in the central nervous system

    DEFF Research Database (Denmark)

    Owens, Trevor; Khorooshi, Reza M. H.; Wlodarczyk, Agnieszka

    2014-01-01

    Interferons (IFNs) are implicated as an important component of the innate immune system influencing viral infections, inflammation, and immune surveillance. We review here the complex biological activity of IFNs in the central nervous system (CNS) and associated glial–immune interactions...

  8. Quantification of interferon signaling in avian cells

    NARCIS (Netherlands)

    Kint, Joeri; Forlenza, Maria

    2015-01-01

    Activation of the type I interferon (IFN) response is an essential defense mechanism against invading pathogens such as viruses. This chapter describes two protocols to quantify activation of the chicken IFN response through analysis of gene expression by real-time quantitative PCR and by

  9. Neuropsychiatric Complications Associated with Interferon - Alpha ...

    African Journals Online (AJOL)

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant ...

  10. [Pegylation and interferons in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Diego Centonze

    2016-07-01

    Full Text Available Pegylation is a procedure used for drug development since the 1970s and consists of the conjugation of a polyethylene glycol molecule (PEG to a drug. PEG has shown to be safe and effective in improving the pharmacokinetic and pharmacodynamic profile of drugs. Recently, a 20 kDa linear chain of PEG was conjugated to interferon beta-1a with the aim to offer a new treatment option to relapsing-remitting multiple sclerosis (RRMS patients. Due to a prolonged bioavailability, this new drug can be administered less frequently (every two weeks than the other interferons beta available, thus allowing to hypothesize a better adherence to the treatment, which, in turn, should result in better clinical and economic outcomes. A phase III clinical trial has proven its effectiveness compared to placebo in RRMS patients, as well as a safety profile comparable to that found in other interferon beta preparations. The immunogenicity of this new molecule is < 1%, thus minimizing the suppression or reduction of interferon beta biological activity that could come from the development of Neutralizing Antibodies (NAbs. [Article in Italian

  11. Type I Interferon Contributes to CD4+ T Cell Depletion Induced by Infection with HIV-1 in the Human Thymus▿

    OpenAIRE

    Sivaraman, Vijay; Zhang, Liguo; Su, Lishan

    2011-01-01

    Persistent induction of type 1 interferon (IFN) is associated with human immunodeficiency virus type 1 (HIV-1) infection. We report here that the pathogenic HIV strain R3A (HIV-R3A) induced high levels of type 1 IFN, while the nonpathogenic HIV-R3B showed no significant induction in human fetal thymus organ culture (HFTOC). We found that IFN contributed to the depletion of human T cells by HIV-R3A in a fusion-independent fashion. The R3B recombinant with the R3A Env V1V2 domain (R3B/A-V1V2) w...

  12. Literature systematic review on the ophthalmological side effects of interferons

    Directory of Open Access Journals (Sweden)

    Yara Dadalti Fragoso

    2011-08-01

    Full Text Available Interferons alpha and beta have been used worldwide for a few decades, altering the natural history of several severe diseases including hepatitis C, cancer and immune-mediated conditions such as multiple sclerosis. The adverse events profile of interferons is well established, but only isolated reports of ophthalmological complications of interferon therapy have been published. The objective of this study was to carry out a literature systematic review on the subject, bringing to light the need for careful ophthalmological monitoring of patients undergoing interferon treatment. Nearly 500 cases of ophthalmological complications related to interferon have been reported. The most frequent findings were soft exudates, hemorrhages and retina ischemia.

  13. Interferon-alpha in the treatment of multiple myeloma

    DEFF Research Database (Denmark)

    Khoo, T.L.; Joshua, D.; Gibson, J.

    2011-01-01

    in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs" - thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment......Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the hematological malignancy multiple myeloma. Interferon has been used...... of multiple myeloma or will interferon be resigned to the history books remains to be seen....

  14. Cystic craniopharyngioma: intratumoral chemotherapy with alpha interferon

    Directory of Open Access Journals (Sweden)

    Patrícia Alessandra Dastoli

    2011-02-01

    Full Text Available OBJECTIVE: To assess whether the cystic craniopharyngiomas can be controlled with the use of intratumoral applications of interferon alpha. METHOD: Nineteen patients with the diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with interferon alpha from January 2002 to April 2006. All patients underwent placement of an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were made applications during chemotherapy cycles. Each cycle corresponded to application of 3,000,000 units of interferon alpha three times per week on alternate days totalizing 36,000,000 units. Response to treatment was evaluated by calculating the tumor volume on MRI control after one, three and six months after the end of each cycle. Patients who developed worsening of symptoms or who had insignificant reduction in tumor volume during follow-up underwent repeat cycle chemotherapy. RESULTS: Four patients received four cycles of chemotherapy, three patients received three cycles, six patients received two cycles and six patients received one. The lower percentage of reduction in tumor volume was 60% and the bigger reduction was 98.37%. Eleven patients had a reduction greater than 90%. Five patients had a tumor reduction between 75 and 90% and in three patients the tumors were reduced by less than 75%. No deaths occurred during treatment and side effects of interferon alpha were well tolerated. No treatment was discontinued. Follow-up after the last application ranged from one year and five months to three years and nine months. CONCLUSION: The intratumoral chemotherapy with interferon alpha decreases the volume of cystic craniopharyngiomas and so far can be considered a new therapeutic alternative.

  15. Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques.

    Directory of Open Access Journals (Sweden)

    Anna de Lang

    2007-08-01

    Full Text Available The pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV is likely mediated by disproportional immune responses and the ability of the virus to circumvent innate immunity. Using functional genomics, we analyzed early host responses to SARS-CoV infection in the lungs of adolescent cynomolgus macaques (Macaca fascicularis that show lung pathology similar to that observed in human adults with SARS. Analysis of gene signatures revealed induction of a strong innate immune response characterized by the stimulation of various cytokine and chemokine genes, including interleukin (IL-6, IL-8, and IP-10, which corresponds to the host response seen in acute respiratory distress syndrome. As opposed to many in vitro experiments, SARS-CoV induced a wide range of type I interferons (IFNs and nuclear translocation of phosphorylated signal transducer and activator of transcription 1 in the lungs of macaques. Using immunohistochemistry, we revealed that these antiviral signaling pathways were differentially regulated in distinctive subsets of cells. Our studies emphasize that the induction of early IFN signaling may be critical to confer protection against SARS-CoV infection and highlight the strength of combining functional genomics with immunohistochemistry to further unravel the pathogenesis of SARS.

  16. Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression.

    Directory of Open Access Journals (Sweden)

    Eva-K Pauli

    2008-11-01

    Full Text Available The type I interferon (IFN system is a first line of defense against viral infections. Viruses have developed various mechanisms to counteract this response. So far, the interferon antagonistic activity of influenza A viruses was mainly observed on the level of IFNbeta gene induction via action of the viral non-structural protein 1 (NS1. Here we present data indicating that influenza A viruses not only suppress IFNbeta gene induction but also inhibit type I IFN signaling through a mechanism involving induction of the suppressor of cytokine signaling-3 (SOCS-3 protein. Our study was based on the observation that in cells that were infected with influenza A virus and subsequently stimulated with IFNalpha/beta, phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1 was strongly reduced. This impaired STAT1 activation was not due to the action of viral proteins but rather appeared to be induced by accumulation of viral 5' triphosphate RNA in the cell. SOCS proteins are potent endogenous inhibitors of Janus kinase (JAK/STAT signaling. Closer examination revealed that SOCS-3 but not SOCS-1 mRNA levels increase in an RNA- and nuclear factor kappa B (NF-kappaB-dependent but type I IFN-independent manner early in the viral replication cycle. This direct viral induction of SOCS-3 mRNA and protein expression appears to be relevant for suppression of the antiviral response since in SOCS-3 deficient cells a sustained phosphorylation of STAT1 correlated with elevated expression of type I IFN-dependent genes. As a consequence, progeny virus titers were reduced in SOCS-3 deficient cells or in cells were SOCS-3 expression was knocked-down by siRNA. These data provide the first evidence that influenza A viruses suppress type I IFN signaling on the level of JAK/STAT activation. The inhibitory effect is at least in part due to the induction of SOCS-3 gene expression, which results in an impaired antiviral response.

  17. Do Gestational Age Dating Criteria Matter in Medically Indicated Late Preterm, Early-Term, and Full-Term Inductions of Labor?

    Science.gov (United States)

    Kelley, Kristen; O'Dillon Goerg, Kristen; Rhinehart-Ventura, Jessica; Eppes, Catherine; Sangi-Haghpeykar, Haleh; Davidson, Christina

    2016-03-01

    To assess short-term neonatal respiratory morbidity from inductions of labor (IOL) in well-dated (WD) pregnancies (dating ultrasound [US] anomaly. The primary outcome was a composite of neonatal respiratory morbidity (respiratory distress syndrome, transient tachypnea of the newborn, ventilator support, oxygen administration, and pneumonia). A total of 476 WD and 231 NWD women underwent IOL during the study period. The groups had similar maternal characteristics, indications for IOL, and mode of delivery. There was no difference in the rate of primary outcome (8.7% in NWD group vs 8.8% in WD group; P = 0.95). This finding persisted after control for parity, gestational age (GA) at first US, operator of the dating US, and exposure to antenatal corticosteroids and magnesium sulfate. When stratified by GA at delivery and GA at first US, these findings persisted even when the dating US was performed at >35 weeks. There were no differences in maternal or other neonatal outcomes between the WD and NWD pregnancies. In our cohort of medically indicated IOL, a dating US before 20 weeks was not associated with a difference in neonatal respiratory morbidity.

  18. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.

    Science.gov (United States)

    Eggermont, Alexander M M; Suciu, Stefan; Santinami, Mario; Testori, Alessandro; Kruit, Wim H J; Marsden, Jeremy; Punt, Cornelis J A; Salès, François; Gore, Martin; Mackie, Rona; Kusic, Zvonko; Dummer, Reinhard; Hauschild, Axel; Musat, Elena; Spatz, Alain; Keilholz, Ulrich

    2008-07-12

    Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in

  19. Chemical Reaction Network Theory elucidates sources of multistability in interferon signaling.

    Science.gov (United States)

    Otero-Muras, Irene; Yordanov, Pencho; Stelling, Joerg

    2017-04-01

    Bistability has important implications in signaling pathways, since it indicates a potential cell decision between alternative outcomes. We present two approaches developed in the framework of the Chemical Reaction Network Theory for easy and efficient search of multiple steady state behavior in signaling networks (both with and without mass conservation), and apply them to search for sources of bistability at different levels of the interferon signaling pathway. Different type I interferon subtypes and/or doses are known to elicit differential bioactivities (ranging from antiviral, antiproliferative to immunomodulatory activities). How different signaling outcomes can be generated through the same receptor and activating the same JAK/STAT pathway is still an open question. Here, we detect bistability at the level of early STAT signaling, showing how two different cell outcomes are achieved under or above a threshold in ligand dose or ligand-receptor affinity. This finding could contribute to explain the differential signaling (antiviral vs apoptotic) depending on interferon dose and subtype (α vs β) observed in type I interferons.

  20. Type I interferon reaction to viral infection in interferon-competent, immortalized cell lines from the African fruit bat Eidolon helvum.

    Directory of Open Access Journals (Sweden)

    Susanne E Biesold

    Full Text Available Bats harbor several highly pathogenic zoonotic viruses including Rabies, Marburg, and henipaviruses, without overt clinical symptoms in the animals. It has been suspected that bats might have evolved particularly effective mechanisms to suppress viral replication. Here, we investigated interferon (IFN response, -induction, -secretion and -signaling in epithelial-like cells of the relevant and abundant African fruit bat species, Eidolon helvum (E. helvum. Immortalized cell lines were generated; their potential to induce and react on IFN was confirmed, and biological assays were adapted to application in bat cell cultures, enabling comparison of landmark IFN properties with that of common mammalian cell lines. E. helvum cells were fully capable of reacting to viral and artificial IFN stimuli. E. helvum cells showed highest IFN mRNA induction, highly productive IFN protein secretion, and evidence of efficient IFN stimulated gene induction. In an Alphavirus infection model, O'nyong-nyong virus exhibited strong IFN induction but evaded the IFN response by translational rather than transcriptional shutoff, similar to other Alphavirus infections. These novel IFN-competent cell lines will allow comparative research on zoonotic, bat-borne viruses in order to model mechanisms of viral maintenance and emergence in bat reservoirs.

  1. BCG strain S4-Jena: An early BCG strain is capable to reduce the proliferation of bladder cancer cells by induction of apoptosis

    Directory of Open Access Journals (Sweden)

    Hermann Inge-Marie

    2010-06-01

    Full Text Available Abstract Background Intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guérin has been established as the most effective adjuvant treatment for high risk non-muscle-invasive bladder cancer (NMIBC. We investigated the differences between the S4-Jena BCG strain and commercially available BCG strains. We tested the genotypic varieties between S4-Jena and other BCG strains and analysed the effect of the BCG strains TICE and S4-Jena on two bladder cancer cell lines. Results In contrast to commercially available BCG strains the S4-Jena strain shows genotypic differences. Spoligotyping verifies the S4-Jena strain as a BCG strain. Infection with viable S4-Jena or TICE decreased proliferation in the T24 cell line. Additionally, hallmarks of apoptosis were detectable. In contrast, Cal29 cells showed only a slightly decreased proliferation with TICE. Cal29 cells infected with S4-Jena, though, showed a significantly decreased proliferation in contrast to TICE. Concordantly with these results, infection with TICE had no effect on the morphology and hallmarks of apoptosis of Cal29 cells. However, S4-Jena strain led to clearly visible morphological changes and caspases 3/7 activation and PS flip. Conclusions S4-Jena strain has a direct influence on bladder cancer cell lines as shown by inhibition of cell proliferation and induction of apoptosis. The data implicate that the T24 cells are responder for S4-Jena and TICE BCG. However, the Cal29 cells are only responder for S4-Jena and they are non-responder for TICE BCG. S4-Jena strain may represent an effective therapeutic agent for NMIBC.

  2. Interferon-γ and Colorectal Cancer: an up-to date.

    Science.gov (United States)

    Kosmidis, Christoforos; Sapalidis, Konstantinos; Koletsa, Triantafyllia; Kosmidou, Maria; Efthimiadis, Christoforos; Anthimidis, George; Varsamis, Nikolaos; Michalopoulos, Nikolaos; Koulouris, Charilaos; Atmatzidis, Stefanos; Liavas, Lazaros; Strati, Titika-Marina; Koimtzis, Georgios; Tsakalidis, Alexandros; Mantalovas, Stylianos; Zarampouka, Katerina; Florou, Maria; Giannakidis, Dimitrios E; Georgakoudi, Eleni; Baka, Sofia; Zarogoulidis, Paul; Man, Yan-Gao; Kesisoglou, Isaac

    2018-01-01

    Colorectal cancer still remains the third cause of cancer death among cancer patients. Early diagnosis is crucial and they can be either endoscopic or with blood biomarkers. Endoscopic methods consist of gastroscopy and colonoscopy, however; in recent years, endoscopic ultrasound is being used. The microenvironment is very important for the successful delivery of the treatment. Several proteins and hormones play a crucial role in the efficiency of the treatment. In the current mini review we will focus on interferon-γ.

  3. Effects of 2-aminoanthracene and benzo(. cap alpha. )pyrene on interferon production in human foreskin fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yu-Shiaw; Vaughn, J.M.; Morales, D.

    1987-11-01

    Human foreskin fibroblast cell cultures (Flow 7000, FS-35) were treated with varying concentrations of 2-aminoanthracene or benzo(..cap alpha..)pyrene for a two-day period prior to interferon (IFN) induction by either poly I . poly C, or 'Vesicular' Stomatitis virus (VSV). IFN in test cell fluids was then assayed and compared to production in untreated cultures. Both cell lines produced similar amounts of beta-interferon in response to poly I . poly C simulus. However, Flow 7000 fibroblasts were extremely sensitive to benzo(..cap alpha..)pyrene, with concentrations as low as 1 ..mu..M treatment inhibiting 93% of IFN-..beta.. productivity. Treatment of FS-35 cells with ten times this concentration was required to inhibit 85% of IFN-..beta.. productivity. Both test chemicals inhibited IFN-..beta.. productivity in FS-35 fibroblasts to the same extent. It was also noted that FS-35 produced alpha-interferon in response to VSV challenge, but this production was vulnerable to treatment with both test chemicals. In all cases, observed levels of IFN inhibition were directly proportional to the concentration of the applied chemical. 1 fig., 4 tabs.

  4. Macroscale production of crystalline interferon alfa-2b in microgravity on STS-52

    Science.gov (United States)

    Nagabhushan, Tattanahalli L.; Reichert, Paul; Long, Marianna M.; DeLucas, Lawrence J.; Bugg, Charles E.

    1995-01-01

    Macroscale crystallization of zinc interferon alfa-2b was achieved on STS-52 in October 1992 in the Protein Crystallization Facility. Conditions for crystallization were established by adapting a microscale vapor diffusion method to a macroscale temperature induction method. A series of earth based pilot experiments established conditions to reproducibly crystallize zinc interferon alfa-2b in high yield and under cleanroom conditions. As a control for the STS-52 mission, a ground experiment was run simultaneously and in the same configuration as the flight experiment. Greater than 95% of the available protein crystallized in both the ground and flight experiments. Using a battery of physical, biochemical and biological characterization assays, demonstrated that sample processing, polysulfone bottle confinement and the conditions used for crystallization did not have a negative effect on protein integrity. Redissolved crystals from the flight and ground experiments showed full biological activity in a cytopathic effect inhibition assay as compared to an interferon control standard. Morphometric analysis comparing the overall length and width of the derived crystals showed a 2.4 fold increase in the length and width of the space grown crystals as compared to earth grown crystals. Space grown crystals have remained a stable free flowing suspension for over 2 years. Based on these results, further experiments are envisioned to investigate macroscale crystallization of biologically active macromolecules in microgravity.

  5. Human genome-wide RNAi screen identifies an essential role for inositol pyrophosphates in Type-I interferon response.

    Directory of Open Access Journals (Sweden)

    Niyas Kudukkil Pulloor

    2014-02-01

    Full Text Available The pattern recognition receptor RIG-I is critical for Type-I interferon production. However, the global regulation of RIG-I signaling is only partially understood. Using a human genome-wide RNAi-screen, we identified 226 novel regulatory proteins of RIG-I mediated interferon-β production. Furthermore, the screen identified a metabolic pathway that synthesizes the inositol pyrophosphate 1-IP7 as a previously unrecognized positive regulator of interferon production. Detailed genetic and biochemical experiments demonstrated that the kinase activities of IPPK, PPIP5K1 and PPIP5K2 (which convert IP5 to1-IP7 were critical for both interferon induction, and the control of cellular infection by Sendai and influenza A viruses. Conversely, ectopically expressed inositol pyrophosphate-hydrolases DIPPs attenuated interferon transcription. Mechanistic experiments in intact cells revealed that the expression of IPPK, PPIP5K1 and PPIP5K2 was needed for the phosphorylation and activation of IRF3, a transcription factor for interferon. The addition of purified individual inositol pyrophosphates to a cell free reconstituted RIG-I signaling assay further identified 1-IP7 as an essential component required for IRF3 activation. The inositol pyrophosphate may act by β-phosphoryl transfer, since its action was not recapitulated by a synthetic phosphonoacetate analogue of 1-IP7. This study thus identified several novel regulators of RIG-I, and a new role for inositol pyrophosphates in augmenting innate immune responses to viral infection that may have therapeutic applications.

  6. Synergistic inhibition of human cytomegalovirus replication by interferon-alpha/beta and interferon-gamma

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2005-02-01

    Full Text Available Abstract Background Recent studies have shown that gamma interferon (IFN-γ synergizes with the innate IFNs (IFN-α and IFN-β to inhibit herpes simplex virus type 1 (HSV-1 replication in vitro. To determine whether this phenomenon is shared by other herpesviruses, we investigated the effects of IFNs on human cytomegalovirus (HCMV replication. Results We have found that as with HSV-1, IFN-γ synergizes with the innate IFNs (IFN-α/β to potently inhibit HCMV replication in vitro. While pre-treatment of human foreskin fibroblasts (HFFs with IFN-α, IFN-β or IFN-γ alone inhibited HCMV plaque formation by ~30 to 40-fold, treatment with IFN-α and IFN-γ or IFN-β and IFN-γ inhibited HCMV plaque formation by 163- and 662-fold, respectively. The generation of isobole plots verified that the observed inhibition of HCMV plaque formation and replication in HFFs by IFN-α/β and IFN-γ was a synergistic interaction. Additionally, real-time PCR analyses of the HCMV immediate early (IE genes (IE1 and IE2 revealed that IE mRNA expression was profoundly decreased in cells stimulated with IFN-α/β and IFN-γ (~5-11-fold as compared to vehicle-treated cells. Furthermore, decreased IE mRNA expression was accompanied by a decrease in IE protein expression, as demonstrated by western blotting and immunofluorescence. Conclusion These findings suggest that IFN-α/β and IFN-γ synergistically inhibit HCMV replication through a mechanism that may involve the regulation of IE gene expression. We hypothesize that IFN-γ produced by activated cells of the adaptive immune response may potentially synergize with endogenous type I IFNs to inhibit HCMV dissemination in vivo.

  7. Potentiating day-old blood samples for detection of interferon-gamma responses following infection with Mycobacterium avium subsp. paratuberculosis

    DEFF Research Database (Denmark)

    Mikkelsen, Heidi; Nielsen, Søren Saxmose; Jungersen, Gregers

    The interferon gamma (IFN-γ) test measuring specific cell-mediated immune responses in whole blood can be used for diagnosis at an early stage of Mycobacterium avium subsp. paratuberculosis (MAP) infection. A major obstacle for the practical use of IFN-γ testing is the recommended maximum 8 hour...

  8. Oromucosal Administration of Interferon to Humans

    Directory of Open Access Journals (Sweden)

    Manfred W. Beilharz

    2010-01-01

    Full Text Available The prevailing dogma is that, to be systemically effective, interferon-alpha (IFNα must be administered in sufficiently high doses to yield functional blood concentrations. Such an approach to IFNa therapy has proven effective in some instances, but high-dose parenteral IFNα therapy has the disadvantage of causing significant adverse events. Mounting evidence suggests that IFNα delivered into the oral cavity in low doses interacts with the oral mucosa in a unique manner to induce systemic host defense mechanisms without IFNα actually entering the circulation, thus reducing the potential for toxic side effects. A better understanding of the applications and potential benefits of this treatment modality are under active investigation. This paper provides a review of the relevant literature on the clinical use of the oromucosal route of administration of interferon, with an emphasis on the treatment of influenza.

  9. Spatiotemporal control of interferon-induced JAK/STAT signalling and gene transcription by the retromer complex

    OpenAIRE

    Chmiest, Daniela; Sharma, Nanaocha; Zanin, Natacha; Viaris De Lesegno, Christine; Shafaq-Zadah, Massiullah; Sibut, Vonick; Dingli, Florent; Hup?, Philippe; Wilmes, Stephan; Piehler, Jacob; Loew, Damarys; Johannes, Ludger; Schreiber, Gideon; Lamaze, Christophe

    2016-01-01

    Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-?/?) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2...

  10. Safety and antiviral activity of albinterferon alfa-2b in prior interferon nonresponders with chronic hepatitis C.

    Science.gov (United States)

    Nelson, David R; Rustgi, Vinod; Balan, Vijayan; Sulkowski, Mark S; Davis, Gary L; Muir, Andrew J; Lambiase, Louis R; Dickson, Rolland C; Weisner, Russell H; Fiscella, Michele; Cronin, Patrick W; Pulkstenis, Erik; McHutchison, John G; Subramanian, G Mani

    2009-02-01

    Pegylated interferon alfa-2a/2b is used in combination with ribavirin to treat patients with chronic hepatitis C (CHC), although many do not achieve a sustained virologic response (SVR). Albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin, may increase drug exposure. This phase 2 study evaluated the safety/efficacy of albinterferon in CHC patients who had not responded to interferon-based regimens. A total of 115 patients were assigned to 5 groups given 1200 microg albinterferon every 4 weeks or 900, 1200, 1500, or 1800 microg every 2 weeks, plus oral ribavirin, for 48 weeks. The primary efficacy end point was achievement of an SVR after 24 weeks. Treatment was extended to 72 weeks for 6 slow responders who were negative for hepatitis C virus RNA after 24 weeks. The types of adverse events were similar across groups; the overall discontinuation rate as a result of adverse events was 10.4%. Reductions in absolute neutrophil counts were less frequent in the every 4 weeks group and comparable among the every 2 weeks groups. The overall SVR rate was 17% (11% for previous nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection). An SVR occurred in 3 of 6 slow responders by 72 weeks. The greatest reductions in hepatitis C virus RNA in nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the 1800-microg group. In patients with CHC who did not respond to interferon-based regimens, higher doses of albinterferon had significant early antiviral activity and a low incidence of adverse events, with the types of adverse events similar to those observed with interferon.

  11. Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells.

    Science.gov (United States)

    Guo, Xuancheng; Liu, Taixiang; Shi, Hengfei; Wang, Jingjing; Ji, Ping; Wang, Hongwei; Hou, Yayi; Tan, Ren Xiang; Li, Erguang

    2015-08-01

    Respiratory syncytial virus (RSV) is the leading cause of acute respiratory tract viral infection in infants, causing bronchiolitis and pneumonia. The host antiviral response to RSV acts via retinoic acid-inducible gene I (RIG-I). We show here that RSV infection upregulates major histocompatibility complex class I (MHC-I) expression through the induction of NLRC5, a NOD-like, CARD domain-containing intracellular protein that has recently been identified as a class I MHC transactivator (CITA). RSV infection of A549 cells promotes upregulation of NLRC5 via beta interferon (IFN-β) production, since the NLRC5-inducing activity in a conditioned medium from RSV-infected A549 cells was removed by antibody to IFN-β, but not by antibody to IFN-γ. RSV infection resulted in RIG-I upregulation and induction of NLRC5 and MHC-I. Suppression of RIG-I induction significantly blocked NLRC5, as well as MHC-I, upregulation and diminished IRF3 activation. Importantly, Vero cells deficient in interferon production still upregulated MHC-I following introduction of the RSV genome by infection or transfection, further supporting a key role for RIG-I. A model is therefore proposed in which the host upregulates MHC-I expression during RSV infection directly via the induction of RIG-I and NLRC5 expression. Since elevated expression of MHC-I molecules can sensitize host cells to T lymphocyte-mediated cytotoxicity or immunopathologic damage, the results have significant implications for the modification of immunity in RSV disease. Human respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and young children worldwide. Infection early in life is linked to persistent wheezing and allergic asthma in later life, possibly related to upregulation of major histocompatibility class I (MHC-I) on the cell surface, which facilitates cytotoxic T cell activation and antiviral immunity. Here, we show that RSV infection of lung epithelial cells induces

  12. Role of interferon regulatory factor 7 in serum-transfer arthritis: regulation of interferon-β production.

    Science.gov (United States)

    Sweeney, Susan E; Corr, Maripat; Kimbler, Trevor B

    2012-04-01

    Innate immune responses activate synoviocytes and recruit inflammatory cells into the rheumatoid joint. Type I interferons (IFNs) play a role in autoimmunity, and IFN gene transcription is activated by IFN-regulatory factors (IRFs) in response to innate sensor recognition. The purpose of this study was to examine the effect of genetic deficiency of IRF-7 in a passive K/BxN serum-transfer model of arthritis. Passive-transfer arthritis was induced in IRF-7(-/-) mice, and additional groups were treated with IFNβ or poly(I-C). Clinical arthritis scoring, histologic assessment, micro-computed tomography, and synovial tissue quantitative polymerase chain reaction analysis were performed. Mouse serum was analyzed by enzyme-linked immunosorbent assay (ELISA). In the passive K/BxN serum-transfer model, arthritis severity was significantly increased in IRF-7(-/-) mice compared with wild-type (WT) mice. In addition, expression of IFNβ in synovium and serum was decreased, potentially contributing to increased arthritis. IRF-7(-/-) mice injected with replacement IFNβ had a decrease in arthritis. Poly(I-C) treatment diminished arthritis in IRF-7(-/-) mice, restored synovial IFNβ gene expression, and increased serum levels of IFNβ. In vitro studies demonstrated that poly(I-C) stimulation of fibroblast-like synoviocytes (FLS) from IRF-7(-/-) mice resulted in increased induction of proinflammatory gene expression as compared with FLS from WT mice; however, IFNβ expression was not significantly different. In contrast, peritoneal macrophages from IRF-7(-/-) mice showed significantly less induction of IFNβ in response to poly(I-C) stimulation. IRF-7 deficiency exacerbates arthritis and replacement treatment with IFNβ or poly(I-C) decreases arthritis severity. Both macrophage- and synoviocyte-specific roles of IRF-7 likely contribute to the increased arthritis. IRF-7 might play an antiinflammatory role in passive-transfer arthritis through regulation of macrophage IFN

  13. The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling.

    Science.gov (United States)

    Schoenemeyer, Annett; Barnes, Betsy J; Mancl, Margo E; Latz, Eicke; Goutagny, Nadege; Pitha, Paula M; Fitzgerald, Katherine A; Golenbock, Douglas T

    2005-04-29

    Interferon regulatory factors (IRFs) are critical components of virus-induced immune activation and type I interferon regulation. IRF3 and IRF7 are activated in response to a variety of viruses or after engagement of Toll-like receptor (TLR) 3 and TLR4 by double-stranded RNA and lipopolysaccharide, respectively. The activation of IRF5, is much more restricted. Here we show that in contrast to IRF3 and IRF7, IRF5 is not a target of the TLR3 signaling pathway but is activated by TLR7 or TLR8 signaling. We also demonstrate that MyD88, interleukin 1 receptor-associated kinase 1, and tumor necrosis factor receptor-associated factor 6 are required for the activation of IRF5 and IRF7 in the TLR7 signaling pathway. Moreover, ectopic expression of IRF5 enabled type I interferon production in response to TLR7 signaling, whereas knockdown of IRF5 by small interfering RNA reduced type I interferon induction in response to the TLR7 ligand, R-848. IRF5 and IRF7, therefore, emerge from these studies as critical mediators of TLR7 signaling.

  14. Interferon Regulatory Factor (Irf)-1 and Irf-2 Regulate Interferon γ–Dependent Cyclooxygenase 2 Expression

    Science.gov (United States)

    Blanco, Jorge C. G.; Contursi, Cristina; Salkowski, Cindy A.; DeWitt, David L.; Ozato, Keiko; Vogel, Stefanie N.

    2000-01-01

    Cyclooxygenases (Cox) are rate-limiting enzymes that initiate the conversion of arachidonic acid to prostanoids. Cox-2 is the inducible isoform that is upregulated by proinflammatory agents, initiating many prostanoid-mediated pathological aspects of inflammation. In this study, we demonstrate that interferon (IFN)-γ alone or in synergy with lipopolysaccharide (LPS) or interleukin 1α induces Cox-2 expression in mouse peritoneal macrophages, which is paralleled by changes in Cox-2 protein levels and prostaglandin E2 (PGE2) release. Induction of Cox-2 was abrogated in macrophages that lack IFN regulatory factor (IRF)-1, consistent with an attenuated hepatic mRNA response in IRF-1−/− mice injected with LPS. Conversely, the absence of IRF-2 in macrophages resulted in a significant increase in both basal and inducible Cox-2 gene and protein expression as well as IFN-γ–stimulated PGE2 release, identifying IRF-2 as negative regulator of this promoter. Two IFN stimulation response elements were identified in the mouse Cox-2 promoter that were highly conserved in the human Cox-2 gene. Both bind endogenous IRF-1 and IRF-2 and regulate transcription in an IRF-1/2–dependent manner. Our data demonstrate conclusively the importance of IFN-γ as a direct activator and coactivator of the Cox-2 gene, and the central role of IRF-1/2 family members in this process. PMID:10859338

  15. Activity-dependent expression of miR-132 regulates immediate-early gene induction during olfactory learning in the greater short-nosed fruit bat, Cynopterus sphinx.

    Science.gov (United States)

    Mukilan, Murugan; Ragu Varman, Durairaj; Sudhakar, Sivasubramaniam; Rajan, Koilmani Emmanuvel

    2015-04-01

    The activity-dependent expression of immediate-early genes (IEGs) and microRNA (miR)-132 has been implicated in synaptic plasticity and the formation of long-term memory (LTM). In the present study, we show that olfactory training induces the expression of IEGs (EGR-1, C-fos, C-jun) and miR-132 at similar time scale in olfactory bulb (OB) of Cynopterus sphinx. We examined the role of miR-132 in the OB using antisense oligodeoxynucleotide (AS-ODN) and demonstrated that a local infusion of AS-ODN in the OB 2h prior to training impaired olfactory memory formation in C. sphinx. However, the infusion of AS-ODN post-training did not cause a deficit in memory formation. Furthermore, the inhibition of miR-132 reduced the olfactory training-induced expression of IEGs and post synaptic density protein-95 (PSD-95) in the OB. Additionally, we show that miR-132 regulates the activation of calcium/calmodulin-dependent protein kinase-II (CaMKII) and cAMP response element binding protein (CREB), possibly through miR-148a. These data suggest that olfactory training induces the expression of miR-132 and IEGs, which in turn activates post-synaptic proteins that regulate olfactory memory formation. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Early evaluation and on field conditions of resistance to Mycosphaerella fijiensis Morelet of plants from Grande naine (AAA cultivar, obtained through out tissue culture and mutations induction

    Directory of Open Access Journals (Sweden)

    Lourdes R. García

    2003-04-01

    Full Text Available The present work was carried out in the Plants Biotechnology Institute of the Central University of Las Villas. The plant material from the cv. Grande Naine (AAA was treated with physical mutagenic agents(gamma radiation 60Co source to induce genetic variability. The behaviour of the population to the black Sigatoka was evaluated. A somaclone was selected by its disease resistance and was in vitro multiplied and the plants were acclimatized to evaluate its behaviour facing the disease on greenhouse conditions and in a second cycle of multiplication in the field. The results showed that in the majority of the plants were not found differences respect cv Grande Naine, just one presented similar reaction to cv. ‘FHIA 18’ (AAAB (partially resistant as for the variable evaluated, being obtained a frequency of 0.018% for this character. This plant was named IBP 446. After 60 days of application of the mycelial homogenized of M. fijiensis in micropropagated plants of this somaclone, differences in the respect affectation states were found at susceptible witness in greenhouse conditions. When plants of the IBP 446 were evaluated in a second cycle of multiplication differences were found with the susceptible control only at flowering, while they behaved similar at susceptible control in the crop. Key words: early detection, breeding, mutation, Black Sigatoka

  17. Thrombotic microangiopathy associated with use of interferon-beta

    Directory of Open Access Journals (Sweden)

    Robles A

    2012-06-01

    Full Text Available Teresa Olea,1 Raquel Díaz-Mancebo,1 Maria-Luz Picazo,2 Jorge Martínez-Ara,1 Angel Robles,3 Rafael Selgas,11Departments of Nephrology, 2Pathology, 3Internal Medicine, Hospital Universitario La Paz, Madrid, SpainAbstract: Interferon-beta is widely used for the treatment of relapsing multiple sclerosis. The drug is usually well tolerated, but autoimmune adverse effects, including kidney disease, have been reported. Only a few cases of hemolytic uremic syndrome-thrombotic microangiopathy associated interferon-alpha have been described so far, and even fewer with beta-interferon. We report a patient who developed thrombotic microangiopathy during treatment with interferon-beta and improved after discontinuation and steroid therapy. Complement cascade and antiphospholipid antibodies are investigated. The spectrum of renal diseases associated with interferon-beta treatment is also reviewed.Keywords: thrombotic microangiopathy hemolytic uremic syndrome, multiple sclerosis, interferon-beta

  18. Antiviral effects of bovine interferons on bovine respiratory tract viruses.

    OpenAIRE

    Fulton, R W; Downing, M M; Cummins, J M

    1984-01-01

    The antiviral effects of bovine interferons on the replication of bovine respiratory tract viruses were studied. Bovine turbinate monolayer cultures were treated with bovine interferons and challenged with several bovine herpesvirus 1 strains, bovine viral diarrhea virus, parainfluenza type 3 virus, goat respiratory syncytial virus, bovine respiratory syncytial virus, bovine adenovirus type 7, or vesicular stomatitis virus. Treatment with bovine interferons reduced viral yield for each of the...

  19. Xenopus Smad4beta is the co-Smad component of developmentally regulated transcription factor complexes responsible for induction of early mesodermal genes.

    Science.gov (United States)

    Howell, M; Itoh, F; Pierreux, C E; Valgeirsdottir, S; Itoh, S; ten Dijke, P; Hill, C S

    1999-10-15

    Smad4 is defined as the common-mediator Smad (co-Smad) required for transducing signals for all TGF-beta superfamily members. This paper describes two Smad4s in Xenopus: XSmad4alpha, which is probably the Xenopus orthologue of human Smad4, and a distinct family member, XSmad4beta, which differs primarily at the extreme N-terminus and in the linker region. Both XSmad4s act as co-Smads, forming ligand-dependent complexes with receptor-regulated Smads 1 and 2 and synergizing with them to activate transcription of mesodermal genes in Xenopus embryos. The two XSmad4 genes have reciprocal temporal expression patterns in Xenopus embryos and are expressed in varying ratios in adult tissues, suggesting distinct functional roles in vivo. XSmad4beta is the predominant maternal co-Smad and we go on to demonstrate its role in the transcriptional regulation of early mesodermal genes. We have identified two distinct nuclear complexes that bind the activin-responsive element of the Xenopus Mix.2 promoter: one formed in response to high levels of activin signaling and the other activated by endogenous signaling pathways. Using specific antisera we demonstrate the presence of endogenous XSmad4beta and also XSmad2 in both of these complexes, and our data indicate that the DNA-binding components of the complexes are different. Furthermore, we show that the presence of these complexes in the nucleus perfectly correlates with the transcriptional activity of the target gene, Mix.2, and we show that one of the XSmad4beta-containing transcription factor complexes undergoes a developmentally regulated nuclear translocation. Copyright 1999 Academic Press.

  20. Stressor and glucocorticoid-dependent induction of the immediate early gene kruppel-like factor 9: implications for neural development and plasticity.

    Science.gov (United States)

    Bonett, Ronald M; Hu, Fang; Bagamasbad, Pia; Denver, Robert J

    2009-04-01

    Krüppel-like factor 9 (KLF9) is a thyroid hormone-induced, immediate early gene implicated in neural development in vertebrates. We analyzed stressor and glucocorticoid (GC)-dependent regulation of KLF9 expression in the brain of the frog Xenopus laevis, and investigated a possible role for KLF9 in neuronal differentiation. Exposure to shaking/confinement stressor increased plasma corticosterone (CORT) concentration, and KLF9 immunoreactivity in several brain regions, which included the medial amygdala and bed nucleus of the stria terminalis, anterior preoptic area (homologous to the mammalian paraventricular nucleus), and optic tectum (homologous to the mammalian superior colliculus). The stressor-induced KLF9 mRNA expression in the brain was blocked by pretreatment with the GC receptor antagonist RU486, or mimicked by injection of CORT. Treatment with CORT also caused a rapid and dose-dependent increase in KLF9 mRNA in X. laevis XTC-2 cells that was resistant to inhibition of protein synthesis. The action of CORT on KLF9 expression in XTC-2 cells was blocked by RU486, but not by the mineralocorticoid receptor antagonist spironolactone. To test for functional consequences of up-regulation of KLF9, we introduced a KLF9 expression plasmid into living tadpole brain by electroporation-mediated gene transfer. Forced expression of KLF9 in tadpole brain caused an increase in Golgi-stained cells, reflective of neuronal differentiation/maturation. Our results support that KLF9 is a direct, GC receptor target gene that is induced by stress, and functions as an intermediary in the actions of GCs on brain gene expression and neuronal structure.

  1. Stressor and Glucocorticoid-Dependent Induction of the Immediate Early Gene Krüppel-Like Factor 9: Implications for Neural Development and Plasticity

    Science.gov (United States)

    Bonett, Ronald M.; Hu, Fang; Bagamasbad, Pia; Denver, Robert J.

    2009-01-01

    Krüppel-like factor 9 (KLF9) is a thyroid hormone-induced, immediate early gene implicated in neural development in vertebrates. We analyzed stressor and glucocorticoid (GC)-dependent regulation of KLF9 expression in the brain of the frog Xenopus laevis, and investigated a possible role for KLF9 in neuronal differentiation. Exposure to shaking/confinement stressor increased plasma corticosterone (CORT) concentration, and KLF9 immunoreactivity in several brain regions, which included the medial amygdala and bed nucleus of the stria terminalis, anterior preoptic area (homologous to the mammalian paraventricular nucleus), and optic tectum (homologous to the mammalian superior colliculus). The stressor-induced KLF9 mRNA expression in the brain was blocked by pretreatment with the GC receptor antagonist RU486, or mimicked by injection of CORT. Treatment with CORT also caused a rapid and dose-dependent increase in KLF9 mRNA in X. laevis XTC-2 cells that was resistant to inhibition of protein synthesis. The action of CORT on KLF9 expression in XTC-2 cells was blocked by RU486, but not by the mineralocorticoid receptor antagonist spironolactone. To test for functional consequences of up-regulation of KLF9, we introduced a KLF9 expression plasmid into living tadpole brain by electroporation-mediated gene transfer. Forced expression of KLF9 in tadpole brain caused an increase in Golgi-stained cells, reflective of neuronal differentiation/maturation. Our results support that KLF9 is a direct, GC receptor target gene that is induced by stress, and functions as an intermediary in the actions of GCs on brain gene expression and neuronal structure. PMID:19036875

  2. Interferon-induced genes of the expanded IFIT family show conserved antiviral activities in non-mammalian species.

    Directory of Open Access Journals (Sweden)

    Mónica Varela

    Full Text Available Interferon-induced proteins with tetratricopeptide repeats (IFITs are involved in the protective response to viral infection, although the precise mechanism of IFITs for reducing viral proliferation is currently unknown. The interaction with the translation initiation factor eIF-3 or viral proteins and the sequestering of viral RNA have been proposed as potential antiviral functions for these proteins. In humans, four members of this family have been characterized. Nevertheless, information about these proteins in fish is almost non-existent. Exploiting the conservation of synteny between human and zebrafish genomes, we have identified ten members of the IFIT family located on four different chromosomes. The induction of these genes was examined both in vitro and in vivo after interferon (IFN administration and rhabdovirus challenge. Whereas an induction of IFIT genes was observed after interferon treatments (IFNΦ1, IFNΦ2 and IFNΦ3, the viral infection did not affect these IFN-induced genes in vitro, and even reduced the IFN-induced expression of these genes. The response was largely different in vivo, with a broad up-regulation of IFIT genes after viral challenge. In addition, three selected IFITs were cloned in an expression vector and microinjected into zebrafish larvae to examine the protective effect of IFITs upon viral infection. Reduction in the mortality rate was observed confirming a conserved antiviral function in non-mammalian species.

  3. TNF-α Induced by Hepatitis C Virus via TLR7 and TLR8 in Hepatocytes Supports Interferon Signaling via an Autocrine Mechanism

    Science.gov (United States)

    Lee, Jiyoung; Tian, Yongjun; Chan, Stephanie Tze; Kim, Ja Yeon; Cho, Cecilia; Ou, Jing-hsiung James

    2015-01-01

    Invasion by infectious pathogens can elicit a range of cytokine responses from host cells. These cytokines provide the initial host defense mechanism. In this report, we demonstrate that TNF-α, a pro-inflammatory cytokine, can be induced by hepatitis C virus (HCV) in its host cells in a biphasic manner. The initial induction of TNF-α by HCV was prompt and could be blocked by the antibody directed against the HCV E2 envelope protein and by chemicals that inhibit endocytosis, indicating the specificity of endocytic uptake of HCV in this induction. Further studies indicated that the induction of TNF-α was dependent on toll-like receptors 7 and 8 (TLR7/8) but not on other intracellular pattern recognition receptors. Consistently, siRNA-mediated gene silencing of the downstream effectors in the TLR7/8 signaling pathway including MyD88, IRAK1, TRAF6, TAK1 and p65 NF-κB suppressed the expression of TNF-α. The role of p65 NF-κB in the induction of TNF-α via transcriptional up-regulation was further confirmed by the chromatin immunoprecipitation assay. TNF-α induced by HCV could activate its own receptor TNFR1 on hepatocytes to suppress HCV replication. This suppressive effect of TNF-α on HCV was due to its role in supporting interferon signaling, as the suppression of its expression led to the loss of IFNAR2 and impaired interferon signaling and the induction of interferon-stimulated genes. In conclusion, our results indicate that hepatocytes can sense HCV infection via TLR7/8 to induce the expression of TNF-α, which inhibits HCV replication via an autocrine mechanism to support interferon signaling. PMID:26023919

  4. Inductive Monitoring System (IMS)

    Data.gov (United States)

    National Aeronautics and Space Administration — IMS: Inductive Monitoring System The Inductive Monitoring System (IMS) is a tool that uses a data mining technique called clustering to extract models of normal...

  5. Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication.

    Directory of Open Access Journals (Sweden)

    Eveline Kindler

    2017-02-01

    Full Text Available Coronaviruses are of veterinary and medical importance and include highly pathogenic zoonotic viruses, such as SARS-CoV and MERS-CoV. They are known to efficiently evade early innate immune responses, manifesting in almost negligible expression of type-I interferons (IFN-I. This evasion strategy suggests an evolutionary conserved viral function that has evolved to prevent RNA-based sensing of infection in vertebrate hosts. Here we show that the coronavirus endonuclease (EndoU activity is key to prevent early induction of double-stranded RNA (dsRNA host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. In macrophages we found immediate induction of IFN-I expression and RNase L-mediated breakdown of ribosomal RNA. Accordingly, EndoU-deficient viruses can retain replication only in cells that are deficient in IFN-I expression or sensing, and in cells lacking both RNase L and PKR. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. The localization of the EndoU activity at the site of viral RNA synthesis-within the replicase complex-suggests that coronaviruses have evolved a viral RNA decay pathway to evade early innate and intrinsic antiviral host cell responses.

  6. Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy.

    Directory of Open Access Journals (Sweden)

    Elena Crespo

    Full Text Available Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90, to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67. We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction

  7. Effects of 100MeV protons delivered at 0.5 or 1cGy/min on the in vivo induction of early and delayed chromosomal damage.

    Science.gov (United States)

    Rithidech, Kanokporn Noy; Honikel, Louise M; Reungpatthanaphong, Paiboon; Tungjai, Montree; Golightly, Marc; Whorton, Elbert B

    2013-08-30

    Little is known about in vivo cytogenetic effects of protons delivered at the dose and dose rates encountered in space. We determined the effects of 100MeV protons, one of the most abundant type of protons produced during solar particle events (SPE), on the induction of chromosome aberrations (CAs) in bone marrow (BM) cells collected at early (3 and 24h) and late (6 months) time-points from groups of BALB/cJ mice (a known radiosensitive strain) exposed whole-body to 0 (sham-controls), 0.5, or 1.0Gy of 100MeV protons, delivered at 0.5 or 1.0cGy/min. These doses and dose-rates are comparable to those produced during SPE events. Additionally, groups of mice were exposed to 0 or 1Gy of (137)Cs γ rays (delivered at 1cGy/min) as a reference radiation. The kinetics of formation/reduction of gamma-histone 2-AX (γH2AX) were determined in BM cells collected at 1.5, 3, and 24h post-irradiation to assess the early-response. There were five mice per treatment-group per harvest-time. Our data indicated that the kinetics of γH2AX formation/reduction differed, depending on the dose and dose rate of protons. Highly significant numbers of abnormal cells and chromatid breaks (pprotons is capable of inducing genomic instability in BM cells. However, the extent of effects induced by these two low dose rates was comparable. Further, the results showed that the in vivo cytogenetic effects induced by 1Gy of 100MeV protons or (137)Cs γ rays (delivered at 1cGy/min) were similar. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4

    Science.gov (United States)

    Gomez-Rodriguez, Julio; Meylan, Françoise; Handon, Robin; Hayes, Erika T.; Anderson, Stacie M.; Kirby, Martha R.; Siegel, Richard M.; Schwartzberg, Pamela L.

    2016-01-01

    Th9 cells produce interleukin (IL)-9, a cytokine implicated in allergic asthma and autoimmunity. Here we show that Itk, a mediator of T cell receptor signalling required for Th2 immune responses and the development of asthma, is a positive regulator of Th9 differentiation. In a model of allergic lung disease, Itk-deficient mice show reduced pulmonary inflammation and IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal early induction of ILC2s. In vitro, Itk−/− CD4+ T cells do not produce IL-9 and have reduced levels of IRF4 (Interferon Regulator Factor 4), a critical transcription factor for effector T cell function. Both IL-9 and IRF4 expression are rescued by either IL-2 or constitutively active STAT5, but not NFATc1. STAT5 binds the Irf4 promoter, demonstrating one mechanism by which IL-2 rescues weakly activated T cells. Itk inhibition also reduces IL-9 expression by human T cells, implicating ITK as a key regulator of Th9 induction. PMID:26936133

  9. Expansion of amphibian intronless interferons revises the paradigm for interferon evolution and functional diversity

    Science.gov (United States)

    Interferons (IFNs) are key cytokines identified in vertebrates, and evolutionary dominance of intronless IFN genes in amniotes is a signature event in IFN evolution. For the first time, we show that the emergence and expansion of intronless IFN genes is evident in amphibians, shown by 24-37 intronle...

  10. Induction machine handbook

    CERN Document Server

    Boldea, Ion

    2002-01-01

    Often called the workhorse of industry, the advent of power electronics and advances in digital control are transforming the induction motor into the racehorse of industrial motion control. Now, the classic texts on induction machines are nearly three decades old, while more recent books on electric motors lack the necessary depth and detail on induction machines.The Induction Machine Handbook fills industry's long-standing need for a comprehensive treatise embracing the many intricate facets of induction machine analysis and design. Moving gradually from simple to complex and from standard to

  11. Salmonella Suppresses the TRIF-Dependent Type I Interferon Response in Macrophages

    Science.gov (United States)

    Owen, Katherine A.; Anderson, C. J.

    2016-01-01

    ABSTRACT Salmonella enterica is an intracellular pathogen that causes diseases ranging from gastroenteritis to typhoid fever. Salmonella bacteria trigger an autophagic response in host cells upon infection but have evolved mechanisms for suppressing this response, thereby enhancing intracellular survival. We recently reported that S. enterica serovar Typhimurium actively recruits the host tyrosine kinase focal adhesion kinase (FAK) to the surface of the Salmonella-containing vacuole (SCV) (K. A. Owen et al., PLoS Pathog 10:e1004159, 2014). FAK then suppresses autophagy through activation of the Akt/mTORC1 signaling pathway. In FAK−/− macrophages, bacteria are captured in autophagosomes and intracellular survival is attenuated. Here we show that the cell-autonomous bacterial suppression of autophagy also suppresses the broader innate immune response by inhibiting production of beta interferon (IFN-β). Induction of bacterial autophagy (xenophagy), but not autophagy alone, triggers IFN-β production through a pathway involving the adapter TRIF and endosomal Toll-like receptor 3 (TLR3) and TLR4. Selective FAK knockout in macrophages resulted in rapid bacterial clearance from mucosal tissues after oral infection. Clearance correlated with increased IFN-β production by intestinal macrophages and with IFN-β-dependent induction of IFN-γ by intestinal NK cells. Blockade of either IFN-β or IFN-γ increased host susceptibility to infection, whereas experimental induction of IFN-β was protective. Thus, bacterial suppression of autophagy not only enhances cell-autonomous survival but also suppresses more-systemic innate immune responses by limiting type I and type II interferons. PMID:26884434

  12. Improved Refolding Efficacy of Recombinant Human Interferon α-2b ...

    African Journals Online (AJOL)

    Purpose: To increase the refolding yield of Recombinant Human Interferon α-2b in order to achieve a highly potent product. Methods: Interferon α-2b inclusion body was dissolved in tris-HCl buffer containing 6 M guanidine-HCl and CuSO4. Different refolding buffers were employed for refolding the target protein.

  13. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, T B; Wittenhagen, P

    2007-01-01

    To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta).......To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta)....

  14. Cyclic changes in gene expression induced by Peg-interferon alfa-2b plus ribavirin in peripheral blood monocytes (PBMC of hepatitis C patients during the first 10 weeks of treatment

    Directory of Open Access Journals (Sweden)

    Edenberg Howard J

    2008-11-01

    Full Text Available Abstract Background and Aims This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron™ and ribavirin (administered by weight in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys™ and ribavirin were administered. Methods RNA was isolated from peripheral blood monocytes (PBMC from twenty treatment-naïve patients just before treatment (day 1 and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1. Results The expression of many genes differed significantly (p ≤ 0.001 and changed at least 1.5-fold at days 3 (290 probes and 10 (255 probes, but the number dropped at days 6 (165 and 13 (142. Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1, TRAIL, IL1Rα and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1 was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR was 35%. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment. Conclusion The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our

  15. Cyclic changes in gene expression induced by Peg-interferon alfa-2b plus ribavirin in peripheral blood monocytes (PBMC) of hepatitis C patients during the first 10 weeks of treatment.

    Science.gov (United States)

    Taylor, Milton W; Tsukahara, Takuma; McClintick, Jeanette N; Edenberg, Howard J; Kwo, Paul

    2008-11-05

    This study determined the kinetics of gene expression during the first 10 weeks of therapy with Pegylated-interferon-alfa2b (PegIntron) and ribavirin (administered by weight) in HCV patients and compared it with the recently completed Virahep C study 12 in which Peginterferon-alfa2a (Pegasys) and ribavirin were administered. RNA was isolated from peripheral blood monocytes (PBMC) from twenty treatment-naïve patients just before treatment (day 1) and at days 3, 6, 10, 13, 27, 42 and 70 days after treatment. Gene expression at each time was measured using Affymetrix microarrays and compared to that of day 1. The expression of many genes differed significantly (p changed at least 1.5-fold) at days 3 (290 probes) and 10 (255 probes), but the number dropped at days 6 (165) and 13 (142). Most genes continued to be up regulated throughout the trial period. A second group of genes, including CXCL10, CMKLR1 (chemokine receptor 1), TRAIL, IL1Ralpha and genes associated with complement and lipid metabolism, was transiently induced early in treatment. CDKN1C (cyclin kinase inhibitor 1) was induced early but repressed at later times. Genes induced at later times were mostly related to blood chemistry and oxygen transport. By week 10, 11 of the patients demonstrated a positive response to therapy, and the final sustained viral response (SVR) was 35%. The levels of gene induction or decrease was very similar to that previously reported with Pegasys/ribavirin treatment. The response to Pegintron/ribavirin was similar to that reported for Pegasys/ribavirin despite some differences in the amount administered. We did not detect major differences at the genomic level between patients responding to treatment or non-responders, perhaps because of limited power. Gene induction occurred in a cyclic fashion, peaking right after administration of interferon and declining between administrations of the drug. Our data suggest that more than once a week dosing might be desirable early during

  16. Interferon-associated retinopathy in a patient with metastatic melanoma

    Directory of Open Access Journals (Sweden)

    Lara Borrego-Sanz

    2014-10-01

    Full Text Available We present the unusual case of a 35 year-old woman with stage IV melanoma and widespread metastases, who was undergoing treatment with interferon alpha-2b and who presented with interferon-associated retinopathy. The patient, who had been taking interferon treatment for three months, complained of a sudden loss of visual acuity in the left eye. An ocular examination revealed multiple cotton wool spots along the retina and macular involvement. Interferon treatment was suspended. Although rare, retinopathy represents a potentially serious adverse effect of interferon treatment. Although normally patients are asymptomatic, complications derived of its use may arise, which can lead to significant visual impairment. We therefore suggest that before initiating treatment with this drug, patients should be informed of its potential ocular risks, and that regular eye examinations are conducted along with the treatment.

  17. Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B

    DEFF Research Database (Denmark)

    Mellerup, M T; Krogsgaard, K; Mathurin, P

    2005-01-01

    Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon....

  18. Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B

    DEFF Research Database (Denmark)

    Mellerup, M T; Krogsgaard, K; Mathurin, P

    2002-01-01

    Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon....

  19. Effects of arsenicals on interferon formation and action

    Energy Technology Data Exchange (ETDEWEB)

    Gainer, J.H.

    1972-01-01

    Interactions between arsenicals and interferon (IF) production and action are described. The protection afforded by poly I/poly C (PIC) against the death of mice from infection with the encephalomyocarditis virus (EMCV) was partially inhibited by sodium arsenite (NaAsO/sub 2/) and by roxarsone. Spleen of EMCV-exposed, NaAsO/sub 2/-treated mice contained 1 to 3 logs more virus than did spleen of saline solution-treated EMCV-exposed controls. A stimulating substance for the formation of plaques by the vesicular stomatitis virus (VSV) was present in spleen of the NaAsO/sub 2/-treated, EMCV-exposed mice. Detectable IF was not seen in spleen of NaAsO/sub 2/-treated, EMCV-exposed mice; low levels of IF were in spleen of EMCV-exposed control mice. Treatment of primary rabbit kidney (PRK) cell cultures with NaAsO/sub 2/ inhibited the induction of IF by PIC. In mouse embryo (ME) cells, NaAsO/sub 2/, sodium arsenate (Na/sub 2/HAsO/sub 4/), roxarsone, and p-arsanilic acid inhibited the action of mouse IF. The inhibition of IF action by the arsenicals was cell mediated and was time dependent, the inhibition by NaAsO/sub 2/ being ineffective before IF was added and 2 hours after IF was added, but being fully active at 0 and 1 hours after exposure of the cells to IF. The NaAsO/sub 2/ did not alter IF activity directly. A dose-response relationship occurred between the concentration of arsenical tested and the percentage of inhibition of IF action which ensued. Data presented have indicated that high concentrations of arsenicals inhibited both the synthesis and the action of IF, whereas low concentrations of arsenicals increased the antiviral activity of low levels of IF. 11 references, 5 figures, 2 tables.

  20. Recognition of interferon-inducible sites, promoters, and enhancers

    Directory of Open Access Journals (Sweden)

    Kondrakhin Yury V

    2007-02-01

    Full Text Available Abstract Background Computational analysis of gene regulatory regions is important for prediction of functions of many uncharacterized genes. With this in mind, search of the target genes for interferon (IFN induction appears of interest. IFNs are multi-functional cytokines. Their effects are immunomodulatory, antiviral, antibacterial, and antitumor. The interaction of the IFNs with their cell surface receptors produces an activation of several transcription factors. Four regulatory factors, ISGF3, STAT1, IRF1, and NF-κB, are essential for the function of the IFN system. The aim of this work is the development of computational approaches for the recognition of DNA binding sites for these factors and computer programs for the prediction of the IFN-inducible regions. Results We developed computational approaches to the recognition of the binding sites for ISGF3, STAT1, IRF1, and NF-κB. Analysis of the distribution of these binding sites demonstrated that the regions -500 upstream of the transcription start site in IFN-inducible genes are enriched in putative binding sites for these transcription factors. Based on selected combinations of the sites whose frequencies were significantly higher than in the other functional gene groups, we developed methods for the prediction of the IFN-inducible promoters and enhancers. We analyzed 1004 sequences of the IFN-inducible genes compiled using microarray data analyses and also about 10,000 human gene sequences from the EPD and RefSeq databases; 74 of 1,664 human genes annotated in EPD were significantly IFN-inducible. Conclusion Analyses of several control datasets demonstrated that the developed methods have a high accuracy of prediction of the IFN-inducible genes. Application of these methods to several datasets suggested that the number of the IFN-inducible genes is approximately 1500–2000 in the human genome.

  1. early versus delayed induction of labour

    African Journals Online (AJOL)

    Schutte UFo Trelfers PE. KIoost.-man GJ, et aJ_ Management of pn!fTIil1UI'e Nptur8 of the memoranes: The fISk of vaganaI exarnmations to !TIlt infant.. Am J 0bsTet. Gyneco/l983: 146: 395-400. 12. Fayu JA, HDan AA. Jonas HS. et aL Mariagem

  2. Interferon Response and Viral Evasion by Members of the Family Rhabdoviridae

    Directory of Open Access Journals (Sweden)

    Matthias J. Schnell

    2009-11-01

    Full Text Available Like many animal viruses, those of the Rhabdoviridae family, are able to antagonize the type I interferon response and cause disease in mammalian hosts. Though these negative-stranded RNA viruses are very simple and code for as few as five proteins, they have been seen to completely abrogate the type I interferon response early in infection. In this review, we will discuss the viral organization and type I interferon evasion of rhabdoviruses, focusing on vesicular stomatitis virus (VSV and rabies virus (RABV. Despite their structural similarities, VSV and RABV have completely different mechanisms by which they avert the host immune response. VSV relies on the matrix protein to interfere with host gene transcription and nuclear export of anti-viral mRNAs. Alternatively, RABV uses its phosphoprotein to interfere with IRF-3 phosphorylation and STAT1 signaling. Understanding the virus-cell interactions and viral proteins necessary to evade the immune response is important in developing effective vaccines and therapeutics for this viral family.

  3. Treatment of eosinophilic otitis media with pegylated interferon-α 2a and 2b.

    Science.gov (United States)

    Neff, Brian A; Voss, Stephen G; Carlson, Matthew L; O'Brien, Erin K; Butterfield, Joseph H

    2017-05-01

    Eosinophilic otitis media (EOM) is a variant of chronic otitis media that is characterized by the development of thick mucoid middle ear effusion, adult onset bronchial asthma, sinonasal polyposis, and aspirin sensitivity. EOM is typically refractory to corticosteroid therapy and surgical intervention. Pegylated interferon (PEG-IFN) has effectively treated hypereosinophilic syndrome in clinical trials; however, the efficacy of this medication for EOM treatment remains undefined. Retrospective, case series, tertiary academic center. A retrospective chart review was performed on EOM patients from 2008-2014. A total of 32 patients met the clinical criteria for EOM according to established diagnostic guidelines. Outcomes of all patients with severe, refractory EOM who initiated PEG-IFN therapy are reported. Eight patients were treated with pegylated interferon-α 2a or 2b for refractory EOM. Half of the patients had significant side effects with interferon treatment. Three of these were able to continue at a reduced dosage without side effect reoccurrence, and one patient stopped the medication permanently. Four of eight (50%) patients had a complete clinical response with total resolution of otorrhea and normalization of middle ear mucosa, and were able to discontinue corticosteroid treatment. Two patients attempted to stop PEG-IFN therapy after prolonged symptom remission and had recurrent otorrhea. Both patients had symptom resolution after PEG-IFN reinitiation. These data demonstrate that pegylated interferon-α 2a and 2b therapy may benefit patients with severe, refractory EOM. Further larger studies with long-term follow-up are required to validate these early but promising results. 4. Laryngoscope, 127:1208-1216, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

  4. Hepatitis C Virus Driven AXL Expression Suppresses the Hepatic Type I Interferon Response.

    Directory of Open Access Journals (Sweden)

    Scott A Read

    Full Text Available Treatment of chronic hepatitis C virus (HCV infection is evolving rapidly with the development of novel direct acting antivirals (DAAs, however viral clearance remains intimately linked to the hepatic innate immune system. Patients demonstrating a high baseline activation of interferon stimulated genes (ISGs, termed interferon refractoriness, are less likely to mount a strong antiviral response and achieve viral clearance when placed on treatment. As a result, suppressor of cytokine signalling (SOCS 3 and other regulators of the IFN response have been identified as key candidates for the IFN refractory phenotype due to their regulatory role on the IFN response. AXL is a receptor tyrosine kinase that has been identified as a key regulator of interferon (IFN signalling in myeloid cells of the immune system, but has not been examined in the context of chronic HCV infection. Here, we show that AXL is up-regulated following HCV infection, both in vitro and in vivo and is likely induced by type I/III IFNs and inflammatory signalling pathways. AXL inhibited type IFNα mediated ISG expression resulting in a decrease in its antiviral efficacy against HCV in vitro. Furthermore, patients possessing the favourable IFNL3 rs12979860 genotype associated with treatment response, showed lower AXL expression in the liver and a stronger induction of AXL in the blood, following their first dose of IFN. Together, these data suggest that elevated AXL expression in the liver may mediate an IFN-refractory phenotype characteristic of patients possessing the unfavourable rs12979860 genotype, which is associated with lower rates of viral clearance.

  5. The ebolavirus VP24 interferon antagonist: know your enemy.

    Science.gov (United States)

    Zhang, Adrianna P P; Abelson, Dafna M; Bornholdt, Zachary A; Liu, Tong; Woods, Virgil L; Saphire, Erica Ollmann

    2012-08-15

    Suppression during the early phases of the immune system often correlates directly with a fatal outcome for the host. The ebolaviruses, some of the most lethal viruses known, appear to cripple initial stages of the host defense network via multiple distinct paths. Two of the eight viral proteins are critical for immunosuppression. One of these proteins is VP35, which binds double-stranded RNA and antagonizes several antiviral signaling pathways. The other protein is VP24, which binds transporter molecules to prevent STAT1 translocation. A more recent discovery is that VP24 also binds STAT1 directly, suggesting that VP24 may operate in at least two separate branches of the interferon pathway. New crystal structures of VP24 derived from pathogenic and nonpathogenic ebolaviruses reveal its novel, pyramidal fold, upon which can be mapped sites required for virulence and for STAT1 binding. These structures of VP24, and new information about its direct binding to STAT1, provide avenues by which we may explore its many roles in the viral life cycle, and reasons for differences in pathogenesis among the ebolaviruses.

  6. Interferon alpha association with neuromyelitis optica

    DEFF Research Database (Denmark)

    Asgari, Nasrin; Voss, Anne; Steenstrup, Troels

    2013-01-01

    - α were significantly associated with EDSS (P = 0.0062). It may be concluded that IFN- α was detectable in a subgroup of NMO patients. Association of IFN- α levels with clinical disease activity and severity suggests a role for IFN- α in disease perpetuation and may provide a plausible explanation......Interferon-alpha (IFN- α ) has immunoregulatory functions in autoimmune inflammatory diseases. The goal of this study was to determine occurrence and clinical consequences of IFN- α in neuromyelitis optica (NMO) patients. Thirty-six NMO and 41 multiple sclerosis (MS) patients from a population......-based retrospective case series were included. Expanded Disability Status Scale (EDSS) score and MRI findings determined disease activity. Linear regression was used to assess the effects of the level of IFN- α on disability (EDSS). IFN- α was determined by sensitive ELISA assays. IFN- α was detectable in sera from 9...

  7. DMPD: Toll-like receptors and Type I interferons. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17395581 Toll-like receptors and Type I interferons. Uematsu S, Akira S. J Biol Che...m. 2007 May 25;282(21):15319-23. Epub 2007 Mar 29. (.png) (.svg) (.html) (.csml) Show Toll-like receptors and Type I interferon...s. PubmedID 17395581 Title Toll-like receptors and Type I interferons. Authors Uematsu S,

  8. Recombinant interferon regulation of lung fibroblast growth

    Energy Technology Data Exchange (ETDEWEB)

    Elias, J.A.; Freundlich, B.; Rossman, M.D.; Gustilo, K.; Jimenez, S.A.

    1986-03-01

    The authors characterized the effect on human lung fibroblast proliferation of recombinant interferons (gamma (..gamma..), alpha/sub A/ (..cap alpha../sub A/), alpha/sub D/ (..cap alpha../sub D/) and beta (..beta..)). Quiescent and log phase fibroblasts were used. Proliferation was assessed using /sup 3/HTdr uptake and cell counts. ..gamma.. stimulated the /sup 3/HTdr uptake of quiescent cells. Maximal stimulation was seen between 100 and 500 IU/ml. Fibroblasts incubated in 100 IU/ml incorporated 160 +/- 9% as much /sup 3/HTdr as quiescent controls (p < .04). In contrast, ..gamma.. caused a dose dependent inhibition of the /sup 3/HTdr uptake of log phase cells. Fibroblasts incubated in 1000 IU/ml incorporated 41 +/- 9% as much /sup 3/HTdr as log phase controls (p < .02). Unlike ..gamma.., ..cap alpha../sub A/, ..cap alpha../sub D/ and ..beta.. did not stimulate the proliferation of quiescent cells. However, they did inhibit the proliferation of log phase cells. Fibroblasts incubated in 1000 IU/ml of ..cap alpha../sub A/, ..cap alpha../sub D/ and ..beta.. incorporated 64 +/- 10, 81 +/- 4 and 62 +/- 7% as much /sup 3/HTdr as log phase controls (p < .03 for all). ..gamma.., ..cap alpha../sub A/, ..cap alpha../sub D/ and ..beta.. did not stimulate fibroblast prostaglandin E (PGE) production and incubating fibroblasts with indomethacin did not reverse the inhibition of fibroblast proliferation caused by the interferons. Thus, (1) ..gamma.. can stimulate or inhibit fibroblast growth, (2) ..cap alpha../sub A/, ..cap alpha../sub D/ and ..beta.. only inhibit fibroblast growth, (3) the inhibition of fibroblast growth caused by ..gamma.., ..cap alpha../sub A/, ..cap alpha../sub D/ and ..beta.. is largely independent of fibroblast PGE production.

  9. Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy.

    Science.gov (United States)

    Medrano, Ruan F V; Hunger, Aline; Mendonça, Samir Andrade; Barbuto, José Alexandre M; Strauss, Bryan E

    2017-09-19

    During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-α and IFN-β, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-α/β share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular phenotypes. For example, type I IFNs drive not only the high maturation status of DCs, but also have a direct impact in cytotoxic T lymphocytes, NK cell activation, induction of tumor cell death and inhibition of angiogenesis. A variety of stimuli, including some standard cancer treatments, promote the expression of endogenous IFN-α/β, which then participates as a fundamental component of immunogenic cell death. Systemic treatment with recombinant protein has been used for the treatment of melanoma. The induction of endogenous IFN-α/β has been tested, including stimulation through pattern recognition receptors. Gene therapies involving IFN-α/β have also been described. Thus, harnessing type I IFNs as an effective tool for cancer therapy continues to be studied.

  10. Interferon α/β receptor knockout mice as a model to study bluetongue virus infection.

    Science.gov (United States)

    Ortego, Javier; de la Poza, Francisco; Marín-López, Alejandro

    2014-03-01

    Bluetongue is an arthropod-borne disease caused by a virus of the genus Orbivirus, the bluetongue virus (BTV), which affects ruminant livestock such as cattle, sheep, and goats and wild ruminants such as deer, and camelids. Recently, adult mice with gene knockouts of the interferon α/β receptor (IFNAR-/-) have been described as a model of lethal BTV infection. IFNAR(-/-) mice are highly susceptible to BTV-1, BTV-4 and BTV-8 infection when the virus is administered intravenously or subcutaneosuly. Disease progression and pathogenesis closely mimics signs of bluetongue disease in ruminants. In the present paper we review the studies where IFNAR(-/-) mice have been used as an animal model to study BTV transmission, pathogenesis, virulence, and protective efficacy of inactivated and new recombinant marker BTV vaccines. Furthermore, we report new data on protective efficacy of different strategies of BTV vaccination and also on induction of interferon α/β and proinflammatory immune responses in IFNAR(-/-) mice infected with BTV. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Activation of type III interferon genes by pathogenic bacteria in infected epithelial cells and mouse placenta.

    Directory of Open Access Journals (Sweden)

    Hélène Bierne

    Full Text Available Bacterial infections trigger the expression of type I and II interferon genes but little is known about their effect on type III interferon (IFN-λ genes, whose products play important roles in epithelial innate immunity against viruses. Here, we studied the expression of IFN-λ genes in cultured human epithelial cells infected with different pathogenic bacteria and in the mouse placenta infected with Listeria monocytogenes. We first showed that in intestinal LoVo cells, induction of IFN-λ genes by L. monocytogenes required bacterial entry and increased further during the bacterial intracellular phase of infection. Other Gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis, also induced IFN-λ genes when internalized by LoVo cells. In contrast, Gram-negative bacteria Salmonella enterica serovar Typhimurium, Shigella flexneri and Chlamydia trachomatis did not substantially induce IFN-λ. We also found that IFN-λ genes were up-regulated in A549 lung epithelial cells infected with Mycobacterium tuberculosis and in HepG2 hepatocytes and BeWo trophoblastic cells infected with L. monocytogenes. In a humanized mouse line permissive to fetoplacental listeriosis, IFN-λ2/λ3 mRNA levels were enhanced in placentas infected with L. monocytogenes. In addition, the feto-placental tissue was responsive to IFN-λ2. Together, these results suggest that IFN-λ may be an important modulator of the immune response to Gram-positive intracellular bacteria in epithelial tissues.

  12. Interferon-tau and oxytocin receptor in bovien placentomes through out pregnancy

    DEFF Research Database (Denmark)

    Dantzer, Vibeke; Ivell, R.; Balvers, M.

    Objective: Interferon-tau (IFNT) secreted by the conceptus is an important factor in the maintenance of luteal function in cows during early pregnancy until day 36. In this multiplex, synepitheliochorial placenta the expression of oxytocin receptor (OXTR) is resumed in the intercaruncular...... but not in the caruncular endometrium on day 50, although being similar in both regions in cyclic cows. The IFNT protein seems to suppress endometrial estrogen (ER) and OXTR thus inhibiting luteolytic PGF 2 alfa. Our hypothesis was that IFNT synthesis continues in placentomal trophoblast after day 36 regulating...

  13. Long-term impact of interferon beta-1b in patients with CIS

    DEFF Research Database (Denmark)

    Edan, G; Kappos, L; Montalbán, X

    2014-01-01

    OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). METHODS: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 μg...... or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. RESULTS: Of the initial...

  14. Induction Therapy for Mesothelioma.

    Science.gov (United States)

    Opitz, Isabelle; Weder, Walter

    2015-01-01

    One particular approach of multimodality treatment for mesothelioma is induction therapy followed by surgery. Among its several advantages, the most important is downstaging of the tumor into a resectable stage, although morbidity and mortality might be increased. In this article we review the principles and outcome of different modalities for induction treatment of mesothelioma. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Steroid receptor coactivator 1 links the steroid and interferon gamma response pathways.

    Science.gov (United States)

    Tzortzakaki, Eleni; Spilianakis, Charalambos; Zika, Eleni; Kretsovali, Androniki; Papamatheakis, Joseph

    2003-12-01

    We show here that steroid receptor coactivator 1 (SRC-1) is a coactivator of MHC class II genes that stimulates their interferon gamma (IFNgamma) and class II transactivator (CIITA)-mediated expression. SRC-1 interacts physically with the N-terminal activation domain of CIITA through two regions: one central [extending from amino acids (aa) 360-839] that contains the nuclear receptors binding region and one C-terminal (aa 1138-1441) that contains the activation domain 2. Using chromatin immunoprecipitation assays we show that SRC-1 recruitment on the class II promoter is enhanced upon IFNgamma stimulation. Most importantly, SRC-1 relieves the inhibitory action of estrogens on the IFNgamma-mediated induction of class II genes in transient transfection assays. We provide evidence that inhibition by estradiol is due to multiple events such as slightly reduced recruitment of CIITA and SRC-1 and severely inhibited assembly of the preinitiation complex.

  16. Intracellular interferons in fish: a unique means to combat viral infection.

    Directory of Open Access Journals (Sweden)

    Ming-Xian Chang

    Full Text Available We demonstrate for the first time in vertebrates, that alternative splicing of interferon (IFN genes can lead to a functional intracellular IFN (iIFN. Fish IFN genes possess introns and in rainbow trout three alternatively spliced transcripts of the IFN1 gene exist. Two of the encoded IFNs are predicted to lack a signal peptide. When overexpressed these iIFNs induce antiviral responses. Variants of the two IFNR receptor chains (IFNAR1 and IFNAR2 lacking a signal peptide are also present in trout. Transfection of HEK 293T cells with the iIFN and iIFNR molecules results in STAT phosphorylation and induction of antiviral genes. These results show that fish possess a functioning iIFN system that may act as a novel defence to combat viral infection.

  17. Cytokines and adhesion molecules in multiple sclerosis patients treated with interferon-beta1b

    DEFF Research Database (Denmark)

    Jensen, Jakob; Krakauer, Martin; Sellebjerg, Finn

    2005-01-01

    Multiple sclerosis (MS), an inflammatory, demyelinating disease of the central nervous system (CNS), is thought to be caused by a T cell-mediated attack on CNS myelin and axons. Recombinant interferon (IFN)-beta is an established treatment of multiple sclerosis, and is known to reduce the number...... of disease relapses and the development of irreversible symptoms and signs of disease. The mechanism of action of IFN-beta treatment is, however, not completely understood. Previous studies have suggested major effects on mononuclear cell cytokine production and T cell migration, but results have been...... initiated on de novo treatment with IFN-beta1b. We found only minor associations between the different changes induced by IFN-beta1b-treatment. Our findings are consistent with changes in T cell expression of CD49d/VLA-4 and induction of sVCAM-1 as important effects of treatment with IFN-beta1b in multiple...

  18. Progress in Induction Linacs

    Energy Technology Data Exchange (ETDEWEB)

    Caporaso, G J

    2000-09-27

    This presentation will be a broad survey of progress in induction technology over the past four years. Much work has been done on accelerators for hydrodynamic test radiography and other applications. Solid-state pulsers have been developed which can provide unprecedented flexibility and precision in pulse format and accelerating voltage for both ion and electron induction machines. Induction linacs can now be built which can operate with MHz repetition rates. Solid-state technology has also made possible the development of fast kickers for precision control of high current beams. New insulator technology has been developed which will improve conventional induction linacs in addition to enabling a new class of high gradient induction linacs.

  19. Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of type I interferon receptor.

    Science.gov (United States)

    Bhattacharya, Sabyasachi; HuangFu, Wei-Chun; Liu, Jianghuai; Veeranki, Sudhakar; Baker, Darren P; Koumenis, Constantinos; Diehl, J Alan; Fuchs, Serge Y

    2010-01-22

    Phosphorylation-dependent ubiquitination and ensuing down-regulation and lysosomal degradation of the interferon alpha/beta receptor chain 1 (IFNAR1) of the receptor for Type I interferons play important roles in limiting the cellular responses to these cytokines. These events could be stimulated either by the ligands (in a Janus kinase-dependent manner) or by unfolded protein response (UPR) inducers including viral infection (in a manner dependent on the activity of pancreatic endoplasmic reticulum kinase). Both ligand-dependent and -independent pathways converge on phosphorylation of Ser(535) within the IFNAR1 degron leading to recruitment of beta-Trcp E3 ubiquitin ligase and concomitant ubiquitination and degradation. Casein kinase 1 alpha (CK1 alpha) was shown to directly phosphorylate Ser(535) within the ligand-independent pathway. Yet given the constitutive activity of CK1 alpha, it remained unclear how this pathway is stimulated by UPR. Here we report that induction of UPR promotes the phosphorylation of a proximal residue, Ser(532), in a pancreatic endoplasmic reticulum kinase-dependent manner. This serine serves as a priming site that promotes subsequent phosphorylation of IFNAR1 within its degron by CK1 alpha. These events play an important role in regulating ubiquitination and degradation of IFNAR1 as well as the extent of Type I interferon signaling.

  20. The heme oxygenase 1 product biliverdin interferes with hepatitis C virus replication by increasing antiviral interferon response.

    Science.gov (United States)

    Lehmann, Elisabeth; El-Tantawy, Walid Hamdy; Ocker, Matthias; Bartenschlager, Ralf; Lohmann, Volker; Hashemolhosseini, Said; Tiegs, Gisa; Sass, Gabriele

    2010-02-01

    The anti-inflammatory and antiapoptotic heme degrading enzyme heme oxygenase-1 (HO-1) has been shown recently to interfere with replication of hepatitis C virus (HCV). We investigated the effect of HO-1 products carbon monoxide (CO), iron and biliverdin on HCV replication using the replicon cell lines Huh-5-15 and LucUbiNeo-ET, stably expressing HCV proteins NS3 through NS5B. Incubation of these cell lines in the presence of the CO donor methylene chloride transiently reduced HCV replication, whereas an increase of iron in cell culture by administration of FeCl(3) or iron-saturated lactoferrin did not interfere with HCV replication. Likewise, depletion of iron by deferoxamine during induction of HO-1 by cobalt-protoporphyrin IX did not restore HCV replication. The most prominent effect was observed after incubation of replicon cell lines in the presence of biliverdin. Biliverdin seems to interfere with HCV replication-mediated oxidative stress by inducing expression of antiviral interferons, such as interferon alpha2 and alpha17. The antioxidant biliverdin reduces HCV replication in vitro by triggering the antiviral interferon response and might improve HCV therapy in the future.

  1. Type I interferon is required for T helper (Th) 2 induction by dendritic cells

    NARCIS (Netherlands)

    Webb, Lauren M.; Lundie, Rachel J.; Borger, Jessica G.; Brown, Sheila L.; Connor, Lisa M.; Cartwright, Adam N.R.; Dougall, Annette M.; Wilbers, Ruud H.P.; Cook, Peter C.; Jackson-Jones, Lucy H.; Phythian-Adams, Alexander T.; Johansson, Cecilia; Davis, Daniel M.; Dewals, Benjamin G.; Ronchese, Franca; Macdonald, Andrew S.

    2017-01-01

    Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a

  2. Disease protection and interleukin-10 induction by endogenous interferon-β in multiple sclerosis?

    DEFF Research Database (Denmark)

    Hesse, D.; Krakauer, M.; Lund, H

    2011-01-01

    with increased spontaneous MX1 expression also had increased expression of other genes induced by regular IFN-ß treatment of MS. MX1 expression correlated with FOXP3 and IL10 expression, and IL10 expression correlated negatively with disease activity on magnetic resonance imaging. Further, in vivo IL10...... expression was lower in NAb-positive patients than in untreated patients with MS and healthy controls. Finally, ex vivo treatment of mononuclear blood cells with IFN-ß induced the expression of IL10, and this was blocked by the addition of serum from NAb-positive patients with MS. CONCLUSION: Our findings...... suggest that endogenous IFN-ß may induce the expression of immunoregulatory IL10 in MS and that this might be associated with dampening of inflammatory disease activity....

  3. Enterovirus 71 suppresses interferon responses by blocking Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling through inducing karyopherin-α1 degradation.

    Science.gov (United States)

    Wang, Chunyang; Sun, Menghuai; Yuan, Xinhui; Ji, Lianfu; Jin, Yu; Cardona, Carol J; Xing, Zheng

    2017-06-16

    Enterovirus 71 (EV71) has emerged as one of the most important enteroviruses since the eradication of poliovirus, and it causes severe neurological symptoms for which no effective antiviral drugs are available. Type I interferons (IFN) α/β have been used clinically as antiviral therapy as the first line of defense against virus infections successfully for decades. However, treatment with type I interferons has not been effective in patients with EV71 infection. In this study, we found that in cells pretreated with IFN-β, EV71 infection could still lead to a cytopathic effect, and the viral replication was not affected. The mechanism by which EV71 antagonizes interferon signaling, however, has been controversial. Our study indicated that EV71 infection did not inhibit phosphorylation of STAT1/2 induced by IFN-β stimulation, but p-STAT1/2 transport into the nucleus was significantly blocked. We showed that EV71 infection reduced the formation of STAT/karyopherin-α1 (KPNA1) complex upon interferon stimulation and that the virus down-regulated the expression of KPNA1, a nuclear localization signal receptor for p-STAT1. Using specific caspase inhibitors and siRNA for caspase-3, we demonstrated that EV71 infection induced degradation of cellular KPNA1 in a caspase-3-dependent manner, which led to decreased induction of interferon-inducible genes and IFN response. Viral 2A and 3C proteases did not degrade KPNA1, inhibit the activity of ISRE or suppress the transcription of interferon-inducible genes induced by IFN-β. Our study demonstrates a novel mechanism by which antiviral signaling is suppressed through degradation of KPNA1 by activated caspase-3 induced in an enteroviral infection. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Extensive psoriasis induced by interferon alfa treatment for chronic hepatitis C

    OpenAIRE

    Taylor, C; Burns, D; Wiselka, M

    2000-01-01

    A 47 year old man with chronic hepatitis C was treated with interferon alfa, 3 million units three times a week, and developed widespread plaque psoriasis within weeks of starting interferon therapy. There was no previous history of psoriasis. The psoriasis was characterised by extensive nail involvement and plaques at the interferon injection sites. The patient relapsed after a total of 12 months of interferon and was subsequently treated with interferon and tribavirin (ribavirin) with recur...

  5. Morning versus evening induction of labour for improving outcomes

    NARCIS (Netherlands)

    Bakker, Jannet J. H.; van der Goes, Birgit Y.; Pel, Maria; Mol, Ben Willem J.; van der Post, Joris A. M.

    2013-01-01

    Background Induction of labour is a common intervention in obstetric practice. Traditionally, inmost hospitals induction of labour with medication starts early in the morning, with the start of the working day for the day shift. In human and animal studies spontaneous onset of labour is proven to

  6. Development of Category-based Induction and Semantic Knowledge

    Science.gov (United States)

    Fisher, Anna V.; Godwin, Karrie E.; Matlen, Bryan J.; Unger, Layla

    2015-01-01

    Category-based induction is a hallmark of mature cognition; however, little is known about its origins. This study evaluated the hypothesis that category-based induction is related to semantic development. Computational studies suggest that early on there is little differentiation among concepts, but learning and development lead to increased…

  7. The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis

    NARCIS (Netherlands)

    Brkic, Z.; Bon, L. van; Cossu, M.; Helden-Meeuwsen, C.G. van; Vonk, M.C.; Knaapen, H.; Berg, W. van den; Dalm, V.A.; Daele, P.L. van; Severino, A.; Maria, N.I.; Guillen, S.; Dik, W.A.; Beretta, L.; Versnel, M.A.; Radstake, T.

    2016-01-01

    BACKGROUND: Interferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in SSc before overt skin fibrosis develops. METHODS: The expression of 11 IFN type I inducible genes was

  8. Beta-interferon inhibits cell infection by Trypanosoma cruzi

    Science.gov (United States)

    Kierszenbaum, F.; Sonnenfeld, G.

    1984-01-01

    Beta interferon has been shown to inhibit the capacity of bloodstream forms of the flagellate Trypanosoma cruzi, the causative agent of Chagas' disease, to associate with and infect mouse peritoneal macrophages and rat heart myoblasts. The inhibitory effect was abrogated in the presence of specific antibodies to the interferon. Pretreatment of the parasites with interferon reduced their infectivity for untreated host cells, whereas pretreament of either type of host cell did not affect the interaction. The effect of interferon on the trypanosomes was reversible; the extent of the inhibitory effect was significantly reduced afer 20 min, and was undetectable after 60 min when macrophages were used as host cells. For the myoblasts, 60 min elapsed before the inhibitory effect began to subside and 120 min elapsed before it became insignificant or undetectable.

  9. Predicative factors for Pegylated interferon-α plus ribavirin ...

    African Journals Online (AJOL)

    Predicative factors for Pegylated interferon-α plus ribavirin combination therapy in Egyptian patients with chronic Hepatitis Cinfected with genotype 4. SM Massoud, MA Shemis, EA Drees, MA Taha, HA Omar, MA Saber ...

  10. Osteopontin as a marker for response to pegylated interferon Alpha ...

    African Journals Online (AJOL)

    Osteopontin as a marker for response to pegylated interferon Alpha-2b treatment in Chronic HCV Saudi patients. Yousri Mostafa Hussein, Ayman Alhazmi, Saad Alzahrani, Ahmad El-Askary, Abdulrahman Alghamdy, Eman Bayomy, Assmaa Selim, Mohammed Alghamdy ...

  11. Health management program: factors influencing completion of therapy with high-dose interferon alfa-2b for high-risk melanoma

    Science.gov (United States)

    Levesque, N.; Mitchinson, K.; Lawrie, D.; Fedorak, L.; MacDonald, D.; Normand, C.; Pouliot, J.F.

    2008-01-01

    The goal of the 1-year observational, multicentre, open-label study reported here was to identify factors influencing adherence to high-dose interferon alfa-2b adjuvant therapy in patients at high risk of recurrence following surgical excision of malignant melanoma. The study was carried out in 23 tertiary-care centres across Canada. The 225 patients enrolled in the study all had malignant melanoma that was surgically excised and that required adjuvant treatment with interferon alfa-2b. Of these patients, 64% were men. Mean age was 51.7 years. All patients received interferon alfa-2b treatment during a 4-week induction phase (20 MU/m2 intravenously 5 days per week) followed by a 48-week maintenance phase (10 MU/m2 subcutaneously 3 days per week). Oncology nurses reviewed side-effect management with the patients before the induction and maintenance phases. Patients were provided with daily diaries, comprehensive educational materials, and ongoing nursing support. Data on side effects and discontinuations were obtained from patient interviews and diaries. The main outcome measurements were related to treatment discontinuation: rate, timing, reason, and prevention. Of the 225 patients, 75 (33.3%) discontinued interferon during the induction phase, and 58 (25.8%) discontinued during the maintenance phase. The main reasons for discontinuation were adverse events (58%) and disease progression (26%). Patients with a daily fluid intake greater than 1.5 L were more likely to complete therapy than were those with an intake less than 1.5 L (64% vs. 36%, p 1.5 L daily) was associated with increased adherence to therapy. PMID:18317583

  12. Whole blood interferon-gamma assay for baseline tuberculosis screening among Japanese healthcare students.

    Directory of Open Access Journals (Sweden)

    Katsuyuki Hotta

    Full Text Available BACKGROUND: The whole blood interferon-gamma assay (QuantiFERON-TB-2G; QFT has not been fully evaluated as a baseline tuberculosis screening test in Japanese healthcare students commencing clinical contact. The aim of this study was to compare the results from the QFT with those from the tuberculin skin test (TST in a population deemed to be at a low risk for infection with Mycobacterium tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: Healthcare students recruited at Okayama University received both the TST and the QFT to assess the level of agreement between these two tests. The interleukin-10 levels before and after exposure to M tuberculosis-specific antigens (early-secreted antigenic target 6-kDa protein [ESAT-6] and culture filtrate protein 10 [CFP-10] were also measured. Of the 536 healthcare students, most of whom had been vaccinated with bacillus-Calmette-Guérin (BCG, 207 (56% were enrolled in this study. The agreement between the QFT and the TST results was poor, with positive result rates of 1.4% vs. 27.5%, respectively. A multivariate analysis also revealed that the induration diameter of the TST was not affected by the interferon-gamma concentration after exposure to either of the antigens but was influenced by the number of BCG needle scars (p = 0.046. The whole blood interleukin-10 assay revealed that after antigen exposure, the median increases in interleukin-10 concentration was higher in the subgroup with the small increase in interferon-gamma concentration than in the subgroup with the large increase in interferon-gamma concentration (0.3 vs. 0 pg/mL; p = 0.004. CONCLUSIONS/SIGNIFICANCE: As a baseline screening test for low-risk Japanese healthcare students at their course entry, QFT yielded quite discordant results, compared with the TST, probably because of the low specificity of the TST results in the BCG-vaccinated population. We also found, for the first time, that the change in the interleukin-10 level after exposure to

  13. Interferon Production by Nonviral Stimuli of Microbial Origin

    Science.gov (United States)

    Youngner, Julius S.

    1970-01-01

    An increasing number of nonviral materials of microbial origin has been reported to stimulate the production of interferon in cell cultures and (or) in animals. These materials include (a) gram-negative bacteria or the endotoxins prepared from their cell walls, (b) other microorganisms such as Rickettsiae, Bedsoniae, Protozoa, and (c) fungal products such as a mannan from Candida and various antibiotics which act as protein synthesis inhibitors, e.g., glutarimide antibiotics and tenuazonic acid. A summary is presented of the current state of knowledge about interferon production in animals by the most thoroughly studied nonviral substance of microbial origin, bacterial endotoxin. Further evidence is presented which clearly distinguishes the "endotoxin-type" of interferon response in animals from the response seen after the injection of virus. The data suggest that the release of preformed interferon from the tissues occurs in animals injected with endotoxin. On the other hand, interferon produced in response to the injection of virus is newly synthesized protein. While the exact chemical structure of the component of bacterial endotoxin responsible for interferon release has not yet been elucidated, it is clear that the lipid portion of the lipopolysaccharide, rather than the O-specific polysaccharide side chains or the core polysaccharide, is the active moiety. PMID:19873672

  14. The human adenovirus type 5 E1B 55 kDa protein obstructs inhibition of viral replication by type I interferon in normal human cells.

    Directory of Open Access Journals (Sweden)

    Jasdave S Chahal

    Full Text Available Vectors derived from human adenovirus type 5, which typically lack the E1A and E1B genes, induce robust innate immune responses that limit their therapeutic efficacy. We reported previously that the E1B 55 kDa protein inhibits expression of a set of cellular genes that is highly enriched for those associated with anti-viral defense and immune responses, and includes many interferon-sensitive genes. The sensitivity of replication of E1B 55 kDa null-mutants to exogenous interferon (IFN was therefore examined in normal human fibroblasts and respiratory epithelial cells. Yields of the mutants were reduced at least 500-fold, compared to only 5-fold, for wild-type (WT virus replication. To investigate the mechanistic basis of such inhibition, the accumulation of viral early proteins and genomes was compared by immunoblotting and qPCR, respectively, in WT- and mutant-infected cells in the absence or presence of exogenous IFN. Both the concentration of viral genomes detected during the late phase and the numbers of viral replication centers formed were strongly reduced in IFN-treated cells in the absence of the E1B protein, despite production of similar quantities of viral replication proteins. These defects could not be attributed to degradation of entering viral genomes, induction of apoptosis, or failure to reorganize components of PML nuclear bodies. Nor was assembly of the E1B- and E4 Orf6 protein- E3 ubiquitin ligase required to prevent inhibition of viral replication by IFN. However, by using RT-PCR, the E1B 55 kDa protein was demonstrated to be a potent repressor of expression of IFN-inducible genes in IFN-treated cells. We propose that a primary function of the previously described transcriptional repression activity of the E1B 55 kDa protein is to block expression of IFN- inducible genes, and hence to facilitate formation of viral replication centers and genome replication.

  15. Cooperative contributions of Interferon regulatory factor 1 (IRF1 and IRF8 to interferon-γ-mediated cytotoxic effects on oligodendroglial progenitor cells

    Directory of Open Access Journals (Sweden)

    Pleasure David

    2011-01-01

    Full Text Available Abstract Background Administration of exogenous interferon-γ (IFNγ aggravates the symptoms of multiple sclerosis (MS, whereas interferon-β (IFNβ is used for treatment of MS patients. We previously demonstrated that IFNγ induces apoptosis of oligodendroglial progenitor cells (OPCs, suggesting that IFNγ is more toxic to OPCs than IFNβ. Thus we hypothesized that a difference in expression profiles between IFNγ-inducible and IFNβ-inducible genes in OPCs would predict the genes responsible for IFNγ-mediated cytotoxic effects on OPCs. We have tested this hypothesis particularly focusing on the interferon regulatory factors (IRFs well-known transcription factors up-regulated by IFNs. Methods Highly pure primary rat OPC cultures were treated with IFNγ and IFNβ. Cell death and proliferation were assessed by MTT reduction, caspse-3-like proteinase activity, Annexin-V binding, mitochondrial membrane potential, and BrdU-incorporation. Induction of all nine IRFs was comprehensively compared by quantitative PCR between IFNγ-treated and IFNβ-treated OPCs. IRFs more strongly induced by IFNγ than by IFNβ were selected, and tested for their ability to induce OPC apoptosis by overexpression and by inhibition by dominant-negative proteins or small interference RNA either in the presence or absence of IFNγ. Results Unlike IFNγ, IFNβ did not induce apoptosis of OPCs. Among nine IRFs, IRF1 and IRF8 were preferentially up-regulated by IFNγ. In contrast, IRF7 was more robustly induced by IFNβ than by IFNγ. Overexpressed IRF1 elicited apoptosis of OPCs, and a dominant negative IRF1 protein partially protected OPCs from IFNγ-induced apoptosis, indicating a substantial contribution of IRF1 to IFNγ-induced OPC apoptosis. On the other hand, overexpression of IRF8 itself had only marginal proapoptotic effects. However, overexpressed IRF8 enhanced the IFNγ-induced cytotoxicity and the proapoptotic effect of overexpressed IRF1, and down-regulation of

  16. Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial.

    Science.gov (United States)

    Asmuth, David M; Murphy, Robert L; Rosenkranz, Susan L; Lertora, Juan J L; Kottilil, Shyam; Cramer, Yoninah; Chan, Ellen S; Schooley, Robert T; Rinaldo, Charles R; Thielman, Nathan; Li, Xiao-Dong; Wahl, Sharon M; Shore, Jessica; Janik, Jennifer; Lempicki, Richard A; Simpson, Yaa; Pollard, Richard B

    2010-06-01

    To our knowledge, the antiviral activity of pegylated interferon alfa-2a has not been studied in participants with untreated human immunodeficiency virus type 1 (HIV-1) infection but without chronic hepatitis C virus (HCV) infection. Untreated HIV-1-infected volunteers without HCV infection received 180 microg of pegylated interferon alfa-2a weekly for 12 weeks. Changes in plasma HIV-1 RNA load, CD4(+) T cell counts, pharmacokinetics, pharmacodynamic measurements of 2',5'-oligoadenylate synthetase (OAS) activity, and induction levels of interferon-inducible genes (IFIGs) were measured. Nonparametric statistical analysis was performed. Eleven participants completed 12 weeks of therapy. The median plasma viral load decrease and change in CD4(+) T cell counts at week 12 were 0.61 log(10) copies/mL (90% confidence interval [CI], 0.20-1.18 log(10) copies/mL) and -44 cells/microL (90% CI, -95 to 85 cells/microL), respectively. There was no correlation between plasma viral load decreases and concurrent pegylated interferon plasma concentrations. However, participants with larger increases in OAS level exhibited greater decreases in plasma viral load at weeks 1 and 2 (r = -0.75 [90% CI, -0.93 to -0.28] and r = -0.61 [90% CI, -0.87 to -0.09], respectively; estimated Spearman rank correlation). Participants with higher baseline IFIG levels had smaller week 12 decreases in plasma viral load (0.66 log(10) copies/mL [90% CI, 0.06-0.91 log(10) copies/mL]), whereas those with larger IFIG induction levels exhibited larger decreases in plasma viral load (-0.74 log(10) copies/mL [90% CI, -0.93 to -0.21 log(10) copies/mL]). Pegylated interferon alfa-2a was well tolerated and exhibited statistically significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein levels (weeks 1 and 2) and IFIG induction levels (week 12) but not with pegylated interferon concentrations.

  17. The contribution of type I interferon signaling to immunity induced by alphavirus replicon vaccines.

    Science.gov (United States)

    Thompson, Joseph M; Whitmore, Alan C; Staats, Herman F; Johnston, Robert

    2008-09-15

    The type I interferon (IFN) system is critical for protecting the mammalian host from numerous virus infections and plays a key role in shaping the antiviral adaptive immune response. In this report, the importance of type I IFN signaling was assessed in a mouse model of alphavirus-induced humoral immune induction. Venezuelan equine encephalitis virus replicon particles (VRP) expressing the hemagglutinin (HA) gene from influenza virus (HA-VRP) were used to vaccinate both wildtype (wt) and IFN alpha/beta receptor knockout (RKO) mice. HA-VRP vaccination induced equivalent levels of flu-specific systemic IgG, mucosal IgG, and systemic IgA antibodies in both wt and IFN RKO mice. In contrast, HA-VRP vaccination of IFN RKO mice failed to induce significant levels of flu-specific mucosal IgA antibodies at multiple mucosal surfaces. In the VRP adjuvant system, co-delivery of null VRP with ovalbumin (OVA) protein significantly increased the levels of OVA-specific serum IgG, fecal IgG, and fecal IgA antibodies in both wt and RKO mice, suggesting that type I IFN signaling plays a less significant role in the VRP adjuvant effect. Taken together, these results suggest that (1) at least in regard to IFN signaling, the mechanisms which regulate alphavirus-induced immunity differ when VRP are utilized as expression vectors as opposed to adjuvants, and (2) type I IFN signaling is required for the induction of mucosal IgA antibodies directed against VRP-expressed antigen. These results shed new light on the regulatory networks which promote immune induction, and specifically mucosal immune induction, with alphavirus vaccine vectors.

  18. Induction melter apparatus

    Science.gov (United States)

    Roach, Jay A [Idaho Falls, ID; Richardson, John G [Idaho Falls, ID; Raivo, Brian D [Idaho Falls, ID; Soelberg, Nicholas R [Idaho Falls, ID

    2008-06-17

    Apparatus and methods of operation are provided for a cold-crucible-induction melter for vitrifying waste wherein a single induction power supply may be used to effect a selected thermal distribution by independently energizing at least two inductors. Also, a bottom drain assembly may be heated by an inductor and may include an electrically resistive heater. The bottom drain assembly may be cooled to solidify molten material passing therethrough to prevent discharge of molten material therefrom. Configurations are provided wherein the induction flux skin depth substantially corresponds with the central longitudinal axis of the crucible. Further, the drain tube may be positioned within the induction flux skin depth in relation to material within the crucible or may be substantially aligned with a direction of flow of molten material within the crucible. An improved head design including four shells forming thermal radiation shields and at least two gas-cooled plenums is also disclosed.

  19. Thermal kinetic inductance detector

    Science.gov (United States)

    Cecil, Thomas; Gades, Lisa; Miceli, Antonio; Quaranta, Orlando

    2016-12-20

    A microcalorimeter for radiation detection that uses superconducting kinetic inductance resonators as the thermometers. The detector is frequency-multiplexed which enables detector systems with a large number of pixels.

  20. Interferon Alpha Association with Neuromyelitis Optica

    Directory of Open Access Journals (Sweden)

    Nasrin Asgari

    2013-01-01

    Full Text Available Interferon-alpha (IFN-α has immunoregulatory functions in autoimmune inflammatory diseases. The goal of this study was to determine occurrence and clinical consequences of IFN-α in neuromyelitis optica (NMO patients. Thirty-six NMO and 41 multiple sclerosis (MS patients from a population-based retrospective case series were included. Expanded Disability Status Scale (EDSS score and MRI findings determined disease activity. Linear regression was used to assess the effects of the level of IFN-α on disability (EDSS. IFN-α was determined by sensitive ELISA assays. IFN-α was detectable in sera from 9/36 NMO patients, significantly more often than in the MS group (2/41 (P=0.0197. A higher frequency of IFN-α was observed in NMO patients with acute relapse compared to NMO patients in remission (P<0.001 and compared to the MS patients with relapse (P=0.010. In NMO patients, the levels of IFN-α were significantly associated with EDSS (P=0.0062. It may be concluded that IFN-α was detectable in a subgroup of NMO patients. Association of IFN-α levels with clinical disease activity and severity suggests a role for IFN-α in disease perpetuation and may provide a plausible explanation for a negative effect of IFN-1 treatment in NMO patients.

  1. Evolution of vertebrate interferon inducible transmembrane proteins

    Directory of Open Access Journals (Sweden)

    Hickford Danielle

    2012-04-01

    Full Text Available Abstract Background Interferon inducible transmembrane proteins (IFITMs have diverse roles, including the control of cell proliferation, promotion of homotypic cell adhesion, protection against viral infection, promotion of bone matrix maturation and mineralisation, and mediating germ cell development. Most IFITMs have been well characterised in human and mouse but little published data exists for other animals. This study characterised IFITMs in two distantly related marsupial species, the Australian tammar wallaby and the South American grey short-tailed opossum, and analysed the phylogeny of the IFITM family in vertebrates. Results Five IFITM paralogues were identified in both the tammar and opossum. As in eutherians, most marsupial IFITM genes exist within a cluster, contain two exons and encode proteins with two transmembrane domains. Only two IFITM genes, IFITM5 and IFITM10, have orthologues in both marsupials and eutherians. IFITM5 arose in bony fish and IFITM10 in tetrapods. The bone-specific expression of IFITM5 appears to be restricted to therian mammals, suggesting that its specialised role in bone production is a recent adaptation specific to mammals. IFITM10 is the most highly conserved IFITM, sharing at least 85% amino acid identity between birds, reptiles and mammals and suggesting an important role for this presently uncharacterised protein. Conclusions Like eutherians, marsupials also have multiple IFITM genes that exist in a gene cluster. The differing expression patterns for many of the paralogues, together with poor sequence conservation between species, suggests that IFITM genes have acquired many different roles during vertebrate evolution.

  2. Inhibitors of the interferon response enhance virus replication in vitro.

    Directory of Open Access Journals (Sweden)

    Claire E Stewart

    Full Text Available Virus replication efficiency is influenced by two conflicting factors, kinetics of the cellular interferon (IFN response and induction of an antiviral state versus speed of virus replication and virus-induced inhibition of the IFN response. Disablement of a virus's capacity to circumvent the IFN response enables both basic research and various practical applications. However, such IFN-sensitive viruses can be difficult to grow to high-titer in cells that produce and respond to IFN. The current default option for growing IFN-sensitive viruses is restricted to a limited selection of cell-lines (e.g. Vero cells that have lost their ability to produce IFN. This study demonstrates that supplementing tissue-culture medium with an IFN inhibitor provides a simple, effective and flexible approach to increase the growth of IFN-sensitive viruses in a cell-line of choice. We report that IFN inhibitors targeting components of the IFN response (TBK1, IKK2, JAK1 significantly increased virus replication. More specifically, the JAK1/2 inhibitor Ruxolitinib enhances the growth of viruses that are sensitive to IFN due to (i loss of function of the viral IFN antagonist (due to mutation or species-specific constraints or (ii mutations/host cell constraints that slow virus spread such that it can be controlled by the IFN response. This was demonstrated for a variety of viruses, including, viruses with disabled IFN antagonists that represent live-attenuated vaccine candidates (Respiratory Syncytial Virus (RSV, Influenza Virus, traditionally attenuated vaccine strains (Measles, Mumps and a slow-growing wild-type virus (RSV. In conclusion, supplementing tissue culture-medium with an IFN inhibitor to increase the growth of IFN-sensitive viruses in a cell-line of choice represents an approach, which is broadly applicable to research investigating the importance of the IFN response in controlling virus infections and has utility in a number of practical applications

  3. Opposing roles for interferon regulatory factor-3 (IRF-3 and type I interferon signaling during plague.

    Directory of Open Access Journals (Sweden)

    Ami A Patel

    Full Text Available Type I interferons (IFN-I broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of septicemic plague. Transcription of IFN-β was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-β following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-β signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-β production.

  4. Type I interferons instigate fetal demise after Zika virus infection.

    Science.gov (United States)

    Yockey, Laura J; Jurado, Kellie A; Arora, Nitin; Millet, Alon; Rakib, Tasfia; Milano, Kristin M; Hastings, Andrew K; Fikrig, Erol; Kong, Yong; Horvath, Tamas L; Weatherbee, Scott; Kliman, Harvey J; Coyne, Carolyn B; Iwasaki, Akiko

    2018-01-05

    Zika virus (ZIKV) infection during pregnancy is associated with adverse fetal outcomes, including microcephaly, growth restriction, and fetal demise. Type I interferons (IFNs) are essential for host resistance against ZIKV, and IFN-α/β receptor (IFNAR)-deficient mice are highly susceptible to ZIKV infection. Severe fetal growth restriction with placental damage and fetal resorption is observed after ZIKV infection of type I IFN receptor knockout (Ifnar1-/-) dams mated with wild-type sires, resulting in fetuses with functional type I IFN signaling. The role of type I IFNs in limiting or mediating ZIKV disease within this congenital infection model remains unknown. In this study, we challenged Ifnar1-/- dams mated with Ifnar1+/- sires with ZIKV. This breeding scheme enabled us to examine pregnant dams that carry a mixture of fetuses that express (Ifnar1+/-) or do not express IFNAR (Ifnar1-/-) within the same uterus. Virus replicated to a higher titer in the placenta of Ifnar1-/- than within the Ifnar1+/- concepti. Yet, rather unexpectedly, we found that only Ifnar1+/- fetuses were resorbed after ZIKV infection during early pregnancy, whereas their Ifnar1-/- littermates continue to develop. Analyses of the fetus and placenta revealed that, after ZIKV infection, IFNAR signaling in the conceptus inhibits development of the placental labyrinth, resulting in abnormal architecture of the maternal-fetal barrier. Exposure of midgestation human chorionic villous explants to type I IFN, but not type III IFNs, altered placental morphology and induced cytoskeletal rearrangements within the villous core. Our results implicate type I IFNs as a possible mediator of pregnancy complications, including spontaneous abortions and growth restriction, in the context of congenital viral infections. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  5. Induction in a Modular Learner.

    Science.gov (United States)

    Carroll, Susanne E.

    2002-01-01

    Presents a theory of inductive learning--Autonomous Induction Theory--a form of induction that takes place within the autonomous and modular representational systems of the language faculty. Argues that Autonomous Induction Theory is constrained enough to be taken seriously as a plausible approach to explaining second language acquisition.…

  6. The evolution of interferon-tau.

    Science.gov (United States)

    Ealy, Alan D; Wooldridge, Lydia K

    2017-11-01

    Thirty years ago, a novel type I interferon (IFN) was identified by molecular cloning of cDNA libraries constructed from RNA extracted from ovine and bovine pre-implantation embryos. This protein was eventually designated as IFN-tau (IFNT) to highlight its trophoblast-dependent expression. IFNT function is not immune related. Instead, it interacts with the maternal system to initiate the establishment and maintenance of pregnancy. This activity is indispensable for the continuation of pregnancy. Our review will describe how IFNT evolved from other type I IFNs to function in this new capacity. IFNT genes have only been identified in pecoran ruminants within the Artiodactyla order (e.g. cattle, sheep, goats, deer, antelope, giraffe). The ancestral IFNT gene emerged approximately 36 million years ago most likely from rearrangement and/or insertion events that combined an ancestral IFN-omega (IFNW) gene with a trophoblast-specifying promoter/enhancer. Since then, IFNT genes have duplicated, likely through conversion events, and mutations have allowed them to adapt to their new function in concert with the emergence of different species. Multiple IFNT polymorphisms have been identified in cattle, sheep and goats. These genes and gene alleles encode proteins that do not display identical antiviral, antiproliferative and antiluteolytic activities. The need for multiple IFNT genes, numerous alleles and distinct activities remains debatable, but the consensus is that this complexity in IFNT expression and biological activity must be needed to provide the best opportunity for pregnancy to be recognized by the maternal system so that gestation may continue. © 2017 Society for Reproduction and Fertility.

  7. Both TLR2 and TRIF contribute to interferon-β production during Listeria infection.

    Directory of Open Access Journals (Sweden)

    Camille Aubry

    Full Text Available Synthesis of interferon-β (IFN-β is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-β synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-β production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, ΔpgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-β gene, requiring TLR2 and bacterial internalization. Induction of IFN-β was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived macrophages. The novelty of our findings thus lies in the first description of TLR2 and TRIF as two critical components leading to the induction of the IFN-β gene and in uncovering that individual macrophage populations adopt different strategies to link pathogen recognition signals to IFN-β gene expression.

  8. Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion

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    Priya Luthra

    2017-04-01

    Full Text Available Ebola virus (EBOV protein VP35 inhibits production of interferon alpha/beta (IFN by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication.

  9. Bilateral Ischemic Optic Neuropathy Developed under Interferon Therapy

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    Fatih Selcukbiricik

    2012-01-01

    Full Text Available Introduction. Interferon is a glycoprotein produced by assigned cells of immune system. It has been used in many different diseases. Although flu-like syndrome, myalgia, rash, hypotension, thrombocytopenia and peripheral neuropathy due to interferon use are encountered frequently, ocular side effects are rare, generally mild and transient. Case Report. 47-year-old female patient, presented with a mass lesion in right renal pelvis. Right radical nephrectomy was applied and the histopathological examination was consistent with papillary renal cell carcinoma. Interferon alpha treatment was started subcutaneously at the dose of 5 MIU/3 times in a week. Four weeks after the interferon therapy, suddenly bilateral visual loss developed. We discussed the diagnosis, followup, and treatment of the patient who developed irreversible ischemic optic neuropathy and had no previous known primary systemic disease to cause this condition. Conclusion. We suggest that patients should be screened for risk factors causing optic ischemic neuropathy, before interferon therapy. Although there was no adequate information in the literature for the followup, patients should be monitorized before, 1 month after, and 2 months after the treatment. And if there is no complication, we suggest that they should be followed up at 3-month intervals.

  10. Phenotypic, morphologic changes and Ig secretion induced on B-NHL cells in vitro by interferon alpha and all-trans-retinoic acid: possible progression toward a more differentiated state.

    Science.gov (United States)

    Bonnefoix, T; Sotto, M F; Gressin, R; Martin, I; Garban, F; Leroux, D; Renversez, J C; Sotto, J J

    1998-08-01

    Twenty-five B-cell-nonHodgkin's lymphomas (B-NHL): 6 lymphocytic, 2 centrocytic, 13 follicular, centrocytic/centroblastic, 2 lymphoplasmocytoid and 2 centroblastic were tested for their ability to acquire features of mature plasma cells under the effect of interferon alpha (final concentration, 600 UI/ml), all-trans-retinoic-acid (ATRA) (final concentration, 10(-6) mol/l) and the association of both. B-NHL cells were negatively purified (>99%) by an immunomagnetic method, cultured for 7 d with or without interferon and ATRA, then stained with anti-CD19, CD20, surface Ig, DR, CD38 and with anti-CD138 (syndecan-1) antibody-recognizing plasma cells. Ig production was estimated in culture supernatants by an ELISA method and changes in cell morphology were investigated on May-Grunwald-Giemsa-stained cytospin preparations. In all cases interferon and ATRA, alone or in association, were able to induce changes in the immunophenotypic profile, associated or not with morphologic changes and induction of Ig secretion. All changes were greatly variable from one to the other B-NHL sample and no relationship could be found between a particular pattern of change and the histological subtype. Interferon alpha was more potent than ATRA in inducing changes. In favour of a differentiation process, we observed a concomitant decrease of DR expression and increase of CD38 expression in 8 cases with interferon alpha, and in 4 cases with ATRA. Although interferon- or ATRA-treated cells did not display cytologic, functional features and changes of the immunophenotypic profile fully compatible with those of terminally differentiated cells, these results suggest a possible transition toward more differentiated elements, especially with interferon alpha.

  11. Induction and Natural Kinds

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    Howard Sankey

    1997-12-01

    Full Text Available The paper sketches an ontological solution to an epistemological problem in the philosophy of science. Taking the work of Hilary Kornblith and Brian Ellis as a point of departure, it presents a realist solution to the Humean problem of induction, which is based on a scientific essentialist interpretation of the principle of the uniformity of nature. More specifically, it is argued that use of inductive inference in science is rationally justified because of the existence of real, natural kinds of things, which are characterized as such by the essential properties which all members of a kind necessarily possess in common. The proposed response to inductive scepticism combines the insights of epistemic naturalism with a metaphysical outlook that is due to s cientific realism.

  12. Hashimoto encephalopathy with pegylated interferon alfa-2b and ribavirin.

    Science.gov (United States)

    Deutsch, Melanie; Koskinas, John; Tzannos, Konstatinos; Vassilopoulos, Dimitrios; Mailis, Antonis; Tolis, George; Hadziyannis, Stephanos

    2005-10-01

    To report an instance of Hashimoto encephalopathy probably resulting from pegylated interferon alfa-2b and ribavirin. A 36-year-old woman with a 10-year history of autoimmune thyroiditis presented with symptoms and signs consistent with Hashimoto encephalopathy during therapy with pegylated interferon alfa-2b and ribavirin for chronic hepatitis C. Hashimoto encephalopathy is a rare autoimmune condition that occurs in patients with Hashimoto thyroiditis and high titers of antithyroid antibodies. It is characterized by a variety of nonspecific neuropsychiatric symptoms, increased cerebrospinal fluid protein level, and abnormal brain imaging and electroencephalogram. Prompt response to corticosteroids is observed in most cases. As of August 29, 2005, this is the first report of such an association. An objective causality assessment revealed that the Hashimoto encephalopathy was probably caused by the patient's medications. Hashimoto encephalopathy may rarely be triggered by interferon alfa therapy in susceptible patients.

  13. Inductive dielectric analyzer

    Science.gov (United States)

    Agranovich, Daniel; Polygalov, Eugene; Popov, Ivan; Ben Ishai, Paul; Feldman, Yuri

    2017-03-01

    One of the approaches to bypass the problem of electrode polarization in dielectric measurements is the free electrode method. The advantage of this technique is that, the probing electric field in the material is not supplied by contact electrodes, but rather by electromagnetic induction. We have designed an inductive dielectric analyzer based on a sensor comprising two concentric toroidal coils. In this work, we present an analytic derivation of the relationship between the impedance measured by the sensor and the complex dielectric permittivity of the sample. The obtained relationship was successfully employed to measure the dielectric permittivity and conductivity of various alcohols and aqueous salt solutions.

  14. Cotinine and interferon-gamma levels in pre-school children exposed to household tobacco smoke

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    Lina Kalalo

    2013-10-01

    Conclusion Cotinine is not related to the interferon-γ level in children exposed to tobacco smoke, however, the interferon-γ level in children with tobacco smoke exposure is lower than in the non-tobacco smoke exposure group.

  15. Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

    DEFF Research Database (Denmark)

    Strickertsson, Jesper A B; Døssing, Kristina B V; Aabakke, Anna JM

    2011-01-01

    To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice.......To investigate if and how the proinflammatory cytokine interferon γ (IFNγ) affects ghrelin expression in mice....

  16. Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

    DEFF Research Database (Denmark)

    Strickertsson, Jesper A B; Døssing, Kristina B V; Aabakke, Anna JM

    2011-01-01

    To investigate if and how the proinflammatory cytokine interferon ¿ (IFN¿) affects ghrelin expression in mice.......To investigate if and how the proinflammatory cytokine interferon ¿ (IFN¿) affects ghrelin expression in mice....

  17. DMPD: Signalling pathways mediating type I interferon gene expression. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17904888 Signalling pathways mediating type I interferon gene expression. Edwards M...csml) Show Signalling pathways mediating type I interferon gene expression. PubmedID 17904888 Title Signalling pathways media

  18. Mutation induction in synchronous hamster cells

    Energy Technology Data Exchange (ETDEWEB)

    Aebersold, P.M.

    1975-11-01

    Mutagenesis of synchronous Mutahinese hamster cells by 5-bromodeoxyuridine (BUdR) shows pronounced cell cycle dependency. Resistance to 6-thioguanine (6-TG) and ouabain are induced maximally by BUdR at different times early in the DNA synthesis period, suggesting that the genes coding for hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and the (Na/sup +/K/sup +/)-associated ATPase of the plasma membrane are replicated early in the DNA synthesis period. Although BUdR induces mutations in specific genes only when present during their replication, the rate of mutation induction is not linearly related to the amount of BUdR incorporated into DNA. The data show a BUdR concentration threshold for mutation induction, suggesting that BUdR exerts some deterimental allosteric effect on DNA synthesis enzymes.

  19. Effects of parental smoking on interferon gamma production in children.

    Science.gov (United States)

    Tebow, Gina; Sherrill, Duane L; Lohman, I Carla; Stern, Debra A; Wright, Anne L; Martinez, Fernando D; Halonen, Marilyn; Guerra, Stefano

    2008-06-01

    Environmental tobacco smoke is associated with several negative health outcomes in children, including an increased susceptibility to infections. One of the postulated mechanisms for these effects is the impairment of the immune system function and/or development. Yet, it remains unknown whether cumulative exposure to parental smoking is associated with altered immune responses in childhood and whether these effects are independent of in utero exposure to maternal smoking. In a population-based birth cohort, we sought to determine the relation of parental smoking, as assessed prospectively since pregnancy, to the child's interferon gamma and interleukin 4 production at 11 years of age. We used data on 512 children and their parents from the Tucson Children's Respiratory Study cohort. Information on maternal and paternal smoking was collected prospectively by questionnaire, and pack-years for mother, father, and both parents combined were assessed prospectively between the prenatal period and year 11. At age 11 years, children's interferon gamma and interleukin 4 production from mitogen-stimulated peripheral blood mononuclear cells was measured. Children of parents who smoked between the prenatal period and year 11 were more likely to be in lower quartiles of interferon gamma production than children of nonsmoking parents. In addition, maternal, paternal, and parental pack-years showed significant inverse dose-response relationships with interferon gamma production in the child. These dose-response relationships with interferon gamma remained significant for both paternal and parental pack-years among children of mothers who did not smoke during pregnancy, suggesting the existence of specific postnatal effects of environmental tobacco smoke exposure. In contrast, no significant effects of parental smoking were found on interleukin 4 production. Interferon gamma responses of school-aged children are impacted by parental smoking.

  20. Recurrent Pericarditis, an Unexpected Effect of Adjuvant Interferon Chemotherapy for Malignant Melanoma

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    Farhan Ashraf

    2016-01-01

    Full Text Available Drug-induced pericarditis is a well-described cardiac pathology that can result from a variety of medications; however, interferon-mediated pericarditis is extremely rare. We present a case of a young female with recurrent pericarditis due to interferon therapy. The role of interferon in adjuvant chemotherapy is well known and yields good effect, but this case highlights the very uncommon phenomena of interferon induced pericarditis and the significant distress it can cause.

  1. Prediction of response to interferon therapy in multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Søndergaard, Helle Bach; Koch-Henriksen, N

    2014-01-01

    OBJECTIVE: Single nucleotide polymorphisms (SNPs) in the genes encoding interferon response factor (IRF)-5, IRF-8 and glypican-5 (GPC5) have been associated with disease activity in multiple sclerosis (MS) patients treated with interferon (IFN)-β. We analysed whether SNPs in the IRF5, IRF8 and GPC5...... prospectively after the initiation of their first treatment with IFN-β. RESULTS: 62% of patients experienced relapses during the first 2 years of treatment, and 32% had disability progression during the first 5 years of treatment. Patients with a pretreatment annualized relapse rate >1 had an increased risk...

  2. Case Report; Heterotopic Pregnancy Following Induction of Ovulation

    African Journals Online (AJOL)

    ... in the early phase of an obvious intrauterine pregnancy following fertility treatment. Transvaginal ultrasonography is a useful diagnostic adjunct. Early intervention is essential to salvage the intrauterine pregnancy and avoid maternal morbidity and mortality. Key Words: Pregnancy, Ectopic, Heterotopic, Ovulation Induction

  3. Interferon regulatory factor 1-Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury.

    Science.gov (United States)

    Yang, Mu-Qing; Du, Qiang; Goswami, Julie; Varley, Patrick R; Chen, Bin; Wang, Rong-Hua; Morelli, Adrian E; Stolz, Donna B; Billiar, Timothy R; Li, Jiyu; Geller, David A

    2017-10-23

    The role and regulators of extracellular vesicles (EV) secretion in hepatic ischemia/reperfusion (IR) injury have not been defined. Rab27a is a GTPase known to control EVs release. Interferon regulatory factor 1 (IRF-1) is a transcription factor that plays an important role in liver IR and regulates certain GTPases. However, the relationships among IRF-1, Rab27a, and EVs secretion are largely unknown. Here, we show induction of IRF-1 and Rab27a both in vitro in hypoxic hepatocytes and in vivo in warm IR and orthotopic liver transplantation livers. Interferon γ stimulation, IRF-1 transduction, or IR promoted Rab27a expression and EVs secretion. Meanwhile, silencing of IRF-1 decreased Rab27a expression and EVs secretion. Rab27a silencing decreased EVs secretion and liver IR injury. Ten putative IRF-1 binding motifs in the 1,692 base pairs Rab27a promoter region were identified. Chromatin immunoprecipitation and electrophoretic mobility shift assay verified five functional IRF-1 binding motifs, which were confirmed by Rab27a promoter luciferase assay. IR-induced EVs contained higher oxidized phospholipids (OxPL). OxPLs on EVs surface activated neutrophil through toll like receptor 4 (TLR-4) pathway. OxPL-neutralizing E06 antibody blocked the effect of EVs and decreased liver IR injury. These findings provide a novel mechanism by which IRF-1 regulates Rab27a transcription and EVs secretion, leading to OxPL activation of neutrophils and subsequent hepatic IR injury. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  4. Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection.

    Science.gov (United States)

    Murira, Armstrong; Lamarre, Alain

    2016-01-01

    Type I interferons (IFN-I) have long been heralded as key contributors to effective antiviral responses. More widely understood in the context of acute viral infection, the role of this pleiotropic cytokine has been characterized as triggering antiviral states in cells and potentiating adaptive immune responses. Upon induction in the innate immune response, IFN-I triggers the expression of interferon-stimulated genes (ISGs), which upregulate the effector function of immune cells (e.g., dendritic cells, B cells, and T cells) toward successful resolution of infections. However, emerging lines of evidence reveal that viral persistence in the course of chronic infections could be driven by deleterious immunomodulatory effects upon sustained IFN-I expression. In this setting, elevation of IFN-I and ISGs is directly correlated to viral persistence and elevated viral loads. It is important to note that the correlation among IFN-I expression, ISGs, and viral persistence may be a cause or effect of chronic infection and this is an important distinction to make toward establishing the dichotomous nature of IFN-I responses. The aim of this mini review is to (i) summarize the interaction between IFN-I and downstream effector responses and therefore (ii) delineate the function of this cytokine on positive and negative immunoregulation in chronic infection. This is a significant consideration given the current therapeutic administration of IFN-I in chronic viral infections whose therapeutic significance is projected to continue despite emergence of increasingly efficacious antiviral regimens. Furthermore, elucidation of the interplay between virus and the antiviral response in the context of IFN-I will elucidate avenues toward more effective therapeutic and prophylactic measures against chronic viral infections.

  5. Generation and characterization of interferon-lambda 1-resistant H1N1 influenza A viruses

    Science.gov (United States)

    Lugovtsev, Vladimir Y.; Samsonova, Anastasia P.; Sheikh, Faruk G.; Bovin, Nicolai V.; Donnelly, Raymond P.

    2017-01-01

    Influenza A viruses pose a constant potential threat to human health. In view of the innate antiviral activity of interferons (IFNs) and their potential use as anti-influenza agents, it is important to know whether viral resistance to these antiviral proteins can arise. To examine the likelihood of emergence of IFN-λ1-resistant H1N1 variants, we serially passaged the A/California/04/09 (H1N1) strain in a human lung epithelial cell line (Calu-3) in the presence of increasing concentrations of recombinant IFN-λ1 protein. To monitor changes associated with adaptation of this virus to growth in Calu-3 cells, we also passaged the wild-type virus in the absence of IFN-λ1. Under IFN-λ1 selective pressure, the parental virus developed two neuraminidase (NA) mutations, S79L and K331N, which significantly reduced NA enzyme activity (↓1.4-fold) and sensitivity to IFN-λ1 (↓˃20-fold), respectively. These changes were not associated with a reduction in viral replication levels. Mutants carrying either K331N alone or S79L and K331N together induced weaker phosphorylation of IFN regulatory factor 3 (IRF3), and, as a consequence, much lower expression of the IFN genes (IFNB1, IFNL1 and IFNL2/3) and proteins (IFN-λ1 and IFN-λ2/3). The lower levels of IFN expression correlated with weaker induction of tyrosine-phosphorylated STAT1 and reduced RIG-I protein levels. Our findings demonstrate that influenza viruses can develop increased resistance to the antiviral activity of type III interferons. PMID:28750037

  6. Bluetongue Virus NS4 Protein Is an Interferon Antagonist and a Determinant of Virus Virulence.

    Science.gov (United States)

    Ratinier, Maxime; Shaw, Andrew E; Barry, Gerald; Gu, Quan; Di Gialleonardo, Luigina; Janowicz, Anna; Varela, Mariana; Randall, Richard E; Caporale, Marco; Palmarini, Massimo

    2016-06-01

    Bluetongue virus (BTV) is the causative agent of bluetongue, a major infectious disease of ruminants with serious consequences to both animal health and the economy. The clinical outcome of BTV infection is highly variable and dependent on a variety of factors related to both the virus and the host. In this study, we show that the BTV nonstructural protein NS4 favors viral replication in sheep, the animal species most affected by bluetongue. In addition, NS4 confers a replication advantage on the virus in interferon (IFN)-competent primary sheep endothelial cells and immortalized cell lines. We determined that in cells infected with an NS4 deletion mutant (BTV8ΔNS4), there is increased synthesis of type I IFN compared to cells infected with wild-type BTV-8. In addition, using RNA sequencing (RNA-seq), we show that NS4 modulates the host IFN response and downregulates mRNA levels of type I IFN and interferon-stimulated genes. Moreover, using reporter assays and protein synthesis assays, we show that NS4 downregulates the activities of a variety of promoters, such as the cytomegalovirus immediate-early promoter, the IFN-β promoter, and a promoter containing interferon-stimulated response elements (ISRE). We also show that the NS4 inhibitory activity on gene expression is related to its nucleolar localization. Furthermore, NS4 does not affect mRNA splicing or cellular translation. The data obtained in this study strongly suggest that BTV NS4 is an IFN antagonist and a key determinant of viral virulence. Bluetongue is one of the main infectious diseases of ruminants and is caused by bluetongue virus (BTV), an arthropod-borne virus transmitted from infected to susceptible animals by Culicoides biting midges. Bluetongue has a variable clinical outcome that can be related to both virus and host factors. It is therefore critical to understand the interplay between BTV and the host immune responses. In this study, we show that a nonstructural protein of BTV (NS4) is

  7. Ultraregular inductive limits

    Directory of Open Access Journals (Sweden)

    Jan Kucera

    1990-01-01

    Full Text Available An inductive limit E=indlim En is ultraregular if it is regular and each set B⊂En, which is bounded in E, is also bounded in En. A necessary and sufficient condition for ultraregularity of E is given provided each En is an LF-space which is closed in En+1.

  8. Modeling Induction Motor Imbalances

    DEFF Research Database (Denmark)

    Armah, Kabenla; Jouffroy, Jerome; Duggen, Lars

    2016-01-01

    This paper gives a study into the development of a generalized model for a three-phase induction motor that offers flexibility of simulating balanced and unbalanced parameter scenarios. By analyzing the interaction of forces within the motor, we achieve our main objective of deriving the system...

  9. Using Continuity Induction

    Science.gov (United States)

    Hathaway, Dan

    2011-01-01

    Here is a technique for proving the fundamental theorems of analysis that provides a unified way to pass from local properties to global properties on the real line, just as ordinary induction passes from local implication (if true for "k", the theorem is true for "k" + 1) to a global conclusion in the natural numbers.

  10. Effects of Interferon-α/β on HBV Replication Determined by Viral Load

    Science.gov (United States)

    Tian, Yongjun; Chen, Wen-ling; Ou, Jing-hsiung James

    2011-01-01

    Interferons α and β (IFN-α/β) are type I interferons produced by the host to control microbial infections. However, the use of IFN-α to treat hepatitis B virus (HBV) patients generated sustained response to only a minority of patients. By using HBV transgenic mice as a model and by using hydrodynamic injection to introduce HBV DNA into the mouse liver, we studied the effect of IFN-α/β on HBV in vivo. Interestingly, our results indicated that IFN-α/β could have opposite effects on HBV: they suppressed HBV replication when viral load was high and enhanced HBV replication when viral load was low. IFN-α/β apparently suppressed HBV replication via transcriptional and post-transcriptional regulations. In contrast, IFN-α/β enhanced viral replication by inducing the transcription factor HNF3γ and activating STAT3, which together stimulated HBV gene expression and replication. Further studies revealed an important role of IFN-α/β in stimulating viral growth and prolonging viremia when viral load is low. This use of an innate immune response to enhance its replication and persistence may represent a novel strategy that HBV uses to enhance its growth and spread in the early stage of viral infection when the viral level is low. PMID:21829354

  11. DMPD: Fifty years of interferon research: aiming at a moving target. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16979566 Fifty years of interferon research: aiming at a moving target. Vilcek J. I...mmunity. 2006 Sep;25(3):343-8. (.png) (.svg) (.html) (.csml) Show Fifty years of interferon research: aiming at a moving... target. PubmedID 16979566 Title Fifty years of interferon research: aiming at a moving target.

  12. Human interferon and its inducers: clinical program overview at Roswell Park Memorial Institute.

    Science.gov (United States)

    Carter, W A; Horoszewicz, J S

    1978-11-01

    An overview of the clinical interferon program at Roswell Park Memorial Institute is presented. Purified fibroblast interferon and a novel inducer of human interferon [rIn-r(C12,U)n] are being evaluated for possible antiviral, antiproliferative, and immunomodulatory activities in patients with cancer.

  13. A modified immune tolerant mouse model to study the immunogenicity of recombinant human interferon beta

    NARCIS (Netherlands)

    Abdolvahab, Mohadeseh Haji; Brinks, Vera; Schellekens, Huub

    2014-01-01

    Interferon beta may induce antibodies in multiple sclerosis patients and the incidence of immunogenicity depends on the type of product. These antibodies can reduce the efficacy of interferon beta. Two transgenic immune tolerant mouse models for human interferon beta (hIFNβ) (C57Bl/6, and

  14. DMPD: Interferon gene regulation: not all roads lead to Tolls. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 16095970 Interferon gene regulation: not all roads lead to Tolls. Jefferies CA, Fit...zgerald KA. Trends Mol Med. 2005 Sep;11(9):403-11. (.png) (.svg) (.html) (.csml) Show Interferon gene regulation: not all roads lead... to Tolls. PubmedID 16095970 Title Interferon gene regulation: not all roads lead to

  15. DMPD: Type I interferon receptors: biochemistry and biological functions. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17502368 Type I interferon receptors: biochemistry and biological functions. de Wee...(.html) (.csml) Show Type I interferon receptors: biochemistry and biological functions. PubmedID 17502368 T...itle Type I interferon receptors: biochemistry and biological functions. Authors

  16. Intact type I Interferon production and IRF7 function in sooty mangabeys.

    Directory of Open Access Journals (Sweden)

    Steven E Bosinger

    Full Text Available In contrast to pathogenic HIV/SIV infections of humans and rhesus macaques (RMs, natural SIV infection of sooty mangabeys (SMs is typically non-pathogenic despite high viremia. Several studies suggested that low immune activation and relative resistance of CD4+ central memory T-cells from virus infection are mechanisms that protect SMs from AIDS. In 2008 it was reported that plasmacytoid dendritic cells (pDCs of SMs exhibit attenuated interferon-alpha (IFN-α responses to TLR7/9 ligands in vitro, and that species-specific amino acid substitutions in SM Interferon Regulatory Factor-7 (IRF7 are responsible for this observation. Based on these findings, these authors proposed that "muted" IFN-α responses are responsible for the benign nature of SIV infection in SMs. However, other studies indicated that acutely SIV-infected SMs show robust IFN-α responses and marked upregulation of Interferon Stimulated Genes (ISGs. To investigate this apparent disparity, we first examined the role of the reported IRF7 amino acid substitutions in SMs. To this end, we sequenced all IRF7 exons in 16 breeders, and exons displaying variability (exons 2,3,5,6,7,8 in the remainder of the colony (177 animals. We found that the reported Ser-Gly substitution at position 191 was a sequencing error, and that several of the remaining substitutions represent only minor alleles. In addition, functional assays using recombinant SM IRF7 showed no defect in its ability to translocate in the nucleus and drive transcription from an IFN-α promoter. Furthermore, in vitro stimulation of SM peripheral blood mononuclear cells with either the TLR7 agonist CL097 or SIV(mac239 induced an 500-800-fold induction of IFN-α and IFN-β mRNA, and levels of IFN-α production by pDCs similar to those of RMs or humans. These data establish that IFN-α and IRF7 signaling in SMs are largely intact, with differences with RMs that are minor and unlikely to play any role in the AIDS resistance of SIV

  17. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate

    DEFF Research Database (Denmark)

    Abrahamsson, Jonas; Forestier, Erik; Heldrup, Jesper

    2011-01-01

    To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course.......To evaluate the early treatment response in children with acute myeloid leukemia (AML) using a response-guided induction strategy that includes idarubicin in the first course....

  18. The use of growth factors to manage the hematologic side effects of PEG-interferon alfa and ribavirin.

    Science.gov (United States)

    Collantes, Rochelle S; Younossi, Zobair M

    2005-01-01

    Hematologic side effects (anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. Dose modification (including discontinuation) diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on sustained virologic response. Additionally, fatigue associated with anemia may impair patients' quality of life. The clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematologic side effects, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Epoetin alfa and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life. Preliminary work suggests that filgrastim, granulocyte colony stimulating factors, may be an effective treatment of interferon-induced neutropenia. Although this early work shows tremendous promise for managing hematologic side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the efficacy, safety, and cost-effectiveness of growth factors in the management of patients with chronic HCV.

  19. Convergence of the NF-kappaB and interferon signaling pathways in the regulation of antiviral defense and apoptosis.

    Science.gov (United States)

    Hiscott, John; Grandvaux, Nathalie; Sharma, Sonia; Tenoever, Benjamin R; Servant, Marc J; Lin, Rongtuan

    2003-12-01

    The ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly activated following virus infection and functions as a key activator of the immediate-early Type 1 interferon (IFN) genes. Using DNA microarray analysis (8,556 genes) in Jurkat T cells inducibly expressing constitutively active IRF-3, several target genes directly regulated by IRF-3 were identified. Among the genes upregulated by IRF-3 were transcripts for a subset of known IFN-stimulated genes (ISGs), including ISG56, which functions as an inhibitor of translation initiation. Phosphorylation of C-terminal Ser/Thr residues--(382)GGASSLENTVDLHISNSHPLSLTSDQY(408)-is required for IRF-3 activation. Using C-terminal point mutations and a novel phosphospecific antibody, Ser396 was characterized as the minimal phosphoacceptor site required in vivo for IRF-3 activation following Sendai virus (SeV) infection, expression of viral nucleocapsid, or double-stranded RNA (dsRNA) treatment. The identity of the virus-activated kinase (VAK) activity that targets and activates IRF-3 and IRF-7 has remained a critical missing link in the understanding of interferon signaling. We report that the IKK-related kinases-IKKepsilon/TBK-1-are components of VAK that mediate IRF-3 and IRF-7 phosphorylation and thus functionally link the NF-kappaB and IRF pathways in the development of the antiviral response.

  20. Feasibility, toxicity, and efficacy of short induction chemotherapy of docetaxel plus cisplatin or carboplatin (TP) followed by concurrent chemoradiotherapy for organ preservation in advanced cancer of the hypopharynx, larynx, and base of tongue. Early results

    Energy Technology Data Exchange (ETDEWEB)

    Semrau, Sabine; Klautke, Gunther; Fietkau, Rainer [Erlangen-Nuernberg Univ., Erlangen (Germany). Klinik und Poliklinik fuer Strahlentherapie; Waldfahrer, Frank; Iro, Heinrich [Erlangen-Nuernberg Univ., Erlangen (Germany). Hals-Nasen-Ohrenklinik, Kopf- und Halschirurgie; Lell, Michael; Uder, Michael [Erlangen-Nuernberg Univ., Erlangen (Germany). Inst. fuer Radiologie; Linke, Rainer; Kuwert, Torsten [Erlangen-Nuernberg Univ., Erlangen (Germany). Inst. und Poliklinik fuer Nuklearmedizin

    2011-01-15

    Concurrent chemoradiotherapy (CRT) is standard treatment for advanced head and neck cancer. Whether short induction chemotherapy (ICT) provides additional benefit or, in particular, predictive benefit for the response to chemoradiotherapy is an open question. The present study aimed to assess the feasibility, toxicity, and efficacy of induction with docetaxel and platinum salt (TP) and subsequent CRT. A total of 25 patients with functionally inoperable cancer of the base of the tongue, hypopharynx, or larynx received 1 cycle of docetaxel (75 mg/m{sup 2}, day 1) combined with either cisplatin (30 mg/m{sup 2}, days 1-3; n = 23) or carboplatin (AUC 1.5 days 1-3; n = 2). Responders (n = 22, > 30% tumor reduction, graded by endoscopy) and 1 non-responder received CRT (target dose: 69-72 Gy) with cisplatin/paclitaxel, carboplatin/paclitaxel, or cisplatin/docetaxel. All patients completed ICT with acceptable toxicity (leukocytopenia grade 4: 8%). The remission rate of the primary tumor was 88% (22/25 patients). There was no need to delay CRT due to toxicity in any case. Each patient received the full radiation dose. Of the patients, 56% received > 80% of the chemotherapy. The acute toxicity of CRT was moderate, no grade 4 toxicities occurred, while grade 3 toxicities included the following: infection (39%), dermatitis (13%), leukocytopenia (30%), and thrombocytopenia (4%). The local control rate was 84.6% {+-} 8.5% and the survival rate was 89.6% {+-} 7.2% at 12 months. Organ preservation was possible in 22/23 (95%) cases. Short induction with a TP regimen and subsequent CRT with a taxan is feasible and associated with an encouraging local control rate. (orig.)

  1. Safety, Tolerability, and Immunogenicity of Interferons

    Directory of Open Access Journals (Sweden)

    Michael G. Tovey

    2010-04-01

    Full Text Available Interferons (IFNs are class II cytokines that are key components of the innate immune response to virus infection. Three IFN sub-families, type I, II, and III IFNs have been identified in man, Recombinant analogues of type I IFNs, in particular IFNα2 and IFNβ1, have found wide application for the treatment of chronic viral hepatitis and remitting relapsing multiple sclerosis respectively. Type II IFN, or IFN gamma, is used principally for the treatment of chronic granulomatous disease, while the recently discovered type III IFNs, also known as IFN lambda or IL-28/29, are currently being evaluated for the treatment of chronic viral hepatitis. IFNs are in general well tolerated and the most common adverse events observed with IFNα or IFNβ therapy are “flu-like” symptoms such as fever, headache, chills, and myalgia. Prolonged treatment is associated with more serious adverse events including leucopenia, thrombocytopenia, increased hepatic transaminases, and neuropsychiatric effects. Type I IFNs bind to high-affinity cell surface receptors, composed of two transmembrane polypeptides IFNAR1 and IFNAR2, resulting in activation of the Janus kinases Jak1 and Tyk2, phosphorylation and activation of the latent cytoplasmic signal transducers and activators of transcription (STAT1 and STAT2, formation of a transcription complex together with IRF9, and activation of a specific set of genes that encode the effector molecules responsible for mediating the biological activities of type I IFNs. Systemic administration of type I IFN results in activation of IFN receptors present on essentially all types of nucleated cells, including neurons and hematopoietic stem cells, in addition to target cells. This may well explain the wide spectrum of IFN associated toxicities. Recent reports suggest that certain polymorphisms in type I IFN signaling molecules are associated with IFN-induced neutropenia and thrombocytopenia in patients with chronic hepatitis C. IFN

  2. Antiproliferative activity of recombinant human interferon-λ2 ...

    African Journals Online (AJOL)

    Jane

    2011-07-20

    Jul 20, 2011 ... This study aimed at the generation of a stable transformed silkworm BmN cell line which can continuously express human interferon-λ2 (IFN-λ2) gene, and investigated the antiproliferative activity of this recombinant human IFN-λ2. Silkworm BmN cells were transfected with the recombinant vector.

  3. Expression of human interferon gamma in Brassica napus seeds ...

    African Journals Online (AJOL)

    In this study, we used seed specific promoter (Napin) and C-terminal KDEL sequence to express human therapeutic protein, interferon gamma (IFN_y) in Brassica napus seeds. Kozak sequence was linked to the 5' end of the IFN_y gene to increase the level of expression. The constructed cassette was transformed into ...

  4. Antiproliferative activity of recombinant human interferon-λ2 ...

    African Journals Online (AJOL)

    This study aimed at the generation of a stable transformed silkworm BmN cell line which can continuously express human interferon-λ2 (IFN-λ2) gene, and investigated the antiproliferative activity of this recombinant human IFN-λ2. Silkworm BmN cells were transfected with the recombinant vector pIZT/V5-His harboring the ...

  5. Expression of recombinant interferon α-2a in tobacco chloroplasts ...

    African Journals Online (AJOL)

    Chloroplast-based expression of pharmaceuticals provides cost-effective benefits to the consumer. In order to establish the transplastomic biopharmaceuticals, the interferon α-2a gene along with aadA gene was flanked by the tobacco chloroplast inverted repeat region for two events of homologous recombination.

  6. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

    OpenAIRE

    Cohen, Jeffrey A; Barkhof, Frederik; Comi, Giancarlo; Hartung, Hans-Peter; Khatri, Bhupendra O; Montalban, Xavier; Pelletier, Jean; Capra, Ruggero; Gallo, Paolo; Izquierdo, Guillermo; Tiel-Wilck, Klaus; de Vera, Ana; Jin, James; Stites, Tracy; Wu, Stacy

    2010-01-01

    This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)

  7. Protective role of interferon against cytotoxcicity induced by rabies ...

    African Journals Online (AJOL)

    Protective role of interferon against cytotoxcicity induced by rabies virus in mice. AA Tohamy, AM Fahmy, MA Dkhil, MSM Diab. Abstract. Rabies remains an important public health problem in the world due to uncontrolled enzootic rabies, lack of safe efficient vaccines and poor information on the risk of contracting rabies ...

  8. Interferon-gamma treatment kinetics among patients with active ...

    African Journals Online (AJOL)

    Introduction: Interferon-γ (IFN-γ) is essential for defence against Mycobacterium tuberculosis; however, levels in patients with active tuberculosis (TB) and changes during treatment have not been documented in our tuberculosis patients in Nigeria, hence this study has been carried out. Objective: To determine variations, ...

  9. Underlying pathways for interferon risk to type II diabetes mellitus.

    Science.gov (United States)

    Abdel-Hamid, Nabil; Jubori, Taghreed Al; Farhan, Amaal; Mahrous, Mariam; Gouri, Adel; Awad, Ezzat; Breuss, Johannes

    2013-11-01

    It has been known that chronic liver treatments interfere with blood glucose metabolism. It was recognized that diabetes mellitus among chronic hepatitis C was greater in other types of chronic liver diseases. Hepatitis C directly promotes insulin resistance through the proteosomal degradation of insulin resistance substrate. It suppressed hepatocyte glucose uptake through down-regulation of surface expression of glucose transporter. Long-term exposure to cytokine over expression seems to be cytotoxic to both beta cells of the pancreas and to hepatocytes. Elevated tumor necrosis factor-a, or its neutralization, increased insulin sensitivity. Interferon-a may also elevate the serum level of interleukin-1 which is cytotoxic to pancreatic islet cells. Both diabetes mellitus and resistance to interferon-a therapy are abnormally mediated by over-expression of suppressor of cytokine signaling-1 in hepatocytes of chronic hepatitis C patients. These data suggest that interferon-a therapy should be administered with caution in patients showing any predisposition to Diabetes mellitus. Anti inflammatory therapy is critically recommended as a protector against disease development due to cytokine mediated Diabetes mellitus during hepatitis C therapy, since inflammation seems to be a main candidate to interferon suspected diabetogenesis.

  10. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, Thomas Birk; Wittenhagen, P

    2007-01-01

    OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were...

  11. Inductive Communication System Design Summary

    Science.gov (United States)

    1978-09-01

    The report documents the experience obtained during the design and development of the Inductive Communications System used in the Morgantown People Mover. The Inductive Communications System is used to provide wayside-to-vehicle and vehicle-to-waysid...

  12. Anti-Interferon Autoantibodies in Autoimmune Polyendocrinopathy Syndrome Type 1

    Science.gov (United States)

    Meager, Anthony; Visvalingam, Kumuthini; Peterson, Pärt; Möll, Kaidi; Murumägi, Astrid; Krohn, Kai; Eskelin, Petra; Perheentupa, Jaakko; Husebye, Eystein; Kadota, Yoshihisa; Willcox, Nick

    2006-01-01

    Background The autoimmune regulator (AIRE) gene influences thymic self-tolerance induction. In autoimmune polyendocrinopathy syndrome type 1 (APS1; OMIM 240300), recessive AIRE mutations lead to autoimmunity targetting endocrine and other epithelial tissues, although chronic candidiasis usually appears first. Autoimmunity and chronic candidiasis can associate with thymomas as well. Patients with these tumours frequently also have high titre immunoglobulin G autoantibodies neutralising type I interferon (IFN)–α and IFN-ω, which are secreted signalling proteins of the cytokine superfamily involved in both innate and adaptive immunity. Methods and Findings We tested for serum autoantibodies to type I IFNs and other immunoregulatory cytokines using specific binding and neutralisation assays. Unexpectedly, in 60/60 Finnish and 16/16 Norwegian APS1 patients with both AIRE alleles mutated, we found high titre neutralising immunoglobulin G autoantibodies to most IFN-α subtypes and especially IFN-ω (60% homologous to IFN-α)—mostly in the earliest samples. We found lower titres against IFN-β (30% homologous to IFN-α) in 23% of patients; two-thirds of these (from Finland only) also had low titres against the distantly related “type III IFN” (IFN-λ1; alias interleukin-29). However, autoantibodies to the unrelated type II IFN, IFN-γ, and other immunoregulatory cytokines, such as interleukin-10 and interleukin-12, were much rarer and did not neutralise. Neutralising titres against type I IFNs averaged even higher in patients with APS1 than in patients with thymomas. Anti–type I IFN autoantibodies preceded overt candidiasis (and several of the autoimmune disorders) in the informative patients, and persisted for decades thereafter. They were undetectable in unaffected heterozygous relatives of APS1 probands (except for low titres against IFN-λ1), in APS2 patients, and in isolated cases of the endocrine diseases most typical of APS1, so they appear to be APS1

  13. prevention and therapy of interferon-induced depressions of psychiatric patients with or without addictive diseases during a therapy of the chronic hepatitis c

    OpenAIRE

    Garkisch, Andrea Sibylla

    2010-01-01

    The increasing use of interferon-alpha (IFN-a) in treating a variety of diseases - including hepatitis C - often causes neuropsychiatric side effects. One of the most important neuropsychiatric side effect of IFN-a during the treatment of the chronic hepatitis C virus (HCV) infection is the induction of episodes of major depression. It is also assumed that IFN-a can worsen pre-existing affective or schizophrenic disorders. Formerly treatment had to be interrupted in such cases or at least re...

  14. Inductive Supervised Quantum Learning

    Science.gov (United States)

    Monràs, Alex; Sentís, Gael; Wittek, Peter

    2017-05-01

    In supervised learning, an inductive learning algorithm extracts general rules from observed training instances, then the rules are applied to test instances. We show that this splitting of training and application arises naturally, in the classical setting, from a simple independence requirement with a physical interpretation of being nonsignaling. Thus, two seemingly different definitions of inductive learning happen to coincide. This follows from the properties of classical information that break down in the quantum setup. We prove a quantum de Finetti theorem for quantum channels, which shows that in the quantum case, the equivalence holds in the asymptotic setting, that is, for large numbers of test instances. This reveals a natural analogy between classical learning protocols and their quantum counterparts, justifying a similar treatment, and allowing us to inquire about standard elements in computational learning theory, such as structural risk minimization and sample complexity.

  15. Induction motor control

    Science.gov (United States)

    Hansen, Irving G.

    1990-01-01

    Electromechanical actuators developed to date have commonly ultilized permanent magnet (PM) synchronous motors. More recently switched reluctance (SR) motors have been advocated due to their robust characteristics. Implications of work which utilized induction motors and advanced control techniques are discussed. When induction motors are operated from an energy source capable of controlling voltages and frequencies independently, drive characteristics are obtained which are superior to either PM or SR motors. By synthesizing the machine frequency from a high-frequency carrier (nominally 20 kHz), high efficiencies, low distortion, and rapid torque response are available. At this time multiple horsepower machine drives were demonstrated, and work is on-going to develop a 20 hp average, 40 hp peak class of aerospace actuators. This effort is based upon high-frequency power distribution and management techniques developed by NASA for Space Station Freedom.

  16. Induction motor control

    Science.gov (United States)

    Hansen, Irving G.

    Electromechanical actuators developed to date have commonly ultilized permanent magnet (PM) synchronous motors. More recently switched reluctance (SR) motors have been advocated due to their robust characteristics. Implications of work which utilized induction motors and advanced control techniques are discussed. When induction motors are operated from an energy source capable of controlling voltages and frequencies independently, drive characteristics are obtained which are superior to either PM or SR motors. By synthesizing the machine frequency from a high-frequency carrier (nominally 20 kHz), high efficiencies, low distortion, and rapid torque response are available. At this time multiple horsepower machine drives were demonstrated, and work is on-going to develop a 20 hp average, 40 hp peak class of aerospace actuators. This effort is based upon high-frequency power distribution and management techniques developed by NASA for Space Station Freedom.

  17. The antiviral action of interferon is potentiated by removal of the conserved IRTAM domain of the IFNAR1 chain of the interferon alpha/beta receptor: effects on JAK-STAT activation and receptor down-regulation.

    Science.gov (United States)

    Basu, L; Yang, C H; Murti, A; Garcia, J V; Croze, E; Constantinescu, S N; Mullersman, J E; Pfeffer, L M

    1998-03-01

    The first cloned chain (IFNAR1) of the human interferon-alpha (IFN alpha) receptor acts as a species-specific transducer for type 1 IFN action when transfected into heterologous mouse cells. Stably transfected mouse L929 cell lines expressing truncation mutants of the intracellular domain of the human IFNAR1 chain were tested for biological responses to human IFN alpha. Deletion of the intracellular domain resulted in a complete loss of sensitivity to the biological activity of human IFN but markedly increased IFNAR1 cell surface expression, demonstrating that the intracellular domain is required for biological function and contains a domain that negatively regulates its cell surface expression. Removal of the conserved membrane distal 16-amino-acid IRTAM (Interferon Receptor Tyrosine Activation Motif) sequence: (1) increased sensitivity to IFN alpha's antiviral activity, (2) increased the rapid IFN alpha-dependent formation of STAT-containing DNA-binding complexes, (3) prolonged tyrosine phosphorylation kinetics of the JAK-STAT pathway, and (4) blocked the IFN-dependent down-regulation of the IFNAR1 chain. These results indicate that the IRTAM negatively regulates signalling events required for the induction of IFN's biological actions via regulating receptor down-regulation.

  18. T-cell homeostasis in chronic HCV-infected patients treated with interferon and ribavirin or an interferon-free regimen

    DEFF Research Database (Denmark)

    Hartling, Hans Jakob; Birch, Carsten; Gaardbo, Julie C

    2015-01-01

    -cell homeostasis before, during, and after HCV treatment with or without interferon-α in patients with chronic HCV infection. A total of 20 patients with chronic HCV infection were treated with pegylated interferon-α and ribavirin, and six patients were treated with an interferon-free regimen. All patients were...... compared to prior treatment values. Finally, a proportion of CD8+ effector memory was lower while proportion of apoptotic T cells was higher after sustained virologic response compared to prior treatment. Despite lymphopenia during interferon, alterations in T-cell homeostasis during treatment were...

  19. Inductive Temporal Logic Programming

    OpenAIRE

    Kolter, Robert

    2009-01-01

    We study the extension of techniques from Inductive Logic Programming (ILP) to temporal logic programming languages. Therefore we present two temporal logic programming languages and analyse the learnability of programs from these languages from finite sets of examples. In first order temporal logic the following topics are analysed: - How can we characterize the denotational semantics of programs? - Which proof techniques are best suited? - How complex is the learning task? In propositional ...

  20. Inductive Pulse Generation

    OpenAIRE

    Lindblom, Adam

    2006-01-01

    Pulsed power generators are a key component in compact systems for generation of high-power microwaves (HPM). HPM generation by virtual cathode devices such as Vircators put high demands on the source. The rise time and the pulse length of the source voltage are two key issues in the generation of HPM radiation. This thesis describes the construction and tests of several inductive high power pulse generators. The pulse generators were designed with the intent to deliver a pulse with fast rise...

  1. Cancer-selective induction of apotosis by leczyme

    Directory of Open Access Journals (Sweden)

    Takeo eTatsuta

    2014-06-01

    Full Text Available Sialic acid-binding lectin (SBL is a multifunctional protein that is isolated from oocytes of Rana catesbeiana. It has both lectin and ribonuclease (enzyme properties, and therefore is called leczyme. We examined the antitumor effects of SBL and discovered that SBL has potential as a new type of anticancer drug. SBL causes a cancer-selective induction of apoptosis by multiple signaling pathways whereby RNA is its target. It is suggested that the mitochondrial pathway and endoplasmic reticulum stress-mediated pathway participate in SBL-induced signaling. The synergistic antitumor effects with other molecules, such as tumor necrosis factor-related apoptosis ligand (TRAIL and interferon γ (IFN-γ, have been reported. In this study, we summarize the effects of SBL and focus on its cancer-selective apoptotic properties. In addition, we present a possible explanation its cancer specificity.

  2. Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an alpha 1-mediated response

    National Research Council Canada - National Science Library

    K Iwaki; V P Sukhatme; H E Shubeita; K R Chien

    1990-01-01

    The present study was designed to determine if alpha- and beta-adrenergic stimulation of neonatal rat myocardial cells might induce common and/or distinct members of the immediate early gene program...

  3. Rapid and long-term induction of effector immediate early genes (BDNF, Neuritin and Arc) in peri-infarct cortex and dentate gyrus after ischemic injury in rat brain

    DEFF Research Database (Denmark)

    Rickhag, Karl Mattias; Teilum, Maria; Wieloch, Tadeusz

    2007-01-01

    The genomic response following brain ischemia is very complex and involves activation of both protective and detrimental signaling pathways. Immediate early genes (IEGs) represent the first wave of gene expression following ischemia and are induced in extensive regions of the ischemic brain...... including cerebral cortex and hippocampus. Brain-derived neurotrophic factor (BDNF), Neuritin and Activity-regulated cytoskeleton-associated protein (Arc) belong to a subgroup of immediate early genes implicated in synaptic plasticity known as effector immediate early genes. Here, we investigated...... at 0-6 h of reperfusion for Neuritin and 0-12 h of reperfusion for Arc while BDNF was induced 0-9 h of reperfusion. Our study demonstrates a rapid and long-term activation of effector immediate early genes in distinct brain areas following ischemic injury in rat. Effector gene activation may be part...

  4. Interferon gamma, interferon-gamma-induced-protein 10, and tuberculin responses of children at high risk of tuberculosis infection

    DEFF Research Database (Denmark)

    Petrucci, Roberta; Abu Amer, Nabil; Gurgel, Ricardo Queiroz

    2008-01-01

    BACKGROUND: Children in contact with adults with pulmonary tuberculosis (TB) are at risk for infection and disease progression, and chemoprophylaxis may reduce this risk. The identification of infection is based on the tuberculin skin test (TST) and interferon-gamma (INF-gamma) release assays...

  5. Combined Interferon-α and Inosiplex Treatment of Subacute Sclerosing Panencephalitis: A Case Report

    Directory of Open Access Journals (Sweden)

    Chy-Yuan Han

    2003-08-01

    Full Text Available Subacute sclerosing panencephalitis (SSPE is rare in Taiwan. On admission to hospital, a 15-year-old boy was diagnosed with SSPE based on the clinical picture, electroencephalogram, cerebrospinal fluid studies, and brain biopsy. The initial clinical picture was a decline in school performance and a change in personality, followed by progressive tic-like involuntary movements and mental impairment for 8 months, then a rapidly progressive course. After the patient was treated with oral inosiplex and intraventricular interferon-! (IFN-!, his condition stabilized and the neurologic disability index score improved slightly. There were no major side effects during treatment except for a transient initial elevation of body temperature that lasted for several days. Oral inosiplex and intraventricular IFN-! appear to be safe and effective. Early identification and aggressive treatment of SSPE is important.

  6. Use of the johnin PPD interferon-gamma assay in control of bovine paratuberculosis

    DEFF Research Database (Denmark)

    Jungersen, Gregers; Mikkelsen, Heidi; Grell, Susanne N.

    2012-01-01

    of an individual animal cannot establish whether the animal is infected or predict the future progression of disease in this animal. The IFN-γ assay should thus be used on a group of animals to test the level of exposure to paratuberculosis bacteria the animals have experienced, and thereby assist in maintaining......Although the interferon-gamma (IFN-γ) assay for measurements of cell-mediated immune (CMI) responses to paratuberculosis PPD (johnin) has been available for close to 20 years, the assay has not yet emerged as the long desired test to identify infected animals at an early time point. Among other...... issues, this relates to problematic interpretation of the test results and maybe an over-expectation of what can be deducted from this kind of test given the chronic nature and slow development of infection of paratuberculosis. Over a number of years a modified IFN-γ assay with addition of recombinant...

  7. Desensitization to type I interferon in HIV-1 infection correlates with markers of immune activation and disease progression.

    Science.gov (United States)

    Hardy, Gareth A D; Sieg, Scott F; Rodriguez, Benigno; Jiang, Wei; Asaad, Robert; Lederman, Michael M; Harding, Clifford V

    2009-05-28

    Type I interferon (IFNalpha/beta) plays a complex role in HIV-1 infection and has been proposed alternately to have roles in either disease protection or progression. Although IFNalpha/beta plays crucial roles in regulating monocytes and dendritic cells, responsiveness of these cells to IFNalpha/beta in HIV-1 infection is poorly understood. We report significant defects in IFNalpha/beta receptor (IFNalpha/betaR) expression, IFNalpha signaling, and IFNalpha-induced gene expression in monocytes from HIV-1-infected subjects. IFNalpha/betaR expression correlated directly with CD4+ T-cell count and inversely with HIV-1 RNA level and expression of CD38 by memory (CD45RO+) CD8+ T cells, a measure of pathologic immune activation in HIV-1 infection associated with disease progression. In addition, monocytes from HIV-1-infected persons showed diminished responses to IFNalpha, including decreased induction of phosphorylated STAT1 and the classical interferon-stimulated gene produces MxA and OAS. These IFNalpha responses were decreased regardless of IFNalpha/betaR expression, suggesting that regulation of intracellular signaling may contribute to unresponsiveness to IFNalpha/beta in HIV-1 disease. Defective monocyte responses to IFNalpha/beta may play an important role in the pathogenesis of HIV-1 infection, and decreased IFNalpha/betaR expression may serve as a novel marker of disease progression.

  8. Intrahepatic mRNA levels of type I interferon receptor and interferon-stimulated genes in genotype 1b chronic hepatitis C. Association between IFNAR1 mRNA level and sustained response to interferon therapy.

    Science.gov (United States)

    Taniguchi, Hideaki; Iwasaki, Yoshiaki; Takahashi, Akira; Shimomura, Hiroyuki; Moriya, Akio; Yu, Piao Cheng; Umeoka, Fumi; Fujioka, Shin-ichi; Koide, Norio; Shiratori, Yasushi

    2007-01-01

    The aim of this study was to determine the association between pretreatment intrahepatic mRNA levels of interferon receptor and interferon-stimulated genes and response to interferon therapy for genotype 1b chronic hepatitis C. Forty-four patients with genotype 1b chronic hepatitis C who underwent liver biopsy and then received interferon therapy participated in this study. Pretreatment intrahepatic mRNA levels of interferon receptor genes (IFNAR1, IFNAR2b, and IFNAR2c) and interferon-stimulated genes (OAS1 and PKR) were quantified by competitive polymerase chain reaction. In the genes examined, only IFNAR1 mRNA level was significantly higher in patients with sustained virological and biochemical response to interferon therapy versus those with nonsustained response (p IFNAR1 to IFNAR2 were also significantly higher in patients with sustained virological and biochemical response to IFN therapy (p IFNAR1 and mRNA ratio of IFNAR1 to IFNAR2 before treatment may be associated with a favorable response to interferon therapy. Copyright 2007 S. Karger AG, Basel.

  9. Inhibition of lymphocyte recirculation by murine interferon: effects of various interferon preparations and timing of administration.

    Science.gov (United States)

    Mann, E A; Markovic, S N; Murasko, D M

    1989-02-01

    The effects of highly purified and/or recombinant interferon (IFN)-alpha/beta, IFN-alpha, IFN-beta, IFN-gamma, and the IFN-inducer, poly(I):poly(C), on the circulation of peripheral blood leukocytes (PBL) and thoracic duct lymphocytes (TDL) of (BALB/cJ x C57Bl/6J)F1 mice were examined. Although all IFN classes could depress significantly the number of circulating PBL and TDL when given at sufficient doses, IFN-alpha appeared to be the most potent. Phenotypic analysis of lymphocytes in the blood and lymph during the decrease induced by IFN suggests that IFN-alpha/beta and IFN-alpha preferentially decrease the Lyt-2+, or suppressor/cytotoxic, subset. Timing of IFN administration was found to be an important factor. Repeated administration of IFN-alpha/beta once a day for 3 days produced continuous suppression of the number of circulating PBL. Administration of either IFN-alpha/beta or IFN-gamma in the evening resulted in a longer and more extensive inhibition of PBL circulation than when IFN was administered in the morning. Our results suggest that the leukopenia observed in many patients undergoing IFN therapy may, in part, be attributed to decreased lymphocyte recirculation, and that the timing of IFN administration may be important in maximizing its therapeutic index.

  10. Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages.

    Science.gov (United States)

    Decalf, Jérémie; Desdouits, Marion; Rodrigues, Vasco; Gobert, François-Xavier; Gentili, Matteo; Marques-Ladeira, Santy; Chamontin, Célia; Mougel, Marylène; Cunha de Alencar, Bruna; Benaroch, Philippe

    2017-08-01

    Along with CD4(+) T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection.IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion

  11. Use of novel recombinant antigens in the interferon gamma assay for detection of Mycobacterium avium subsp. paratuberculosis infection in cattle

    DEFF Research Database (Denmark)

    Mikkelsen, Heidi; Aagaard, C.; Nielsen, Søren Saxmose

    2012-01-01

    Early stage Mycobacterium avium subsp. paratuberculosis (MAP) infection may be detected by measuring antigen specific cell-mediated immune responses by the interferon-gamma (IFN-¿) assay. Available IFN-¿ assay use purified protein derivate of Johnin (PPDj) leading to low specificity. The objectives.......85) which also had high specificity (0.92-1.00). Three latency proteins showed positive IFN-¿ tests that correlated highly with the case definition and one of these antigens (LATP-2) had no homologue sequence in the M. avium subsp. avium or M. bovis genome and could be a promising diagnostic antigen...

  12. Use of Novel Recombinant Antigens in the Interferon Gamma Assay for Detection of Mycobacterium Avium Subsp. Paratuberculosis Infection in Cattle

    DEFF Research Database (Denmark)

    Mikkelsen, Heidi; Aagaard, Claus; Nielsen, Søren Saxmose

    Early stage Mycobacterium avium subsp. paratuberculosis (MAP) infection can be detected by measuring antigen specific cell mediated immune responses by the interferon gamma (IFN-γ) assay. Available IFN-γ assay use purified protein derivate of Johnin (PPDj) leading to low specificity. The objectives...... high specificity (0.92-1.00). Three latency proteins showed positive IFN-γ tests that correlated highly with the case definition and one of these antigens (LATP-2) had no homologue sequence in the M. avium subsp. avium or M. bovis genome and could be a promising diagnostic antigen. The combination...

  13. The impact of interferon-alpha2 on HLA genes in patients with polycythemia vera and related neoplasms.

    Science.gov (United States)

    Skov, Vibe; Riley, Caroline Hasselbalch; Thomassen, Mads; Kjær, Lasse; Stauffer Larsen, Thomas; Bjerrum, Ole Weis; Kruse, Torben A; Hasselbalch, Hans Carl

    2017-08-01

    Gene expression profiling in Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have unraveled significant deregulation of several immune and inflammation genes of potential importance for clonal evolution. Other mechanisms might be downregulation of major histocompatibility class I and II genes used by tumor cells to escape antitumor T-cell-mediated immune responses. Several genes encoding human leukocyte antigen (HLA) class I and II molecules have been shown to be significantly downregulated. Upregulation of HLA genes is considered one of the mechanisms of action of interferon (IFN)-alpha2, but regulation of these genes during IFN-alpha2 treatment in MPNs has never been studied. Our findings show a significant upregulation of several HLA genes of importance for tumor immune surveillance by IFN-alpha2 treatment in MPNs. This mechanism might enhance the cytotoxic potential of immune cells against MPNs and explain the induction of minimal residual disease by IFN-alpha2 treatment in these patients.

  14. Interferon alpha and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS.

    Science.gov (United States)

    Zagury, D; Lachgar, A; Chams, V; Fall, L S; Bernard, J; Zagury, J F; Bizzini, B; Gringeri, A; Santagostino, E; Rappaport, J; Feldman, M; Burny, A; Gallo, R C

    1998-03-31

    HIV type 1 (HIV-1) not only directly kills infected CD4(+) T cells but also induces immunosuppression of uninfected T cells. Two immunosuppressive proteins, interferon alpha (IFNalpha) and extracellular Tat, mediate this process because specific antibodies against these proteins prevent generation of suppressor cells in HIV-1-infected peripheral blood mononuclear cell cultures. Furthermore, the production of C-C chemokines in response to immune cell activation, initially enhanced by IFNalpha and Tat, ultimately is inhibited by these proteins in parallel with their induction of immunosuppression. The clinical corollary is the immunosuppression of uninfected T cells and the decline in C-C chemokine release found at advanced stages of HIV-1 infection paralleling rising levels of IFNalpha and extracellular Tat. We, therefore, suggest that IFNalpha and Tat may be critical targets for anti-AIDS strategies.

  15. [Current aspects of labor induction].

    Science.gov (United States)

    Surbek, D V; Hösli, I; Holzgreve, W

    2002-12-01

    Induction of labor is one of the most important means for therapeutic intervention in modern obstetrics. The aim of labor induction is to achieve a better perinatal result for mother and baby as compared to expectative management. Different methods for induction include administration of oxytocin or prostaglandins, amniotomy, and mechanical means of cervical dilatation. The success of the labor induction depends primarily on the readiness of the uterus to go into labor, and the method used for induction. If the cervical ripeness is very advanced, induction with amniotomy and oxytocin seems beneficial. However if the cervix is not yet ready, intravaginal or intracervical prostaglandins are more promising. Until recently, prostaglandins E2 are used in the first line. Now, the prostaglandin E1-analogon misoprostol is also increasingly used. As a rule, induction of labor should be performed as an inpatient procedure in order to be able to provide the surveillance for maternal and fetal safety.

  16. An interferon alpha2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitumor activities.

    Science.gov (United States)

    Kalie, Eyal; Jaitin, Diego A; Abramovich, Renne; Schreiber, Gideon

    2007-04-13

    All alpha-interferons (IFNalpha) bind the IFNAR1 receptor subunit with low affinity. Increasing the binding affinity was shown to specifically increase the antiproliferative potency of IFNalpha2. Here, we constructed a phage display library by randomizing three positions on IFNalpha2 previously shown to confer weak binding to IFNAR1. The tightest binding variant selected, comprised of mutations H57Y, E58N, and Q61S (YNS), was shown to bind IFNAR1 60-fold tighter compared with wild-type IFNalpha2, and 3-fold tighter compared with IFNbeta. Binding of YNS to IFNAR2 was comparable with wild-type IFNalpha2. The YNS mutant conferred a 150-fold higher antiproliferative potency in WISH cells compared with wild-type IFNalpha2, whereas its antiviral activity was increased by only 3.5-fold. The high antiproliferative activity was related to an induction of apoptosis, as demonstrated by annexin V binding assays, and to specific gene induction, particularly TRAIL. To determine the potency of the YNS mutant in a xenograft cancer model, we injected it twice a week to nude mice carrying transplanted MDA231 human breast cancer cells. After 5 weeks, no tumors remained in mice treated with YNS, whereas most mice treated with wild-type IFNalpha2 showed visible tumors. Histological analysis of these tumors showed a significant anti-angiogenic effect of YNS, compared with wild-type IFNalpha2. This work demonstrates the application of detailed biophysical understanding in the process of protein engineering, yielding an interferon variant with highly increased biological potency.

  17. Interferon Stimulated Gene Expression in HIV/HCV Coinfected Patients Treated with Nitazoxanide/Peginterferon-Alfa-2a and Ribavirin.

    Science.gov (United States)

    Petersen, Tess; Lee, Yu-Jin; Osinusi, Anu; Amorosa, Valerianna K; Wang, Crystal; Kang, Minhee; Matining, Roy; Zhang, Xiao; Dou, Diana; Umbleja, Triin; Kottilil, Shyam; Peters, Marion G

    2016-07-01

    A combination of nitazoxanide (NTZ), peginterferon (PegIFN), and ribavirin (RBV) may result in higher sustained virologic response (SVR) rates in hepatitis C virus (HCV) monoinfected patients. This study evaluated the effect of NTZ on interferon-stimulated gene (ISG) expression in vitro and in vivo among HIV/HCV genotype-1 (GT-1) treatment-naive patients. The ability of NTZ to enhance host response to interferon (IFN) signaling using the HCV cell culture system was initially evaluated. Second, ISG expression in 53 patients with treatment outcomes [21 SVR and 32 nonresponders (NR)] in the ACTG A5269 trial, a phase-II study (4-week lead in of NTZ 500 mg daily followed by 48 weeks of NTZ, PegIFN, and weight-based RBV), was assessed. The relative expression of 48 ISGs in peripheral blood mononuclear cells (PBMCs) was measured at baseline, week 4, and week 8 of treatment in a blinded manner. In vitro NTZ produced a direct and additive antiviral effect with IFN-alfa, with pretreatment of NTZ resulting in maximal HCV suppression. NTZ augmented IFN-mediated ISG induction in PBMCs from relapsers and SVRs (p < 0.05), but not NR. In ACTG A5269, baseline expression of most ISGs was similar between NR and SVR. NTZ minimally induced 17 genes in NR and 13 genes in SVR after 4 weeks of therapy. However, after initiation of PegIFN and RBV, ISG induction was predominantly observed in the SVR group and not NR group. NTZ treatment facilitates IFN-induced suppression of HCV replication. Inability to achieve SVR with IFN-based therapy in this clinical trial is associated with diminished ISG response to therapy that is refractory to NTZ.

  18. Low inductance gas switching.

    Energy Technology Data Exchange (ETDEWEB)

    Chavez, Ray; Harjes, Henry Charles III; Wallace, Zachariah; Elizondo, Juan E.

    2007-10-01

    The laser trigger switch (LTS) is a key component in ZR-type pulsed power systems. In ZR, the pulse rise time through the LTS is > 200 ns and additional stages of pulse compression are required to achieve the desired <100 ns rise time. The inductance of the LTS ({approx}500nH) in large part determines the energy transfer time through the switch and there is much to be gained in improving system performance and reducing system costs by reducing this inductance. The current path through the cascade section of the ZR LTS is at a diameter of {approx} 6-inches which is certainly not optimal from an inductance point of view. The LTS connects components of much greater diameter (typically 4-5 feet). In this LDRD the viability of switch concepts in which the diameter of cascade section is greatly increased have been investigated. The key technical question to be answered was, will the desired multi-channel behavior be maintained in a cascade section of larger diameter. This LDRD proceeded in 2 distinct phases. The original plan for the LDRD was to develop a promising switch concept and then design, build, and test a moderate scale switch which would demonstrate the key features of the concept. In phase I, a switch concept which meet all electrical design criteria and had a calculated inductance of 150 nH was developed. A 1.5 MV test switch was designed and fabrication was initiated. The LDRD was then redirected due to budgetary concerns. The fabrication of the switch was halted and the focus of the LDRD was shifted to small scale experiments designed to answer the key technical question concerning multi-channel behavior. In phase II, the Multi-channel switch test bed (MCST) was designed and constructed. The purpose of MCST was to provide a versatile, fast turn around facility for the study the multi-channel electrical breakdown behavior of a ZR type cascade switch gap in a parameter space near that of a ZR LTS. Parameter scans on source impedance, gap tilt, gap spacing and

  19. Upregulation of Interferon-inducible and damage response pathways in chronic graft-versus-host disease

    Science.gov (United States)

    Hakim, Frances T.; Memon, Sarfraz; Jin, Ping; Imanguli, Matin M.; Wang, Huan; Rehman, Najibah; Yan, Xiao-Yi; Rose, Jeremy; Mays, Jacqueline W.; Dhamala, Susan; Kapoor, Veena; Telford, William; Dickinson, John; Davis, Sean; Halverson, David; Naik, Haley B.; Baird, Kristin; Fowler, Daniel; Stroncek, David; Cowen, Edward W.; Pavletic, Steven Z.; Gress, Ronald E.

    2016-01-01

    Although Chronic Graft-versus-Host Disease (CGVHD) is the primary non-relapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: (1) Interferon-inducible genes and (2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation and antigen presentation) were concurrently upregulated in CGVHD monocytes compared to normal and nonCGVHD controls. IFN-inducible chemokines were elevated in both lichenoid and sclerotic CGHVD plasma and linked to CXCR3+ lymphocyte trafficking. Furthermore, the IFN-inducible genes CXCL10 and TNFSF13B (BAFF) levels were correlated at both the gene and plasma levels, implicating IFN-induction as a factor in elevated BAFF levels in CGVHD. In the second pathway, DAMP/PAMP receptor genes capable of inducing Type I IFN were upregulated. Type I IFN-inducible MxA was expressed in proportion to CGVHD activity in skin, mucosa and glands, and expression of TLR and RIG-1 receptor genes correlated with upregulation of Type I IFN-inducible genes in monocytes. Finally, in serial analyses following transplant, IFN-inducible and damage-response genes were upregulated in monocytes at CGVHD onset and declined upon therapy and resolution in both lichenoid and sclerotic CGVHD patients. This interlocking analysis of IFN-inducible genes, plasma analytes and tissue immunohistochemistry strongly supports a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD. PMID:27694491

  20. Type I interferon responses are impaired in latently HIV infected cells.

    Science.gov (United States)

    Ranganath, Nischal; Sandstrom, Teslin S; Fadel, Saleh; Côté, Sandra C; Angel, Jonathan B

    2016-09-09

    The latent HIV-1 reservoir represents the primary barrier to the eradication of HIV-1 infection. The design of novel reservoir-clearance strategies, however, is impeded in part by the inability to distinguish latently HIV-infected cells from uninfected cells. Significant impairment of the type I interferon (IFN-I) response is observed during productive HIV-1 infection. Although this remains poorly described in the context of latent HIV-1 infection, presence of potential defects may serve as a novel therapeutic target. Therefore, IFN-I pathways were characterized using two latently HIV-1-infected cell lines, U1 and OM10.1, in comparison to their respective uninfected parental U937 and HL60 cell lines. Constitutive expression and induction of important mediators of IFN-I signaling including IFNα/β cytokines, IFNAR1, MHC-I, ISG15, and PKR were evaluated following exogenous IFNα or poly(I:C) treatment. Differences in basal expression of IFNAR1, MHC-I, and PKR were observed between the latently HIV-1 infected and uninfected cell lines. In parallel, significant impairments in the induction of MHC-I, ISG15 and PKR, as well as secretion of IFNα/β cytokines were observed in response to appropriate exogenous stimulation within the two latently HIV-infected U1 and OM10.1 cells, relative to their HIV-uninfected parental cells. In comparison to the HIV-uninfected U937 and HL60 cell lines, widespread defects in IFN-I responsiveness were observed within the latently HIV-infected U1 and OM10.1 cells. These impairments represent novel therapeutic targets, which may be amenable to strategies currently employed in cancer therapy.

  1. Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)-possible immunosuppressive role of IFN-alpha in HIV infection

    DEFF Research Database (Denmark)

    Stylianou, E; Aukrust, P; Bendtzen, K

    2000-01-01

    Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-alpha, IFN-gamma, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV...

  2. Acute pericarditis due to pegylated interferon alpha therapy for chronic HCV hepatitis - Case report

    Science.gov (United States)

    2011-01-01

    Background Cardio toxicity due to interferon therapy was reported only in small case series or case reports. The most frequent cardiac adverse effects related to interferon are arrhythmias and ischemic manifestations. The cardiomyopathy and pericarditis are rare but can be life threatening. The predisposing factors for interferon cardio toxicity were described only for ischemic manifestations and arrhythmias. Case presentation The authors report a case of pericarditis due to alpha interferon therapy for chronic hepatitis C, in a young woman without previous cardiac pathology. The clinical manifestations started during the 7-th month of interferon treatment. The cessation of interferon was necessary. After interferon discontinuation the patient recovered, with complete resolution of pericarditis. The patient scored 9 points on the Naranjo ADR probability scale, indicating a very probable association between pericarditis and interferon administration. Conclusion If a patient receiving interferon therapy complains of chest pain of sudden onset, a cardiac ultrasound should be performed in order to rule out pericarditis. We point out the possibility of an infrequent but severe adverse effect of interferon therapy. PMID:21453456

  3. Mumps Virus Induces Protein-Kinase-R-Dependent Stress Granules, Partly Suppressing Type III Interferon Production.

    Directory of Open Access Journals (Sweden)

    Shin Hashimoto

    Full Text Available Stress granules (SGs are cytoplasmic granular aggregations that are induced by cellular stress, including viral infection. SGs have opposing antiviral and proviral roles, which depend on virus species. The exact function of SGs during viral infection is not fully understood. Here, we showed that mumps virus (MuV induced SGs depending on activation of protein kinase R (PKR. MuV infection strongly induced interferon (IFN-λ1, 2 and 3, and IFN-β through activation of IFN regulatory factor 3 (IRF3 via retinoic acid inducible gene-I (RIG-I and the mitochondrial antiviral signaling (MAVS pathway. MuV-induced IFNs were strongly upregulated in PKR-knockdown cells. MuV-induced SG formation was suppressed by knockdown of PKR and SG marker proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and T-cell-restricted intracellular antigen-1, and significantly increased the levels of MuV-induced IFN-λ1. However, viral titer was not altered by suppression of SG formation. PKR was required for induction of SGs by MuV infection and regulated type III IFN (IFN-λ1 mRNA stability. MuV-induced SGs partly suppressed type III IFN production by MuV; however, the limited suppression was not sufficient to inhibit MuV replication in cell culture. Our results provide insight into the relationship between SGs and IFN production induced by MuV infection.

  4. Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling

    Science.gov (United States)

    Wilmes, Stephan; Beutel, Oliver; Li, Zhi; Francois-Newton, Véronique; Richter, Christian P.; Janning, Dennis; Kroll, Cindy; Hanhart, Patrizia; Hötte, Katharina; You, Changjiang; Uzé, Gilles; Pellegrini, Sandra

    2015-01-01

    Type I interferons (IFNs) activate differential cellular responses through a shared cell surface receptor composed of the two subunits, IFNAR1 and IFNAR2. We propose here a mechanistic model for how IFN receptor plasticity is regulated on the level of receptor dimerization. Quantitative single-molecule imaging of receptor assembly in the plasma membrane of living cells clearly identified IFN-induced dimerization of IFNAR1 and IFNAR2. The negative feedback regulator ubiquitin-specific protease 18 (USP18) potently interferes with the recruitment of IFNAR1 into the ternary complex, probably by impeding complex stabilization related to the associated Janus kinases. Thus, the responsiveness to IFNα2 is potently down-regulated after the first wave of gene induction, while IFNβ, due to its ∼100-fold higher binding affinity, is still able to efficiently recruit IFNAR1. Consistent with functional data, this novel regulatory mechanism at the level of receptor assembly explains how signaling by IFNβ is maintained over longer times compared with IFNα2 as a temporally encoded cause of functional receptor plasticity. PMID:26008745

  5. Distinct Effects of Type I and III Interferons on Enteric Viruses

    Directory of Open Access Journals (Sweden)

    Harshad Ingle

    2018-01-01

    Full Text Available Interferons (IFNs are key host cytokines in the innate immune response to viral infection, and recent work has identified unique roles for IFN subtypes in regulating different aspects of infection. Currently emerging is a common theme that type III IFNs are critical in localized control of infection at mucosal barrier sites, while type I IFNs are important for broad systemic control of infections. The intestine is a particular site of interest for exploring these effects, as in addition to being the port of entry for a multitude of pathogens, it is a complex tissue with a variety of cell types as well as the presence of the intestinal microbiota. Here we focus on the roles of type I and III IFNs in control of enteric viruses, discussing what is known about signaling downstream from these cytokines, including induction of specific IFN-stimulated genes. We review viral strategies to evade IFN responses, effects of IFNs on the intestine, interactions between IFNs and the microbiota, and briefly discuss the role of IFNs in controlling viral infections at other barrier sites. Enhanced understanding of the coordinate roles of IFNs in control of viral infections may facilitate development of antiviral therapeutic strategies; here we highlight potential avenues for future exploration.

  6. Henipaviruses Employ a Multifaceted Approach to Evade the Antiviral Interferon Response

    Directory of Open Access Journals (Sweden)

    Megan L. Shaw

    2009-12-01

    Full Text Available Hendra and Nipah virus, which constitute the genus Henipavirus, are zoonotic paramyxoviruses that have been associated with sporadic outbreaks of severe disease and mortality in humans since their emergence in the late 1990s. Similar to other paramyxoviruses, their ability to evade the host interferon (IFN response is conferred by the P gene. The henipavirus P gene encodes four proteins; the P, V, W and C proteins, which have all been described to inhibit the antiviral response. Further studies have revealed that these proteins have overlapping but unique properties which enable the virus to block multiple signaling pathways in the IFN response. The best characterized of these is the JAK-STAT signaling pathway which is targeted by the P, V and W proteins via an interaction with the transcription factor STAT1. In addition the V and W proteins can both limit virus-induced induction of IFN but they appear to do this via distinct mechanisms that rely on unique sequences in their C-terminal domains. The ability to generate recombinant Nipah viruses now gives us the opportunity to determine the precise role for each of these proteins and address their contribution to pathogenicity. Additionally, the question of whether these multiple anti-IFN strategies are all active in the different mammalian hosts for henipaviruses, particularly the fruit bat reservoir, warrants further exploration.

  7. Viewpoint: factors involved in type I interferon responses during porcine virus infections.

    Science.gov (United States)

    Summerfield, Artur

    2012-07-15

    Since type I interferon (IFN-I) is considered a potent antiviral defence mechanism, it is not surprising that during evolution viruses have development of various mechanisms to counteract IFN-I induction or release. Despite this, certain virus infections are associated with very high levels of systemic IFN-I. One explanation for this observation is the presence of plasmacytoid dendritic cells (pDC), which are able to produce high levels of IFN-I despite the presence of viral IFN-I antagonists. Examples of virus infection in pigs including classical swine fever virus, influenza virus, foot-and-mouth disease virus, and porcine circo virus type 2 highlight factors involved in controlling such responses and illustrate potential negative and positive effects for the host. Based on published data, we propose that in addition to the ability to activate pDC, the ability to spread systemically, and the tropism for lymphoid tissue also represent important factors contributing to strong systemic IFN-I responses during certain virus infections. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. IκB kinase ε targets interferon regulatory factor 1 in activated T lymphocytes.

    Science.gov (United States)

    Sgarbanti, Marco; Marsili, Giulia; Remoli, Anna Lisa; Stellacci, Emilia; Mai, Antonello; Rotili, Dante; Perrotti, Edvige; Acchioni, Chiara; Orsatti, Roberto; Iraci, Nunzio; Ferrari, Mathieu; Borsetti, Alessandra; Hiscott, John; Battistini, Angela

    2014-03-01

    IκB kinase ε (IKK-ε) has an essential role as a regulator of innate immunity, functioning downstream of pattern recognition receptors to modulate NF-κB and interferon (IFN) signaling. In the present study, we investigated IKK-ε activation following T cell receptor (TCR)/CD28 stimulation of primary CD4(+) T cells and its role in the stimulation of a type I IFN response. IKK-ε was activated following TCR/CD28 stimulation of primary CD4(+) T cells; however, in T cells treated with poly(I·C), TCR/CD28 costimulation blocked induction of IFN-β transcription. We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity. At the mechanistic level, IRF-1 phosphorylation impaired the physical interaction between IRF-1 and the NF-κB RelA subunit and interfered with PCAF-mediated acetylation of NF-κB RelA. These results demonstrate that TCR/CD28 stimulation of primary T cells stimulates IKK-ε activation, which in turn contributes to suppression of IFN-β production.

  9. Identification of a Predominantly Interferon-λ-Induced Transcriptional Profile in Murine Intestinal Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Tharini A. Selvakumar

    2017-10-01

    Full Text Available Type I (α and β and type III (λ interferons (IFNs induce the expression of a large set of antiviral effector molecules via their respective surface membrane receptors. Whereas most cell types respond to type I IFN, type III IFN preferentially acts on epithelial cells and protects mucosal organs such as the lung and gastrointestinal tract. Despite the engagement of different receptor molecules, the type I and type III IFN-induced signaling cascade and upregulated gene profile is thought to be largely identical. Here, we comparatively analyzed the response of gut epithelial cells to IFN-β and IFN-λ2 and identified a set of genes predominantly induced by IFN-λ2. We confirm the influence of epithelial cell polarization for enhanced type III receptor expression and demonstrate the induction of predominantly IFN-λ2-induced genes in the gut epithelium in vivo. Our results suggest that IFN-λ2 targets the epithelium and induces genes to adjust the antiviral host response to the requirements at mucosal body sites.

  10. Endometriosis and Type I Interferon & Characterization of a Mammalian Flippase

    DEFF Research Database (Denmark)

    Vestergaard, Anna Lindeløv

    2010-01-01

    Endometriosis and Type I Interferon   Endometriosis is a painful chronic disease in which endometrium-like lesions are located ectopically, frequently in the pelvic cavity but also in more distant sites. The pathogenesis of endometriosis is unclear and involves complex hormonal, genetic, environm......Endometriosis and Type I Interferon   Endometriosis is a painful chronic disease in which endometrium-like lesions are located ectopically, frequently in the pelvic cavity but also in more distant sites. The pathogenesis of endometriosis is unclear and involves complex hormonal, genetic......, Wilson, and Byler disease, migraine, and parkinsonism. The P4-type ATPases, also named the flippases, translocate aminophospholipids rather than ions to the cytosolic side of the membrane bilayer and are allegedly crucial for the essential asymmetry of bilayered biological membranes. Members of the CDC50...

  11. Early juvenile idiopathic arthritis.

    Science.gov (United States)

    Marzan, Katherine Anne B; Shaham, Bracha

    2012-05-01

    Early juvenile idiopathic arthritis (JIA) is important to recognize as timely diagnosis and treatment improves prognosis. It is a misconception that complications of JIA arise only from long-standing disease and that children will outgrow it. Early aggressive treatment is the paradigm as early disease activity has long-term consequences. There are predictors of persistent disease and joint erosions that may identify patients at higher risk. Control of disease activity within the first 6 months of onset confers improved clinical course and outcomes. The treatment perspective is thus one of early aggressive treatment for induction of disease control and ultimately remission. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Transient expression of chicken alpha interferon gene in lettuce*

    OpenAIRE

    Song, Li; Zhao, De-Gang; Wu, Yong-Jun; Li, Yi

    2008-01-01

    We investigated the possibility of producing chicken alpha interferon (ChIFN-α) in transgenic plants. The cDNA encoding ChIFN-α was introduced into lettuce (Lactuca sativa L.) plants by using an agro-infiltration transient expression system. The ChIFN-α gene was correctly transcribed and translated in the lettuce plants according to RT-PCR and ELISA assays. Recombinant protein exhibited antiviral activity in vitro by inhibition of vesicular stomatitis virus (VSV) replication on chicken embryo...

  13. Peripheral Vasculitis, Intermediate Uveitis and Interferon Use in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Haluk Esgin

    2016-01-01

    Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system. A 40-year-old female patient with a 12-year history of MS was admitted to our clinic with blurred vision and floaters in her right eye for about 1 month. Here, we share the findings and the management of intermediate uveitis and retinal periphlebitis in an MS case being treated with interferon beta-1a for 7 years.

  14. Pharmacokinetics of interferon alpha-2b in healthy volunteers.

    Science.gov (United States)

    Radwanski, E; Perentesis, G; Jacobs, S; Oden, E; Affrime, M; Symchowicz, S; Zampaglione, N

    1987-01-01

    In a three-way crossover design, 12 healthy male volunteers received 5 X 10(6) IU/m2 body surface area interferon alpha-2b(IFN alpha-2b) by intravenous (IV) infusion over 30 minutes, intramuscular (IM) injections, and subcutaneous (SC) injections. Blood and urine samples were collected at specified times, and analysis of IFN alpha-2b concentrations was performed by immunoradiometric assay. "Flulike" symptoms were the most frequently reported adverse experiences and were independent of the route of administration. After a 30-minute IV infusion, IFN alpha-2b disappeared rapidly from serum, with distribution and elimination phase half-lives of 0.1 hour and 1.7 hours, respectively. Interferon alpha-2b was absorbed slowly after IM and SC administration, with similar absorption half-lives of 5.8 and 5.5 hours, respectively. The observed maximal concentrations after IM and SC administration were 42.1 IU/mL at six hours and 45.8 IU/mL at eight hours, respectively. Interferon alpha-2b was eliminated with half-lives of 2.2 hours after IM administration and 2.9 hours after SC administration. The areas under the serum concentration-time curves for the SC and IM doses were higher than those obtained for the IV infusion. Measurable amounts of IFN alpha-2b were not found in urine regardless of the route of administration.

  15. Uso de los interferones en Dermatología: experiencia con el alfa-interferon en la micosis fungoide Use of interferons in Dermatology: experience with alpha-interferon in mycosis fungoides

    Directory of Open Access Journals (Sweden)

    Edelisa Moredo Romo

    2004-08-01

    Full Text Available Se revisó la literatura y se constató la amplia utilización de los interferones (INFs en Dermatología. Se presenta un estudio retrospectivo de 7 pacientes con diagnóstico de micosis fungoides tratados con alfa-interferón recombinante (alfa-INFR y se concluye su efectividad en el tratamiento de esta enfermedad y su disponibilidad en el tratamiento en Cuba. Los efectos adversos observados a las dosis utilizadas fueron fundamentalmente fiebre, escalofríos y malestar general que cedieron con tratamiento analgésico. No se encontraron efectos adversos hematológicos.Literature was reviewed and the wide use of interferons (INFs in Dermatology was proved. A retrospective study of 7 patients that were diagnosed mycosis fungoides and treated with recombinant alpha-interferon (alpha-INFR was presented It effectiveness in the treatment of this disease and its availability in Cuba were demonstrated. The adverse effects observed in the used doses were mainly fever, chills and malaise that improved with analgesic treatment. No hematological adverse effects were observed.

  16. [Gamma interferon: basics aspects, clinic significance and terapeutic uses].

    Science.gov (United States)

    Mata-Espinosa, Dulce A; Hernández-Pando, Rogelio

    2008-01-01

    Interferons are a family of pleiotropic cytokines, their name was assigned because of their anti-replicative viral activity. IFNgamma or immune type II interferon does not share receptors with the type I interferon, its structure is different and its gene is located in different chromosome, although its biologic effects are similar. Along of several years of research, it has been found that IFNgamma enhances the transcription of genes involved in immunomodulation, antiviral responses and antitumoral activities. Regarding to the immune system, IFNgamma increases the cytotoxic and phagocytic activity of macrophages and upregulates the expression of major histocompatibility complex (MHC) class I and class II molecules in dendritics cells and other antigen presenting cells. IFNgamma also promotes the development and differentiation of naive CD4+ T lymphocytes to Th1 helper subset. Indeed, this cytokine has a key role in the control of bacterial, micotic, viral and parasitic infections. Depending of the micro-environment, IFNgamma has a dual role as pro or anti inflammatory cytokine. Novel therapeutic strategies are currently being developed with the aim to enhance the immune response or replace IFNgamma gene abnormal expression with beneficial results in humans, being recombinant IFNgamma safe and well tolerated.

  17. Hepatitis C Virus Frameshift/Alternate Reading Frame Protein Suppresses Interferon Responses Mediated by Pattern Recognition Receptor Retinoic-Acid-Inducible Gene-I.

    Directory of Open Access Journals (Sweden)

    Seung Bum Park

    Full Text Available Hepatitis C virus (HCV actively evades host interferon (IFN responses but the mechanisms of how it does so are not completely understood. In this study, we present evidence for an HCV factor that contributes to the suppression of retinoic-acid-inducible gene-I (RIG-I-mediated IFN induction. Expression of frameshift/alternate reading frame protein (F/ARFP from HCV -2/+1 frame in Huh7 hepatoma cells suppressed type I IFN responses stimulated by HCV RNA pathogen-associated molecular pattern (PAMP and poly(IC. The suppression occurred independently of other HCV factors; and activation of interferon stimulated genes, TNFα, IFN-λ1, and IFN-λ2/3 was likewise suppressed by HCV F/ARFP. Point mutations in the full-length HCV sequence (JFH1 genotype 2a strain were made to introduce premature termination codons in the -2/+1 reading frame coding for F/ARFP while preserving the original reading frame, which enhanced IFNα and IFNβ induction by HCV. The potentiation of IFN response by the F/ARFP mutations was diminished in Huh7.5 cells, which already have a defective RIG-I, and by decreasing RIG-I expression in Huh7 cells. Furthermore, adding F/ARFP back via trans-complementation suppressed IFN induction in the F/ARFP mutant. The F/ARFP mutants, on the other hand, were not resistant to exogenous IFNα. Finally, HCV-infected human liver samples showed significant F/ARFP antibody reactivity, compared to HCV-uninfected control livers. Therefore, HCV F/ARFP likely cooperates with other viral factors to suppress type I and III IFN induction occurring through the RIG-I signaling pathway. This study identifies a novel mechanism of pattern recognition receptor modulation by HCV and suggests a biological function of the HCV alternate reading frame in the modulation of host innate immunity.

  18. Expression of type I interferon by splenic macrophages suppresses adaptive immunity during sepsis.

    Science.gov (United States)

    Schwandt, Timo; Schumak, Beatrix; Gielen, Gerrit H; Jüngerkes, Frank; Schmidbauer, Patricia; Klocke, Katrin; Staratschek-Jox, Andrea; van Rooijen, Niko; Kraal, Georg; Ludwig-Portugall, Isis; Franken, Lars; Wehner, Sven; Kalff, Jörg C; Weber, Olaf; Kirschning, Carsten; Coch, Christoph; Kalinke, Ulrich; Wenzel, Jörg; Kurts, Christian; Zawatzky, Rainer; Holzmann, Bernhard; Layland, Laura; Schultze, Joachim L; Burgdorf, Sven; den Haan, Joke M M; Knolle, Percy A; Limmer, Andreas

    2012-01-04

    Early during Gram-negative sepsis, excessive release of pro-inflammatory cytokines can cause septic shock that is often followed by a state of immune paralysis characterized by the failure to mount adaptive immunity towards secondary microbial infections. Especially, the early mechanisms responsible for such immune hypo-responsiveness are unclear. Here, we show that TLR4 is the key immune sensing receptor to initiate paralysis of T-cell immunity after bacterial sepsis. Downstream of TLR4, signalling through TRIF but not MyD88 impaired the development of specific T-cell immunity against secondary infections. We identified type I interferon (IFN) released from splenic macrophages as the critical factor causing T-cell immune paralysis. Early during sepsis, type I IFN acted selectively on dendritic cells (DCs) by impairing antigen presentation and secretion of pro-inflammatory cytokines. Our results reveal a novel immune regulatory role for type I IFN in the initiation of septic immune paralysis, which is distinct from its well-known immune stimulatory effects. Moreover, we identify potential molecular targets for therapeutic intervention to overcome impairment of T-cell immunity after sepsis.

  19. JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa.

    Science.gov (United States)

    Boor, Patrick P C; de Ruiter, Petra E; Asmawidjaja, Patrick S; Lubberts, Erik; van der Laan, Luc J W; Kwekkeboom, Jaap

    2017-10-01

    Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using in vitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Human pDCs display sex-specific differences in type I interferon subtypes and interferon α/β receptor expression.

    Science.gov (United States)

    Ziegler, Susanne M; Beisel, Claudia; Sutter, Kathrin; Griesbeck, Morgane; Hildebrandt, Heike; Hagen, Sven H; Dittmer, Ulf; Altfeld, Marcus

    2017-02-01

    The outcomes of many diseases differ between women and men, with women experiencing a higher incidence and more severe pathogenesis of autoimmune and some infectious diseases. It has been suggested that this is partially due to activation of plasmacytoid dendritic cells (pDCs), the main producers of interferon (IFN)-α, in response to toll-like receptor (TLR)7 stimulation. We investigated the induction of type I IFN (IFN-I) subtypes upon TLR7 stimulation on isolated pDCs. Our data revealed a sex-specific differential expression of IFN-Is, with pDCs from females showing a significantly higher mRNA expression of all 13 IFN-α subtypes. In addition, pDCs from females had higher levels of IFN-β mRNA after stimulation, indicating that sex differences in IFN-I production by pDCs were mediated by a signaling event upstream of the first loop of IFN-I mRNA transcription. Furthermore, the surface expression levels of the common IFN-α/β receptor subunit 2 were significantly higher on pDCs from females in comparison to males. These data indicate that higher IFN-α production is already established at the mRNA level and propose a contribution of higher IFN-α/β receptor 2 expression on pDCs to the immunological differences in IFN-I production observed between females and males. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Interferon gamma, interferon-gamma-induced-protein 10, and tuberculin responses of children at high risk of tuberculosis infection

    DEFF Research Database (Denmark)

    Petrucci, Roberta; Abu Amer, Nabil; Gurgel, Ricardo Queiroz

    2008-01-01

    BACKGROUND: Children in contact with adults with pulmonary tuberculosis (TB) are at risk for infection and disease progression, and chemoprophylaxis may reduce this risk. The identification of infection is based on the tuberculin skin test (TST) and interferon-gamma (INF-gamma) release assays....... Other biomarkers such as interferon-gamma-induced-protein 10 (IP-10) may have potential for the diagnosis of latent TB infections. OBJECTIVES: To describe IP-10 concentrations and their association to TST and INF-gamma responses in children recently exposed to adults with smear-positive TB in Brazil...... and Nepal. METHODS:: Two surveys using the same design were undertaken to describe TST, INF-gamma, and IP-10 responses in 146 children in Nepal and 113 children in Brazil. RESULTS: The concordance of TST and QuantiFERON-TB gold in-tube (QFT-IT) was high (kappa 0.73 in Brazil and 0.80 in Nepal). IP-10...

  2. Human cytomegalovirus exploits interferon-induced transmembrane proteins to facilitate morphogenesis of the virion assembly compartment.

    Science.gov (United States)

    Xie, Maorong; Xuan, Baoqin; Shan, Jiaoyu; Pan, Deng; Sun, Yamei; Shan, Zhao; Zhang, Jinping; Yu, Dong; Li, Bin; Qian, Zhikang

    2015-03-01

    Recently, interferon-induced transmembrane proteins (IFITMs) have been identified to be key effector molecules in the host type I interferon defense system. The invasion of host cells by a large range of RNA viruses is inhibited by IFITMs during the entry step. However, the roles of IFITMs in DNA virus infections have not been studied in detail. In this study, we report that human cytomegalovirus (HCMV), a large human DNA virus, exploits IFITMs to facilitate the formation of the virion assembly compartment (vAC) during infection of human fibroblasts. We found that IFITMs were expressed constitutively in human embryonic lung fibroblasts (MRC5 cells). HCMV infection inhibited IFITM protein accumulation in the later stages of infection. Overexpression of an IFITM protein in MRC5 cells slightly enhanced HCMV production and knockdown of IFITMs by RNA interference reduced the virus titer by about 100-fold on day 8 postinfection, according to the findings of a virus yield assay at a low multiplicity of infection. Virus gene expression and DNA synthesis were not affected, but the typical round structure of the vAC was not formed after the suppression of IFITMs, thereby resulting in defective virion assembly and the production of less infectious virion particles. Interestingly, the replication of herpes simplex virus, a human herpesvirus that is closely related to HCMV, was not affected by the suppression of IFITMs in MRC5 cells. These results indicate that IFITMs are involved in a specific pathway required for HCMV replication. HCMV is known to repurpose the interferon-stimulated genes (ISGs) viperin and tetherin to facilitate its replication. Our results expand the range of ISGs that can be exploited by HCMV for its replication. This is also the first report of a proviral function of IFITMs in DNA virus replication. In addition, whereas previous studies showed that IFITMs modulate virus entry, which is a very early stage in the virus life cycle, we identified a new

  3. Enhanced interferon-gamma production and B7-2 expression in isolated intestinal mononuclear cells from patients with Crohn's disease.

    Science.gov (United States)

    Noguchi, M; Hiwatashi, N; Liu, Z; Toyota, T

    1995-11-01

    Many of the in vivo activities of interferon (IFN)-gamma match the changes found in inflammatory bowel disease, but its importance is controversial. Interferon (IFN)-gamma induces the expression of B7-2 costimulatory molecules on monocytes. We measured levels of IFN-gamma production in intestinal mucosa and isolated lamina propria mononuclear cells (LPMC) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We also investigated the induction of B7-2 on the LPMC by flow cytometry. Mucosal IFN-gamma production was higher than the control level in patients with CD, but this was not the case in UC. IFN-gamma production and B7-2 expression in the LPMC of CD were higher than in the LPMC of UC and controls, and high levels of B7-2 expression were observed on the LPMC of CD after incubation with endotoxin. The induction of B7-2 on the LPMC of CD may provide a mechanism for the amplification of T cell proliferation and lymphokine production by IFN-gamma-activated LPMC.

  4. Nonstructural 5A Protein of Hepatitis C Virus Interferes with Toll-Like Receptor Signaling and Suppresses the Interferon Response in Mouse Liver.

    Directory of Open Access Journals (Sweden)

    Takeya Tsutsumi

    Full Text Available The hepatitis C virus nonstructural protein NS5A is involved in resistance to the host immune response, as well as the viral lifecycle such as replication and maturation. Here, we established transgenic mice expressing NS5A protein in the liver and examined innate immune responses against lipopolysaccharide (LPS in vivo. Intrahepatic gene expression levels of cytokines such as interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly suppressed after LPS injection in the transgenic mouse liver. Induction of the C-C motif chemokine ligand 2, 4, and 5 was also suppressed. Phosphorylation of the signal transducer and activator of transcription 3, which is activated by cytokines, was also reduced, and expression levels of interferon-stimulated genes, 2'-5' oligoadenylate synthase, interferon-inducible double-stranded RNA-activated protein kinase, and myxovirus resistance 1 were similarly suppressed. Since LPS binds to toll-like receptor 4 and stimulates the downstream pathway leading to induction of these genes, we examined the extracellular signal-regulated kinase and IκB-α. The phosphorylation levels of these molecules were reduced in transgenic mouse liver, indicating that the pathway upstream of the molecules was disrupted by NS5A. Further analyses revealed that the interaction between interleukin-1 receptor-associated kinase-1 and tumor necrosis factor receptor associated factor-6 was dispersed in transgenic mice, suggesting that NS5A may interfere with this interaction via myeloid differentiation primary response gene 88, which was shown to interact with NS5A. Since the gut microbiota, a source of LPS, is known to be associated with pathological conditions in liver diseases, our results suggest the involvement of NS5A in the pathogenesis of HCV infected-liver via the suppression of innate immunity.

  5. Vector control of induction machines

    CERN Document Server

    Robyns, Benoit

    2012-01-01

    After a brief introduction to the main law of physics and fundamental concepts inherent in electromechanical conversion, ""Vector Control of Induction Machines"" introduces the standard mathematical models for induction machines - whichever rotor technology is used - as well as several squirrel-cage induction machine vector-control strategies. The use of causal ordering graphs allows systematization of the design stage, as well as standardization of the structure of control devices. ""Vector Control of Induction Machines"" suggests a unique approach aimed at reducing parameter sensitivity for

  6. Technological inductive power transfer systems

    National Research Council Canada - National Science Library

    Nikolay D. Madzharov; Valentin S. Nemkov

    2017-01-01

    Inductive power transfer is a very fast expanding technology with multiple design principles and practical implementations ranging from charging phones and computers to bionic systems, car chargers...

  7. Understanding beginning teacher induction: A contextualized examination of best practice

    Directory of Open Access Journals (Sweden)

    Sean Kearney

    2014-12-01

    Full Text Available The problems that teachers face early in their careers are a major factor in growing rates of attrition among neophyte teachers. According to the Organisation for Economic Co-operation and Development, high rates of attrition, coupled with and aging teacher population in many countries in the developed world, may cause a teacher shortage crisis in coming years. Beginning teacher induction is an imperative process in acculturating teachers to their new careers and helping them overcome the hardships of teaching and the accreditation process. While induction practices have become more common in recent years, there are still no mandated structures for inducting teachers into the profession throughout Australia. This article reviews a number of international induction programs, which have been successful in supporting beginning teachers and curbing attrition rates, to emphasize why many programs are inadequate at meeting the needs of beginning teachers. The review proposes a definition for induction to better understand common misconceptions and highlights best practice induction as a way to retain quality teachers in the profession and help ameliorate conditions for beginning teachers. Finally, recommendations are made, specifically in the Australian context, which could help to improve induction practices to better acculturate neophyte teachers to their profession.

  8. Enhanced antitumor reactivity of tumor-sensitized T cells by interferon alfa

    Energy Technology Data Exchange (ETDEWEB)

    Vander Woude, D.L.; Wagner, P.D.; Shu, S.; Chang, A.E. (Univ. of Michigan, Ann Arbor (USA))

    1991-03-01

    Tumor-draining lymph node cells from mice bearing the methylcholanthrene-induced MCA 106 tumors can be sensitized in vitro to acquire antitumor reactivity. We examined the effect of interferon alfa on the function of cells that underwent in vitro sensitization in adoptive immunotherapy. Interferon alfa increased the antitumor reactivity of in vitro sensitized cells in the treatment of MCA 106 pulmonary metastases. This effect was evident in irradiated mice, indicating that a host response to the interferon alfa was not required. Interferon alfa treatment increased class I major histocompatibility complex antigen expression on tumor cells and increased their susceptibility to lysis by in vitro sensitized cells. These results suggest that interferon alfa enhancement of adoptive immunotherapy was mediated by its effect on tumor cells. Interferon alfa may be a useful adjunct to the adoptive immunotherapy of human cancer.

  9. Spatiotemporal control of interferon-induced JAK/STAT signalling and gene transcription by the retromer complex

    Science.gov (United States)

    Chmiest, Daniela; Sharma, Nanaocha; Zanin, Natacha; Viaris de Lesegno, Christine; Shafaq-Zadah, Massiullah; Sibut, Vonick; Dingli, Florent; Hupé, Philippe; Wilmes, Stephan; Piehler, Jacob; Loew, Damarys; Johannes, Ludger; Schreiber, Gideon; Lamaze, Christophe

    2016-01-01

    Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation. Depletion of VPS35 leads to abnormally prolonged residency and association of the IFNAR subunits at the early endosome, resulting in increased activation of STAT1- and IFN-dependent gene transcription. These experimental data establish the retromer complex as a key spatiotemporal regulator of IFNAR endosomal sorting and a new factor in type-I IFN-induced JAK/STAT signalling and gene transcription. PMID:27917878

  10. Spatiotemporal control of interferon-induced JAK/STAT signalling and gene transcription by the retromer complex.

    Science.gov (United States)

    Chmiest, Daniela; Sharma, Nanaocha; Zanin, Natacha; Viaris de Lesegno, Christine; Shafaq-Zadah, Massiullah; Sibut, Vonick; Dingli, Florent; Hupé, Philippe; Wilmes, Stephan; Piehler, Jacob; Loew, Damarys; Johannes, Ludger; Schreiber, Gideon; Lamaze, Christophe

    2016-12-05

    Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation. Depletion of VPS35 leads to abnormally prolonged residency and association of the IFNAR subunits at the early endosome, resulting in increased activation of STAT1- and IFN-dependent gene transcription. These experimental data establish the retromer complex as a key spatiotemporal regulator of IFNAR endosomal sorting and a new factor in type-I IFN-induced JAK/STAT signalling and gene transcription.

  11. Comprehensive Teacher Induction: Linking Teacher Induction to Theory

    Science.gov (United States)

    Keilwitz, Heather A.

    2014-01-01

    Teacher retention is a wide concern in education and in response school districts throughout the United States are developing more comprehensive teacher induction programs. Components of teacher induction programs that have assisted with successful teacher development include release time for teacher observation, assignment of a knowledgeable…

  12. Pre-Induction and Intrapartum Correlates of Successful Induction Of ...

    African Journals Online (AJOL)

    Context: Induction of labour (IOL) is a therapeutic challenge and an alternative to Caesarean section. Objectives: To evaluate the success rate of IOL and its determinants at the Ebonyi State University Teaching Hospital (EBSUTH), Abakaliki. Methods: A retrospective study involving 251 parturients who had induction of ...

  13. Induction heating using induction coils in series-parallel circuits

    Energy Technology Data Exchange (ETDEWEB)

    Matsen, Marc Rollo; Geren, William Preston; Miller, Robert James; Negley, Mark Alan; Dykstra, William Chet

    2017-11-14

    A part is inductively heated by multiple, self-regulating induction coil circuits having susceptors, coupled together in parallel and in series with an AC power supply. Each of the circuits includes a tuning capacitor that tunes the circuit to resonate at the frequency of AC power supply.

  14. Donor graft interferon regulatory factor-1 gene transfer worsens liver transplant ischemia/reperfusion injury.

    Science.gov (United States)

    Kim, Kee-Hwan; Dhupar, Rajeev; Ueki, Shinya; Cardinal, Jon; Pan, Pinhua; Cao, Zongxian; Cho, Sung W; Murase, Noriko; Tsung, Allan; Geller, David A

    2009-08-01

    Liver ischemia and reperfusion (IR) injury is a phenomenon that leads to graft dysfunction after liver transplantation. Understanding the molecular mechanisms behind this process is crucial to developing strategies to prevent short- and long-term graft dysfunction. The purpose of this study was to explore the role of the transcription factor interferon regulatory factor-1 (IRF-1) in a model of orthotopic rat liver transplantation. Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 3 hours preservation in cold University of Wisconsin solution. Adenovirus-expressing IRF-1 (AdIRF-1) or control gene vector (Adnull) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as controls. Recipients were humanely killed 1-24 hours post-transplantation. Rats that underwent OLT with long-term preserved grafts (18 hours) displayed increased hepatic nuclear expression of IRF-1 protein at 1 and 3 hours. Rats pretreated with AdIRF-1 before transplantation had elevated alanine aminotransferase levels and increased expression of interferon (IFN)-beta, IFN-gamma, interleukin-12, and inducible nitric oxide synthase in the short-term period (3 hours) when compared with donor livers pretreated with Adnull. AdIRF-1 pretreated donor livers also exhibited increased susceptibility to early apoptosis in the transplanted grafts as shown by increased terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining and expression of cleaved caspase-3. Additionally, AdIRF-1 pretreated donor livers had increased activation of the MAP kinase Jun N-terminal kinase as compared with Adnull pretreated donor livers. IRF-1 is an important regulator of IR injury after OLT in rats. Targeting of IRF-1 may be a potential strategy to ameliorate ischemic liver injury after transplantation to minimize organ dysfunction.

  15. Type I interferons promote severe disease in a mouse model of lethal ehrlichiosis.

    Science.gov (United States)

    Zhang, Yubin; Thai, Vinh; McCabe, Amanda; Jones, Maura; MacNamara, Katherine C

    2014-04-01

    Human monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the order Rickettsiales. HME disease can range from mild to a fatal, toxic shock-like syndrome, yet the mechanisms regulating pathogenesis are not well understood. We define a central role for type I interferons (alpha interferon [IFN-α] and IFN-β) in severe disease in a mouse model of fatal ehrlichiosis caused by Ixodes ovatus Ehrlichia (IOE). IFN-α and IFN-β were induced by IOE infection but not in response to a less virulent strain, Ehrlichia muris. The major sources of type I IFNs during IOE infection were plasmacytoid dendritic cells and monocytes. Mice lacking the receptor for type I IFNs (Ifnar deficient) or neutralization of IFN-α and IFN-β resulted in a reduced bacterial burden. Ifnar-deficient mice exhibited significantly increased survival after IOE infection, relative to that of wild-type (WT) mice, that correlated with increased type II IFN (IFN-γ) production. Pathogen-specific antibody responses were also elevated in Ifnar-deficient mice, and this required IFN-γ. Remarkably, increased IFN-γ and IgM were not essential for protection in the absence of type I IFN signaling. The direct effect of type I IFNs on hematopoietic and nonhematopoietic cells was evaluated in bone marrow chimeric mice. We observed that chimeric mice containing Ifnar-deficient hematopoietic cells succumbed to infection early, whereas Ifnar-deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-α receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infection in vivo and promote severe disease.

  16. Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

    Science.gov (United States)

    Lawler, Clara; Tan, Cindy S. E.; Simas, J. Pedro

    2016-01-01

    ABSTRACT Gammaherpesviruses establish persistent, systemic infections and cause cancers. Murid herpesvirus 4 (MuHV-4) provides a unique window into the early events of host colonization. It spreads via lymph nodes. While dendritic cells (DC) pass MuHV-4 to lymph node B cells, subcapsular sinus macrophages (SSM), which capture virions from the afferent lymph, restrict its spread. Understanding how this restriction works offers potential clues to a more comprehensive defense. Type I interferon (IFN-I) blocked SSM lytic infection and reduced lytic cycle-independent viral reporter gene expression. Plasmacytoid DC were not required, but neither were SSM the only source of IFN-I, as IFN-I blockade increased infection in both intact and SSM-depleted mice. NK cells restricted lytic SSM infection independently of IFN-I, and SSM-derived virions spread to the spleen only when both IFN-I responses and NK cells were lacking. Thus, multiple innate defenses allowed SSM to adsorb virions from the afferent lymph with relative impunity. Enhancing IFN-I and NK cell recruitment could potentially also restrict DC infection and thus improve infection control. IMPORTANCE Human gammaherpesviruses cause cancers by infecting B cells. However, vaccines designed to block virus binding to B cells have not stopped infection. Using a related gammaherpesvirus of mice, we have shown that B cells are infected not via cell-free virus but via infected myeloid cells. This suggests a different strategy to stop B cell infection: stop virus production by myeloid cells. Not all myeloid infection is productive. We show that subcapsular sinus macrophages, which do not pass infection to B cells, restrict gammaherpesvirus production by recruiting type I interferons and natural killer cells. Therefore, a vaccine that speeds the recruitment of these defenses might stop B cell infection. PMID:27466430

  17. Late multiple organ surge in interferon-regulated target genes characterizes staphylococcal enterotoxin B lethality.

    Directory of Open Access Journals (Sweden)

    Gabriela A Ferreyra

    Full Text Available BACKGROUND: Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB challenge was investigated in six tissues. RESULTS: The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC, spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RT-PCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN/antiviral-response and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature. CONCLUSION: Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes.

  18. Erythema annulare centrifugum-like eruption associated with pegylated interferon treatment for hepatitis C

    Directory of Open Access Journals (Sweden)

    Mark Naccarato

    2013-07-01

    Full Text Available Current standard of treatment for chronic hepatitis C virus infection requires the use of pegylated interferon plus ribavirin. Treatment with these two agents has been associated with numerous side effects, which frequently include dermatologic eruptions. We report a cutaneous eruption associated with interferon having clinical presentation of erythema annulare centrifugum. The eruption occurred within days of the first interferon injection and repeatedly flared following subsequent injections. Our patient was able to continue therapy without interruption, while managing the reaction with topical corticosteroid and oral antihistamine. We conclude that this is a benign cutaneous eruption associated with interferon which can be managed without dis- continuing treatment for hepatitis C.

  19. Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis

    DEFF Research Database (Denmark)

    Dalbjerg, Sara Maria; Tsakiri, Anna; Fredriksen, Jette Lautrup

    2016-01-01

    associated with Interferon-beta treatment. Case presentation We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved...... Interferon-beta-1-alpha therapy in patients with multiple sclerosis.......Background Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis...

  20. Transcriptome analysis reveals a classical interferon signature induced by IFNλ4 in human primary cells

    DEFF Research Database (Denmark)

    Lauber, Chris; Vieyres, Gabrielle; Terczynska-Dyla, Ewa

    2015-01-01

    4 could be a tissue-specific regulation of an unknown subset of genes. To address both tissue and subtype specificity in the interferon response, we treated primary human hepatocytes and airway epithelial cells with IFNα, IFNλ3 or IFNλ4 and assessed interferon mediated gene regulation using...... genes being regulated in hepatocytes as well as airway epithelial cells. Thus we provide an in-depth analysis of the liver interferon response seen over an array of interferon subtypes and compare it to the response in the lung epithelium....

  1. Tumor-suppressive effects of natural-type interferon-β through CXCL10 in melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Hikaru; Nobeyama, Yoshimasa, E-mail: nobederm@jikei.ac.jp; Nakagawa, Hidemi

    2015-08-21

    Introduction: Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-β (IFN-β) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up-regulated by IFN-β treatment of lymphatic endothelial cells. Materials and methods: Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-β, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-β treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. A proliferation assay was performed to examine the effects of IFN-β and CXCL10 in melanoma cells. Results: Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up-regulated by IFN-β in lymphatic endothelial cells. IFN-β treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-β. CXCL10 reduced melanoma cell proliferation in IFN-β-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-β. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-β and down-regulated in melanoma cells with medium to low sensitivity. Conclusions: Our data suggest that IFN-β suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-β may be associated with resistance to IFN-β. - Highlights: • We search melanoma-suppressive molecules induced by IFN-β. • IFN-β induces a high amount of CXCL10 from lymphatic endothelial cells. • CXCL10 induction level in melanoma cells is correlated

  2. Interferon regulatory factor 5 genetic variants are associated with cardiovascular disease in patients with rheumatoid arthritis.

    Science.gov (United States)

    García-Bermúdez, Mercedes; López-Mejías, Raquel; Genre, Fernanda; Castañeda, Santos; Llorca, Javier; González-Juanatey, Carlos; Corrales, Alfonso; Ubilla, Begoña; Miranda-Filloy, José A; Pina, Trinitario; Gómez-Vaquero, Carmen; Rodríguez-Rodríguez, Luis; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Pascual-Salcedo, Dora; López-Longo, Francisco J; Carreira, Patricia; Blanco, Ricardo; Martín, Javier; González-Gay, Miguel A

    2014-07-10

    Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk. Interferon regulatory factor 5 (IRF5) is a regulator of type I interferon induction. Recently, researchers have described an association between multiple single-nucleotide polymorphisms of the IRF5 gene and some rheumatic disorders. In this study, we aimed to evaluate whether three different haplotype blocks within the IRF5 locus which have been shown to alter the protein function are involved in the risk of CV events occurring in Spanish RA patients. Three IRF5 polymorphisms (rs2004640, rs2070197 and rs10954213) representative of each haplotype group were genotyped by performing TaqMan assays using a 7900HT Fast Real-Time PCR System with tissue from a total of 2,137 Spanish patients diagnosed with RA. Among them, 390 (18.2%) had experienced CV events. The relationship of IRF5 genotypes and haplotypes to CV events was tested using Cox regression. Male sex, age at RA diagnosis and most traditional risk factors (hypertension, dyslipidemia and smoking habit) were associated with increased risk for CV events in the RA population. Interestingly, a protective effect of both IRF5 rs2004640 GG and IRF5 rs10954213 GG genotypes against the risk for CV events after adjusting the results for sex, age at RA diagnosis and traditional CV disease risk factors was observed (hazard ratio (HR) = 0.6, 95% confidence interval (CI) = 0.38 to 0.92, P = 0.02; and HR = 0.58, 95% CI = 0.36 to 0.95, P = 0.03, respectively). Moreover, we detected a protective effect of the GTG haplotype against the risk for CV events after adjusting the results for potential confounding factors (HR = 0.72, 95% CI = 0.56 to 0.93, P = 0.012). Our results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA.

  3. Sampling Assumptions in Inductive Generalization

    Science.gov (United States)

    Navarro, Daniel J.; Dry, Matthew J.; Lee, Michael D.

    2012-01-01

    Inductive generalization, where people go beyond the data provided, is a basic cognitive capability, and it underpins theoretical accounts of learning, categorization, and decision making. To complete the inductive leap needed for generalization, people must make a key "sampling" assumption about how the available data were generated.…

  4. Regularity of conservative inductive limits

    Directory of Open Access Journals (Sweden)

    Jan Kucera

    1999-01-01

    Full Text Available A sequentially complete inductive limit of Fréchet spaces is regular, see [3]. With a minor modification, this property can be extended to inductive limits of arbitrary locally convex spaces under an additional assumption of conservativeness.

  5. A comparison of induction of anaesthesia using two different ...

    African Journals Online (AJOL)

    Background: Investigators have reported inter-patient variability with regard to propofol dosage for induction of anesthesia, since early dose finding studies. With the arrival of generic formulations of propofol, questions have arisen regarding further variability in dose requirements. Various studies have confirmed that generic ...

  6. Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation.

    Science.gov (United States)

    Brasseit, Jennifer; Kwong Chung, Cheong K C; Noti, Mario; Zysset, Daniel; Hoheisel-Dickgreber, Nina; Genitsch, Vera; Corazza, Nadia; Mueller, Christoph

    2018-01-01

    Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1 -/- recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1 -/- recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved.

  7. Ca²⁺ influx-linked protein kinase C activity regulates the β-catenin localization, micromere induction signalling and the oral-aboral axis formation in early sea urchin embryos.

    Science.gov (United States)

    Yazaki, Ikuko; Tsurugaya, Toko; Santella, Luigia; Chun, Jong Tai; Amore, Gabriele; Kusunoki, Shinichiro; Asada, Akiko; Togo, Tatsuru; Akasaka, Koji

    2015-06-01

    Sea urchin embryos initiate cell specifications at the 16-cell stage by forming the mesomeres, macromeres and micromeres according to the relative position of the cells in the animal-vegetal axis. The most vegetal cells, micromeres, autonomously differentiate into skeletons and induce the neighbouring macromere cells to become mesoendoderm in the β-catenin-dependent Wnt8 signalling pathway. Although the underlying molecular mechanism for this progression is largely unknown, we have previously reported that the initial events might be triggered by the Ca2+ influxes through the egg-originated L-type Ca2+ channels distributed asymmetrically along the animal-vegetal axis and through the stretch-dependent Ca2+channels expressed specifically in the micromere at the 4th cleavage. In this communication, we have examined whether one of the earliest Ca2+ targets, protein kinase C (PKC), plays a role in cell specification upstream of β-catenin. To this end, we surveyed the expression pattern of β-catenin in early embryos in the presence or absence of the specific peptide inhibitor of Hemicentrotus pulcherrimus PKC (HpPKC-I). Unlike previous knowledge, we have found that the initial nuclear entrance of β-catenin does not take place in the micromeres, but in the macromeres at the 16-cell stage. Using the HpPKC-I, we have demonstrated further that PKC not only determines cell-specific nucleation of β-catenin, but also regulates a variety of cell specification events in the early sea urchin embryos by modulating the cell adhesion structures, actin dynamics, intracellular Ca2+ signalling, and the expression of key transcription factors.

  8. Interferon enhancement of the invasive capacity of Ewing sarcoma cells in vitro

    Science.gov (United States)

    Siegal, Gene P.; Thorgeirsson, Unnur P.; Russo, Raimondo G.; Wallace, Donald M.; Liotta, Lance A.; Berger, Shelby L.

    1982-01-01

    The ability of interferons to reduce cell proliferation in vitro and in vivo is a well-studied phenomenon. To extend such observations, the effect of interferons on the invasiveness in vitro of human malignant cells derived from a Ewing sarcoma was evaluated. Two related parameters were examined: (i) production of type IV (basement membrane) collagenase and (ii) penetration of human amnion basement membrane and collagenous stroma. After 6 days of treatment with crude fibroblast, leukocyte, or lymphoblastoid interferon at 100 units/ml in serum-free medium, type IV collagenase levels increased 2- to 4-fold per cell relative to those of untreated controls. With homogeneous fibroblast and lymphoblastoid interferons, a 2-fold elevation in type IV collagenase was detected after 2 days, with further increases, occasionally dramatic, occurring on the 4th and 6th day of treatment. The ability of Ewing sarcoma cells to invade human amnion connective tissue was measured after 6 days of treatment with various interferons. Relative to the behavior of untreated controls, crude leukocyte interferon, homogeneous lymphoblastoid interferon, and homogeneous fibroblast interferon at 100 units/ml augmented invasiveness 3-, 17- and 22-fold, respectively, when cells were allowed 4 days in which to traverse the amnion. When untreated cells were exposed simultaneously to the amnion and to homogeneous lymphoblastoid or fibroblast interferon, a 4- to 5-fold increase in invasiveness above control levels was observed in 2 days. These data emphasize the complexity of interferon-induced phenomena. In any overview, the effects of interferon on both the tumor cell and the host must be considered. PMID:6180434

  9. Polymorphism in the interferon-{alpha} gene family

    Energy Technology Data Exchange (ETDEWEB)

    Golovleva, I.; Lundgren, E.; Beckman, L. [Univ. of Umea (Sweden); Kandefer-Szerszen, M. [Maria Curie-Sklodowska Univ., Lublin (Poland)

    1996-09-01

    A pronounced genetic polymorphism of the interferon type I gene family has been assumed on the basis of RFLP analysis of the genomic region as well as the large number of sequences published compared to the number of loci. However, IFNA2 is the only locus that has been carefully analyzed concerning gene frequency, and only naturally occurring rare alleles have been found. We have extended the studies on a variation of expressed sequences by studying the IFNA1, IFNA2, IFNA10, IFNA13, IFNA14, and IFNA17 genes. Genomic white-blood-cell DNA from a population sample of blood donors and from a family material were screened by single-nucleotide primer extension (allele-specific primer extension) of PCR fragments. Because of sequence similarities, in some cases {open_quotes}nested{close_quotes} PCR was used, and, when applicable, restriction analysis or control sequencing was performed. All individuals carried the interferon-{alpha} 1 and interferon-{alpha} 13 variants but not the LeIF D variant. At the IFNA2 and IFNA14 loci only one sequence variant was found, while in the IFNA10 and IFNA17 groups two alleles were detected in each group. The IFNA10 and IFNA17 alleles segregated in families and showed a close fit to the Hardy-Weinberg equilibrium. There was a significant linkage disequilibrium between IFNA10 and IFNA17 alleles. The fact that the extent of genetic polymorphism was lower than expected suggests that a majority of the previously described gene sequences represent nonpolymorphic rare mutants that may have arisen in tumor cell lines. 44 refs., 4 figs., 4 tabs.

  10. Interferon-γ links ultraviolet radiation to melanomagenesis in mice.

    Science.gov (United States)

    Zaidi, M Raza; Davis, Sean; Noonan, Frances P; Graff-Cherry, Cari; Hawley, Teresa S; Walker, Robert L; Feigenbaum, Lionel; Fuchs, Elaine; Lyakh, Lyudmila; Young, Howard A; Hornyak, Thomas J; Arnheiter, Heinz; Trinchieri, Giorgio; Meltzer, Paul S; De Fabo, Edward C; Merlino, Glenn

    2011-01-27

    Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.

  11. Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-α 2b treatment

    Directory of Open Access Journals (Sweden)

    Ascierto Paolo A

    2010-08-01

    Full Text Available Abstract Background High-dose interferon-alpha 2b (IFN-α 2b is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-α 2b by measuring serum regulatory T cell (Treg, serum transforming growth factor-β (TGF-β, interleukin (IL-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-α 2b regimen. Methods Patients with melanoma received IFN-α 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks. Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-β, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. Results Twenty-two patients with melanoma received IFN-α 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test. Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week, statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082, early recurrence versus no recurrence (P = 0.017, deceased versus surviving patients (P = 0.021, and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant. No significant effects were observed on the levels of TGF-β, IL-10, and autoantibodies in patients with melanoma treated with IFN-α 2b. Conclusions Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-α 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response

  12. Uso de los interferones en Dermatología: experiencia con el alfa-interferon en la micosis fungoide Use of interferons in Dermatology: experience with alpha-interferon in mycosis fungoides

    OpenAIRE

    Edelisa Moredo Romo; Marisela Moreira Preciado; Aylet Pérez López

    2004-01-01

    Se revisó la literatura y se constató la amplia utilización de los interferones (INFs) en Dermatología. Se presenta un estudio retrospectivo de 7 pacientes con diagnóstico de micosis fungoides tratados con alfa-interferón recombinante (alfa-INFR) y se concluye su efectividad en el tratamiento de esta enfermedad y su disponibilidad en el tratamiento en Cuba. Los efectos adversos observados a las dosis utilizadas fueron fundamentalmente fiebre, escalofríos y malestar general que cedieron con tr...

  13. [Solubilization Specificities Interferon beta-1b from Inclusion Bodies].

    Science.gov (United States)

    Zhuravko, A S; Kononova, N V; Bobruskin, A I

    2015-01-01

    A new solubilization method of recombinant interferon beta-1b (IFNβ-1b) from the inclusion bodies was developed. This method allows to extract the target protein selectively in the solutions of different alcohols, such as ethanol, propanol and isopropanol. It was shown that the more effective IFNβ-1b solubilization was achieved in the 55% propanol solution. This method allowed to extract the target protein from inclusion bodies around 85-90%, and significantly reduced Escherichia coli content in the solubilizate, in comparison with standard methods.

  14. Early biodistribution and persistence of a protective live attenuated SIV vaccine elicits localised innate responses in multiple lymphoid tissues.

    Directory of Open Access Journals (Sweden)

    Deborah Ferguson

    Full Text Available Vaccination of Mauritian cynomolgus macaques with the attenuated nef-truncated C8 variant of SIVmac251/32H (SIVmacC8 induces early, potent protection against pathogenic, heterologous challenge before the maturation of cognate immunity. To identify processes that contribute to early protection in this model the pathogenesis, anatomical distribution and viral vaccine kinetics were determined in relation to localised innate responses triggered by vaccination. The early biodistribution of SIVmacC8 was defined by rapid, widespread dissemination amongst multiple lymphoid tissues, detectable after 3 days. Cell-associated viral RNA dynamics identified mesenteric lymph nodes (MLN and spleen, as well as the gut mucosae, as early major contributors of systemic virus burden. Rapid, localised infection was populated by discrete foci of persisting virus-infected cells. Localised productive infection triggered a broad innate response, with type-1 interferon sensitive IRF-7, STAT-1, TRIM5α and ApoBEC3G genes all upregulated during the acute phase but induction did not prevent viral persistence. Profound changes in vaccine-induced cell-surface markers of immune activation were detected on macrophages, B-cells and dendritic cells (DC-SIGN, S-100, CD40, CD11c, CD123 and CD86. Notably, high DC-SIGN and S100 staining for follicular and interdigitating DCs respectively, in MLN and spleen were detected by 3 days, persisting 20 weeks post-vaccination. Although not formally evaluated, the early biodistribution of SIVmacC8 simultaneously targets multiple lymphoid tissues to induce strong innate immune responses coincident at the same sites critical for early protection from wild-type viruses. HIV vaccines which stimulate appropriate innate, as well as adaptive responses, akin to those generated by live attenuated SIV vaccines, may prove the most efficacious.

  15. Antibody induction versus corticosteroid induction for liver transplant recipients

    DEFF Research Database (Denmark)

    Penninga, Luit; Wettergren, André; Wilson, Colin H

    2014-01-01

    BACKGROUND: Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell specific antibody induction compared with corticosteroid induction of immunosuppression after liver transplantation....... OBJECTIVES: To assess the benefits and harms of T-cell specific antibody induction versus corticosteroid induction for prevention of acute rejection in liver transplant recipients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register...... of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 September 2013 together with reference checking, citation searching, contact with trial authors and pharmaceutical companies...

  16. Induction, complexity, and economic methodology

    OpenAIRE

    Smith, Peter

    2009-01-01

    This paper focuses on induction, because the supposed weaknesses of that process are the main reason for favouring falsificationism, which plays an important part in scientific methodology generally; the paper is part of a wider study of economic methodology. The standard objections to, and paradoxes of, induction are reviewed, and this leads to the conclusion that the supposed ‘problem’ or ‘riddle’ of induction is a false one. It is an artefact of two assumptions: that the classic two-valued...

  17. Overview of Bearingless Induction Motors

    Directory of Open Access Journals (Sweden)

    Xiaodong Sun

    2014-01-01

    Full Text Available Bearingless induction motors combining functions of both torque generation and noncontact magnetic suspension together have attracted more and more attention in the past decades due to their definite advantages of compactness, simple structure, less maintenance, no wear particles, high rotational speed, and so forth. This paper overviews the key technologies of the bearingless induction motors, with emphasis on motor topologies, mathematical models, and control strategies. Particularly, in the control issues, the vector control, independent control, direct torque control, nonlinear decoupling control, sensorless control, and so forth are investigated. In addition, several possible development trends of the bearingless induction motors are also discussed.

  18. Term induction of labor and subsequent preterm birth.

    Science.gov (United States)

    Levine, Lisa D; Bogner, Hillary R; Hirshberg, Adi; Elovitz, Michal A; Sammel, Mary D; Srinivas, Sindhu K

    2014-04-01

    Although the rate of inductions continues to rise, there is a paucity of data investigating subsequent pregnancy outcomes after induction. Our objective was to compare term inductions with term spontaneous labor and evaluate the rate of subsequent spontaneous preterm birth (sPTB). A retrospective cohort study of women with 2 consecutive deliveries from 2005 through 2010 was performed. Term inductions or term spontaneous labor in the index pregnancy was included, and those with a prior sPTB were excluded. Data were obtained through chart abstraction. The primary outcome was sPTB (Term inductions were less likely to have a subsequent sPTB compared with term spontaneous labor (6% vs 11%; odds ratio [OR], 0.49; 95% confidence interval, 0.29-0.81; P = .005). This remained after adjusting for confounders (adjusted OR, 0.55; P = .04). The sPTB risk depended on gestational age of index delivery. At 37-38.9 weeks, the sPTB rate after spontaneous labor was 24% vs 9% after induction (OR, 3.0; 95% confidence interval, 1.44-6.16; P = .003). This was not significant for 39-39.9 weeks (P = .2) or 40 weeks or longer (P = .8). Induction is not a risk factor for subsequent sPTB. Spontaneous labor, however, in the early term period is associated with subsequent sPTB. Further investigation among early term deliveries is warranted to evaluate the risk of sPTB and target interventions in this cohort. Copyright © 2014 Mosby, Inc. All rights reserved.

  19. Neuromyelitis optica-like pathology is dependent on type I interferon response

    DEFF Research Database (Denmark)

    Khorooshi, Reza; Wlodarczyk, Agnieszka; Asgari, Nasrin

    2013-01-01

    in the formation of neuromyelitis optica lesions. Immunoglobulin G from a neuromyelitis optica patient was injected intracerebrally with human complement to type I interferon receptor deficient and wildtype mice. Loss of aquaporin-4 and glial fibrillary acidic protein was reduced in type I interferon receptor...

  20. Delirium after interleukin-2 and alpha-interferon therapy for renal cell carcinoma

    NARCIS (Netherlands)

    Van Steijn, JHM; Nieboer, P; Hospers, GAP; De Vries, EGE; Mulder, NH

    2001-01-01

    A 55-year-old man receiving alpha-interferon and interieukin-2 therapy for renal cell carcinoma presented with seizures and delirium. A CT-scan of the cerebrum did not reveal any disorder. Both alpha-interferon and interleukin-2 were stopped Treatment with steroids led to complete regression of

  1. Administration of interferon-gamma in healthy subjects does not modulate thyroid hormone metabolism

    NARCIS (Netherlands)

    de Metz, J.; Romijn, J. A.; Endert, E.; Corssmit, E. P.; Sauerwein, H. P.

    2000-01-01

    Cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL-2), IL-6, and interferon-alpha (IFN-alpha), alter human thyroid hormone metabolism and may be involved in the pathogenesis the euthyroid sick syndrome. Experimental data suggest that interferon-gamma (IFN-gamma) could be

  2. Targeted Therapies: Bevacizumab and interferon-alpha in metastatic renal-cell carcinoma.

    Science.gov (United States)

    Bukowski, Ronald M

    2009-05-01

    Rini and colleagues provide additional data on bevacizumab and interferon-alpha in clear-cell carcinoma of the kidney; a comparison of these results with the findings from contemporary trials suggests that bevacizumab and interferon-alpha is another clinically useful treatment option for patients with metastatic renal-cell carcinoma.

  3. A simple method for quantification of interferon-α2b through surface ...

    African Journals Online (AJOL)

    USER

    2010-03-15

    Mar 15, 2010 ... Parmeggiani F, Qin X, Rebe S, Tomasevic N, Tsang T, Waddell MB,. Zhang FF, Leavitt S, Myszka DG (2007). Thermodynamic benchmark study using Biacore technology. Anal. Biochem. 364: 67-77. Pestka S, Krause CD, Walter MR (2004). Interferons, interferon-like cytokines, and their receptors. Immunol.

  4. [Enhanced porcine interferon-alpha production by Pichia pastoris by methanol/sorbitol co-feeding and energy metabolism shift].

    Science.gov (United States)

    Wang, Huihui; Jin, Hu; Gao, Minjie; Dai, Keke; Dong, Shijuan; Yu, Ruisong; Li, Zhen; Shi, Zhongping

    2012-02-01

    Porcine interferon-alpha (pIFN-alpha) fermentative production by recombinant Pichia pastoris was carried out in a 10-L bioreactor to study its metabolism changes and effects on fermentation under different inducing strategies, by analyzing the change patterns of the corresponding metabolism and energy regeneration. The results show that the specific activities of alcohol oxidase (AOX), formaldehyde dehydrogenase (FLD) and formate dehydrogenase (FDH) largely increased when reducing temperature from 30 degrees C to 20 degrees C under pure methanol induction, leading significant enhancements in methanol metabolism, formaldehyde dissimilatory energy metabolism and pIFN-alpha antiviral activity. The highest pIFN-alpha antiviral activity reached 1.4 x 10(6) IU/mL, which was about 10-folds of that obtained under 30 degrees C induction. Using methanol/sorbitol co-feeding strategy at 30 degrees C, the major energy metabolism energizing pIFN-alpha synthesis shifted from formaldehyde dissimilatory energy metabolism pathway to TCA cycle, formaldehyde dissimilatory pathway was weakened and accumulation of toxic intermediate metabolite-formaldehyde was relieved, and methanol flux distribution towards to pIFN-alpha synthesis was enhanced. Under this condition, the highest pIFN-alpha antiviral activity reached 1.8 x 10(7) IU/mL which was about 100-folds of that obtained under pure methanol induction at 30 degrees C. More important, enhanced pIFN-alpha production with methanol/sorbitol co-feeding strategy could be implemented under mild conditions, which greatly reduced the fermentation costs and improved the entire fermentation performance.

  5. Effect of interferon on the development of Trypanosoma cruzi in tissue culture "Vero" cells

    Directory of Open Access Journals (Sweden)

    R. R. Golgher

    1980-01-01

    Full Text Available Results are presented on the effects of interferon on the intracellular stages of T. cruzi in tissue culture "Vero" cells. Interferon was obtained by infecting monolayers of human amniotic cells with inactivated Newcastle disease virus. Interferon has not affected the cell infection by T. cruzi culture infective stages and neither has it prevented the transformation of amastigote into trypomastigote stages.Interferon obtido através da infecção de células amnióticas humanas por vírus inativado da doença de Newcastle foi incapaz de influir sobre a infectividade de formas de cultura do T. cruzi para células "Vero" de cultura de tecido. A transformação amastigota-tripomastigota também não foi afetada pelo interferon.

  6. Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

    LENUS (Irish Health Repository)

    Enudi, W

    2012-02-01

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

  7. Neuropsychiatric complications associated with interferon - alpha -2b treatment of malignant melanoma.

    LENUS (Irish Health Repository)

    Enudi, W

    2009-08-01

    Several adverse effects have been associated with interferon alpha 2b treatment and neuropsychiatric effects have also been commonly reported. Psychosis and mood disorders have been described in the literature. This case report is of a 30 year old man with malignant melanoma stage 3a who was receiving adjuvant alpha 2b interferon and developed a manic episode two weeks post switching after one month of treatment on a high dose to a low dose. There was no previous psychiatric illness and no known family history of mental illness. This is in keeping with previous reports that mania has been observed in patients undergoing interferon treatment especially after significant dose-reduction or treatment breaks. Mania induced by interferon responds well to antimanic drugs .Since interferon alpha 2b is now commonly used in the treatment of malignant melanoma and other conditions, the need to be aware of its neuropsychiatric complications is essential.

  8. CLINICAL IMMUNOLOGIC GROUNDS FOR LOCAL INTERFERON USE IN ACUTE VIRAL INFECTION TREATMENT

    Directory of Open Access Journals (Sweden)

    I.N. Zakharova

    2011-01-01

    Full Text Available Broad spectrum of antiviral activity of interferons lays grounds to its use in complex therapy of acute viral infections. It has been shown that antiviral and antibacterial interferon activity reveals itself while used both systematically and locally. Clinical efficacy of locally applied viferon is accompanied by nasal mucosa cytokine status changes, as has been shown in nasal swabs. There has been shown dependency of local immune response on the age, severity of the disease, clinical forms of respiratory syndrome, bacterial complications, if present, intensity and characteristics of viral contamination against the background of viferon treatment. Key words: acute respiratory viral disease, interferon, cell immunity, humoral immunity, interferon status, cytokine status, recombinant α-interferon, immunocorrection. (Voprosy sovremennoi pediatrii — Current Pediatrics. — 2011; 10 (5: 117–123.

  9. Hepatitis B, interferon, and acne fulminans in a young girl

    Directory of Open Access Journals (Sweden)

    Sandeep Arora

    2016-01-01

    Full Text Available Acne fulminans (AF is a very rare severe form of acne seen in young males, characterized by a sudden and explosive onset of hemorrhagic pustules and ulceration on the trunk, systemic features in the form of fever, polyarthropathy, malaise, erythema nodosum and painful osteolytic bone involvement with leukocytosis, and an elevated erythrocyte sedimentation rate. Conventional treatment of AF includes corticosteroids or immunosuppressive agents for the initial phase followed by isotretinoin. Active hepatitis B infection with a high viral load precludes the administration of any immunosuppressive drugs. We present the case of an 18-year-old girl with a history of occasional acne who presented with AF of sudden onset following administration of interferon-alpha-2a for her recently detected hepatitis B infection. Management of hepatitis B was withheld in view of her general condition. The patient was managed with low dose isotretinoin with subsidence of lesions. AF in a young female precipitated by interferon and its management with isotretinoin in the presence of active hepatitis B infection make the case unique.

  10. Decreased interferon-β induced STAT-4 activation in immune cells and clinical outcome in multiple sclerosis.

    Science.gov (United States)

    Tanasescu, R; Midgley, A; Robins, R A; Constantinescu, C S

    2017-09-01

    Interferon-β (IFN-β) is used in the treatment of multiple sclerosis (MS). IFN-β activation of signal transduction and activation of transcription (STAT)-4 is linked to its immunomodulatory effects. Previous studies suggest a type I IFN deficit in immune cells of patients MS, but data on interferon-α/β receptor (IFNAR) expression and the relationship with treatment response are conflicting. Here, we compare IFN-β-mediated STAT4 activation in immune cells of untreated patients with MS and controls. Peripheral blood mononuclear cells from 27 untreated patients with relapsing MS, obtained before the initiation of IFN-β treatment, and 12 matched controls were treated in vitro with IFN-β. Total and phosphorylated STAT4 (pSTAT4) and IFNAR were measured by flow cytometry and quantitative PCR. The patients were followed up for 5 years. pSTAT4 induction by IFN-β was lower in patients with MS than in controls, as was expression of IFNAR. pSTAT4 expression did not correlate with the clinical outcome at 5 years, measured by EDSS change. There was a negative correlation between the baseline IFNAR1 mRNA levels and relapse rate. The results suggest decreased IFN-β responsiveness in patients with MS, associated with reduced STAT4 activation and reduced IFNAR expression. This reduced responsiveness does not appear to affect the long-term clinical outcome of IFN-β treatment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Expression and biological activity of two recombinant polypeptides related to subunit 1 of the interferon-a receptor

    Directory of Open Access Journals (Sweden)

    S. Yoon

    2000-07-01

    Full Text Available Abnormal production of interferon alpha (IFN-a has been found in certain autoimmune diseases and can be also observed after prolonged therapy with IFN-a. IFN-a can contribute to the pathogenesis of allograft rejection in bone marrow transplants. Therefore, the development of IFN-a inhibitors as a soluble receptor protein may be valuable for the therapeutic control of these diseases. We have expressed two polypeptides encoding amino acids 93-260 (P1 and 261-410 (P2 of the extracellular domain of subunit 1 of the interferon-a receptor (IFNAR 1-EC in E. coli. The activities of the recombinant polypeptides and of their respective antibodies were evaluated using antiproliferative and antiviral assays. Expression of P1 and P2 polypeptides was achieved by transformation of cloned plasmid pRSET A into E. coli BL21(DE3pLysS and by IPTG induction. P1 and P2 were purified by serial sonication steps and by gel filtration chromatography with 8 M urea and refolded by dialysis. Under reducing SDS-PAGE conditions, the molecular weight of P1 and P2 was 22 and 17 kDa, respectively. Polyclonal anti-P1 and anti-P2 antibodies were produced in mice. P1 and P2 and their respective polyclonal antibodies were able to block the antiproliferative activity of 6.25 nM IFN-aB on Daudi cells, but did not block IFN-aB activity at higher concentrations (>6.25 nM. On the other hand, the polypeptides and their respective antibodies did not inhibit the antiviral activity of IFN-aB on Hep 2/c cells challenged with encephalomyocarditis virus.

  12. Survey of Inductive Communication Systems

    Science.gov (United States)

    1975-04-01

    A survey is made of various inductive systems proposed for low frequency train communication. It is found that thick dielectric jackets or coaxial and metallic shields may be required to reduce the environmental effects that lead to high attenuation....

  13. Fault diagnosis of induction motors

    CERN Document Server

    Faiz, Jawad; Joksimović, Gojko

    2017-01-01

    This book is a comprehensive, structural approach to fault diagnosis strategy. The different fault types, signal processing techniques, and loss characterisation are addressed in the book. This is essential reading for work with induction motors for transportation and energy.

  14. ORGANIZATIONAL DEVELOPMENT ACTION: INDUCTION PROGRAM

    National Research Council Canada - National Science Library

    José G. VARGAS-HERNÁNDEZ

    2016-01-01

    .... Also, an induction program is presented as an intervention proposal of organization development, on the premise that this program is a first step in the solving of the existing low productivity problem...

  15. The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold.

    Science.gov (United States)

    Zhang, Adrianna P P; Bornholdt, Zachary A; Liu, Tong; Abelson, Dafna M; Lee, David E; Li, Sheng; Woods, Virgil L; Saphire, Erica Ollmann

    2012-02-01

    Ebolaviruses cause hemorrhagic fever with up to 90% lethality and in fatal cases, are characterized by early suppression of the host innate immune system. One of the proteins likely responsible for this effect is VP24. VP24 is known to antagonize interferon signaling by binding host karyopherin α proteins, thereby preventing them from transporting the tyrosine-phosphorylated transcription factor STAT1 to the nucleus. Here, we report that VP24 binds STAT1 directly, suggesting that VP24 can suppress at least two distinct branches of the interferon pathway. Here, we also report the first crystal structures of VP24, derived from different species of ebolavirus that are pathogenic (Sudan) and nonpathogenic to humans (Reston). These structures reveal that VP24 has a novel, pyramidal fold. A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1. This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence. These crystal structures and accompanying biochemical analysis map differences between pathogenic and nonpathogenic viruses, offer templates for drug design, and provide the three-dimensional framework necessary for biological dissection of the many functions of VP24 in the virus life cycle.

  16. Multiple interferon stimulated genes synergize with the zinc finger antiviral protein to mediate anti-alphavirus activity.

    Directory of Open Access Journals (Sweden)

    Sophiya Karki

    Full Text Available The zinc finger antiviral protein (ZAP is a host factor that mediates inhibition of viruses in the Filoviridae, Retroviridae and Togaviridae families. We previously demonstrated that ZAP blocks replication of Sindbis virus (SINV, the prototype Alphavirus in the Togaviridae family at an early step prior to translation of the incoming genome and that synergy between ZAP and one or more interferon stimulated genes (ISGs resulted in maximal inhibitory activity. The present study aimed to identify those ISGs that synergize with ZAP to mediate Alphavirus inhibition. Using a library of lentiviruses individually expressing more than 350 ISGs, we screened for inhibitory activity in interferon defective cells with or without ZAP overexpression. Confirmatory tests of the 23 ISGs demonstrating the largest infection reduction in combination with ZAP revealed that 16 were synergistic. Confirmatory tests of all potentially synergistic ISGs revealed 15 additional ISGs with a statistically significant synergistic effect in combination with ZAP. These 31 ISGs are candidates for further mechanistic studies. The number and diversity of the identified ZAP-synergistic ISGs lead us to speculate that ZAP may play an important role in priming the cell for optimal ISG function.

  17. The ebola virus interferon antagonist VP24 directly binds STAT1 and has a novel, pyramidal fold.

    Directory of Open Access Journals (Sweden)

    Adrianna P P Zhang

    2012-02-01

    Full Text Available Ebolaviruses cause hemorrhagic fever with up to 90% lethality and in fatal cases, are characterized by early suppression of the host innate immune system. One of the proteins likely responsible for this effect is VP24. VP24 is known to antagonize interferon signaling by binding host karyopherin α proteins, thereby preventing them from transporting the tyrosine-phosphorylated transcription factor STAT1 to the nucleus. Here, we report that VP24 binds STAT1 directly, suggesting that VP24 can suppress at least two distinct branches of the interferon pathway. Here, we also report the first crystal structures of VP24, derived from different species of ebolavirus that are pathogenic (Sudan and nonpathogenic to humans (Reston. These structures reveal that VP24 has a novel, pyramidal fold. A site on a particular face of the pyramid exhibits reduced solvent exchange when in complex with STAT1. This site is above two highly conserved pockets in VP24 that contain key residues previously implicated in virulence. These crystal structures and accompanying biochemical analysis map differences between pathogenic and nonpathogenic viruses, offer templates for drug design, and provide the three-dimensional framework necessary for biological dissection of the many functions of VP24 in the virus life cycle.

  18. DMPD: The role of the interferon regulatory factor (IRF) family in dendritic celldevelopment and function. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17702640 The role of the interferon regulatory factor (IRF) family in dendritic cel...b 2007 Aug 16. (.png) (.svg) (.html) (.csml) Show The role of the interferon regulatory factor (IRF) family ...e interferon regulatory factor (IRF) family in dendritic celldevelopment and function. Authors Gabriele L, O

  19. DMPD: The interferon regulatory factor family in host defense: mechanism of action. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17502370 The interferon regulatory factor family in host defense: mechanism of acti....html) (.csml) Show The interferon regulatory factor family in host defense: mechanism of action. PubmedID 1...7502370 Title The interferon regulatory factor family in host defense: mechanism

  20. DMPD: The interferon signaling network and transcription factor C/EBP-beta. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18163952 The interferon signaling network and transcription factor C/EBP-beta. Li H... The interferon signaling network and transcription factor C/EBP-beta. PubmedID 18163952 Title The interfero...n signaling network and transcription factor C/EBP-beta. Authors Li H, Gade P, Xi

  1. DMPD: Interferons at age 50: past, current and future impact on biomedicine. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18049472 Interferons at age 50: past, current and future impact on biomedicine. Bor...975-90. (.png) (.svg) (.html) (.csml) Show Interferons at age 50: past, current and future impact on biomedicine.... PubmedID 18049472 Title Interferons at age 50: past, current and future impact on biomedicine

  2. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.

    Science.gov (United States)

    Lazear, Helen M; Daniels, Brian P; Pinto, Amelia K; Huang, Albert C; Vick, Sarah C; Doyle, Sean E; Gale, Michael; Klein, Robyn S; Diamond, Michael S

    2015-04-22

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

  3. Inductance and hypergeometric functions. II

    DEFF Research Database (Denmark)

    Karlsson, Per W.

    2000-01-01

    A previously obtained integral for the self-inductance of a solenoid is further transformed. The resulting formula involves double Kampé de Fériet functions which are analytic continuations rather than power series.......A previously obtained integral for the self-inductance of a solenoid is further transformed. The resulting formula involves double Kampé de Fériet functions which are analytic continuations rather than power series....

  4. Chicken interferon alpha pretreatment reduces virus replication of pandemic H1N1 and H5N9 avian influenza viruses in lung cell cultures from different avian species

    Directory of Open Access Journals (Sweden)

    Yang Hanchun

    2011-09-01

    Full Text Available Abstract Background Type I interferons, including interferon alpha (IFN-α, represent one of the first lines of innate immune defense against influenza virus infection. Following natural infection of chickens with avian influenza virus (AIV, transcription of IFN-α is quickly up regulated along with multiple other immune-related genes. Chicken IFN-α up regulates a number of important anti-viral response genes and has been demonstrated to be an important cytokine to establish anti-viral immunity. However, the mechanisms by which interferon inhibit virus replication in avian species remains unknown as does the biological activity of chicken interferon in other avian species. Methods In these studies, we assessed the protective potential of exogenous chicken IFN-α applied to chicken, duck, and turkey primary lung cell cultures prior to infection with the pandemic H1N1 virus (A/turkey/Virginia/SEP-4/2009 and an established avian H5N9 virus (A/turkey/Wisconsin/1968. Growth kinetics and induction of select immune response genes, including IFN-α and myxovirus-resistance gene I (Mx, as well as proinflammatory cytokines (IL-1β and IL-6, were measured in response to chicken IFN-α and viral infection over time. Results Results demonstrate that pretreatment with chicken IFN-α before AIV infection significantly reduced virus replication in both chicken-and turkey-origin lung cells and to a lesser degree the duck-origin cells. Virus growth was reduced by approximately 200-fold in chicken and turkey cells and 30-fold in duck cells after 48 hours of incubation. Interferon treatment also significantly decreased the interferon and proinflammatory response during viral infection. In general, infection with the H1N1 virus resulted in an attenuated interferon and proinflammatory response in these cell lines, compared to the H5N9 virus. Conclusions Taken together, these studies show that chicken IFN-α reduces virus replication, lower host innate immune

  5. Expression of human interferon-α8 synthetic gene under P(BAD) promoter.

    Science.gov (United States)

    Mohammed, Y; El-Baky, N A; Redwan, N A; Redwan, E M

    2012-10-01

    Recombinant human interferon-α8 (rhIFN-α8) was obtained by synthesizing a codon-optimized gene in a two-step polymerase chain reaction (PCR) and expressing it in Escherichia coli. The gene encoding human IFN-α8 shows a high content of rare codons. These were replaced based on E. coli codon usage and balancing TA-GC ratio contents of the entire gene. The two-step PCR was performed using long (45-60 nucleotides) overlapped primers and two Taq polymerases (pfu clone and GC-rich system) and resulted in a DNA band of 504 base pairs (bp) corresponding to the calculated size of the IFN-α8 coding sequence; the pfu clone failed to amplify the gene in the correct size without unspecific bands. The full gene was cloned into the pBAD-TOPO expression vector. After cloning, the gene was reoriented by NcoI restriction digestion and religation. The ligated pBAD-TOPO-IFN-α8 (pBAD-IFNα8) plasmid carried the IFN-α8 gene under transcriptional control of the L-arabinose-inducible P(BAD) promoter. IFN-α8 expression was optimized with respect to L-arabinose concentration, temperature, and time of induction in shake flask cultures to maximize the yield of soluble IFN-α8. The produced IFN-α8 was characterized by polyacrylamide gel electrophoresis and immunoassays. After purification on DEAE-Sepharose, the yield was 100 mg/liter. The antiviral and anticancer activities of the IFN-α8 were evaluated in comparison with IFN-α2a, and the results are discussed.

  6. [Intragastric administration of interferon-α-transformed Bifidobacterium promotes lymphocyte proliferation and maturation in mice].

    Science.gov (United States)

    Zeng, Weisen; Zhang, Shuxian; Shao, Congwen; Huang, Yuanjian; Liang, Wenying; Zheng, Mingyue

    2015-03-01

    To investigate the effects of intragastric administration of human interferon-α (hIFN-α)-transformed Bifidobacterium on immune functions of mice. The E.coli-Bifidobacterium shuttle expression vector containing hIFN-α gene was constructed and transformed into Bifidobacterium. The hIFN-α-transformed Bifidobacterium suspension (1010 /ml) was prepared after induction with 0.2% L-arabinose for hIFN-α expression and administered intragastrically in male Balb/C mice at the dose of 0.1 ml every other day for 2 weeks, with the mice receiving empty vector-transformed Bifidobacteria as the negative control and those having an equal volume of saline as the blank control. The percentages of mononuclear cell subsets in the thymus, spleen and blood were detected in the mice by flow cytometry, and the serum levels of IL-4, IL-12, IFN-γ and TNF-α were assayed using mouse cytokine FlowCytomix Kit. The percentages of CD3⁺CD8⁺ and CD4⁺CD8⁺ cells in the thymus, CD3⁺CD4⁺, CD3⁺CD8⁺ and CD4⁺CD8⁺ cells in the spleen, and CD3⁺CD8⁺ cells in the blood all increased significantly in IFN group as compared with those in the negative and blank control groups (PBifidobacterium promotes lymphocyte proliferation and maturation and increases the serum levels of Th1 cytokines in mice.

  7. Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells.

    Science.gov (United States)

    Bowen, James R; Quicke, Kendra M; Maddur, Mohan S; O'Neal, Justin T; McDonald, Circe E; Fedorova, Nadia B; Puri, Vinita; Shabman, Reed S; Pulendran, Bali; Suthar, Mehul S

    2017-02-01

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target.

  8. Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery.

    Directory of Open Access Journals (Sweden)

    Tsung-Hsien Chang

    2009-06-01

    Full Text Available Ebola Zaire virus is highly pathogenic for humans, with case fatality rates approaching 90% in large outbreaks in Africa. The virus replicates in macrophages and dendritic cells (DCs, suppressing production of type I interferons (IFNs while inducing the release of large quantities of proinflammatory cytokines. Although the viral VP35 protein has been shown to inhibit IFN responses, the mechanism by which it blocks IFN production has not been fully elucidated. We expressed VP35 from a mouse-adapted variant of Ebola Zaire virus in murine DCs by retroviral gene transfer, and tested for IFN transcription upon Newcastle Disease virus (NDV infection and toll-like receptor signaling. We found that VP35 inhibited IFN transcription in DCs following these stimuli by disabling the activity of IRF7, a transcription factor required for IFN transcription. By yeast two-hybrid screens and coimmunoprecipitation assays, we found that VP35 interacted with IRF7, Ubc9 and PIAS1. The latter two are the host SUMO E2 enzyme and E3 ligase, respectively. VP35, while not itself a SUMO ligase, increased PIAS1-mediated SUMOylation of IRF7, and repressed Ifn transcription. In contrast, VP35 did not interfere with the activation of NF-kappaB, which is required for induction of many proinflammatory cytokines. Our findings indicate that Ebola Zaire virus exploits the cellular SUMOylation machinery for its advantage and help to explain how the virus overcomes host innate defenses, causing rapidly overwhelming infection to produce a syndrome resembling fulminant septic shock.

  9. 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.

  10. Tryptophan Codon-Dependent Transcription in Chlamydia pneumoniae during Gamma Interferon-Mediated Tryptophan Limitation.

    Science.gov (United States)

    Ouellette, Scot P; Rueden, Kelsey J; Rucks, Elizabeth A

    2016-09-01

    In evolving to an obligate intracellular niche, Chlamydia has streamlined its genome by eliminating superfluous genes as it relies on the host cell for a variety of nutritional needs like amino acids. However, Chlamydia can experience amino acid starvation when the human host cell in which the bacteria reside is exposed to interferon gamma (IFN-γ), which leads to a tryptophan (Trp)-limiting environment via induction of the enzyme indoleamine-2,3-dioxygenase (IDO). The stringent response is used to respond to amino acid starvation in most bacteria but is missing from Chlamydia Thus, how Chlamydia, a Trp auxotroph, responds to Trp starvation in the absence of a stringent response is an intriguing question. We previously observed that C. pneumoniae responds to this stress by globally increasing transcription while globally decreasing translation, an unusual response. Here, we sought to understand this and hypothesized that the Trp codon content of a given gene would determine its transcription level. We quantified transcripts from C. pneumoniae genes that were either rich or poor in Trp codons and found that Trp codon-rich transcripts were increased, whereas those that lacked Trp codons were unchanged or even decreased. There were exceptions, and these involved operons or large genes with multiple Trp codons: downstream transcripts were less abundant after Trp codon-rich sequences. These data suggest that ribosome stalling on Trp codons causes a negative polar effect on downstream sequences. Finally, reassessing previous C. pneumoniae microarray data based on codon content, we found that upregulated transcripts were enriched in Trp codons, thus supporting our hypothesis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  11. Type I Interferon Counters or Promotes Coxiella burnetii Replication Dependent on Tissue.

    Science.gov (United States)

    Hedges, Jodi F; Robison, Amanda; Kimmel, Emily; Christensen, Kelly; Lucas, Erin; Ramstead, Andrew; Jutila, Mark A

    2016-06-01

    Coxiella burnetii is an intracellular pathogen and the cause of Q fever. Gamma interferon (IFN-γ) is critical for host protection from infection, but a role for type I IFN in C. burnetii infection has not been determined. Type I IFN supports host protection from a related pathogen, Legionella pneumophila, and we hypothesized that it would be similarly protective in C. burnetii infection. In contrast to our prediction, IFN-α receptor-deficient (IFNAR(-/-)) mice were protected from C. burnetii-induced infection. Therefore, the role of type I IFN in C. burnetii infection was distinct from that in L. pneumophila Mice treated with a double-stranded-RNA mimetic were protected from C. burnetii-induced weight loss through an IFNAR-independent pathway. We next treated mice with recombinant IFN-α (rIFN-α). When rIFN-α was injected by the intraperitoneal route during infection, disease-induced weight loss was exacerbated. Mice that received rIFN-α by this route had dampened interleukin 1β (IL-1β) expression in bronchoalveolar lavage fluids. However, when rIFN-α was delivered to the lung, bacterial replication was decreased in all tissues. Thus, the presence of type I IFN in the lung protected from infection, but when delivered to the periphery, type I IFN enhanced disease, potentially by dampening inflammatory cytokines. To better characterize the capacity for type I IFN induction by C. burnetii, we assessed expression of IFN-β transcripts by human macrophages following stimulation with lipopolysaccharide (LPS) from C. burnetii Understanding innate responses in C. burnetii infection will support the discovery of novel therapies that may be alternative or complementary to the current antibiotic treatment. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  12. Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells

    Science.gov (United States)

    Maddur, Mohan S.; O’Neal, Justin T.; Fedorova, Nadia B.; Puri, Vinita; Pulendran, Bali; Suthar, Mehul S.

    2017-01-01

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target. PMID:28152048

  13. Zika Virus Antagonizes Type I Interferon Responses during Infection of Human Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    James R Bowen

    2017-02-01

    Full Text Available Zika virus (ZIKV is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target.

  14. Cytokine Interferon-γ suppresses the function of capsule myofibroblasts and induces cell apoptosis.

    Science.gov (United States)

    Mattyasovszky, Stefan G; Mausbach, Stefan; Ritz, Ulrike; Wollstädter, Jochen; Schmidtmann, Irene; Baranowski, Andreas; Drees, Phillipp; Rommens, Pol M; Hofmann, Alexander

    2017-02-08

    Myofibroblasts (MFs), a contractile subset of fibroblasts, play a pivotal role in physiological wound healing and in the development of many fibroconnective disorders. The complex cytokine network regulating the function of MFs in joint stiffness is still poorly understood. In this in vitro study, we investigated the effect of the cytokine Interferon-gamma (IFN-γ) on MFs isolated from human joint capsules. MFs were cultivated either in the presence of increasing concentrations of IFN-γ alone or in combination with IFN-γ neutralizing antibodies. Cell viability, cytotoxicity, apoptosis, and mRNA gene expression of the MF markers alpha-smooth muscle actin (α-SMA) and collagen type I were analyzed in MF cultures. Contraction potential was analyzed in an established collagen gel contraction assay simulating the extracellular matrix. Using immunofluorescence staining, we could verify that MFs express IFN-γ-receptor (R)-1 on their membrane. IFN-γ decreased MF viability and significantly elevated the apoptosis rate in a dose-dependent manner. IFN-γ down-regulated α-SMA and collagen type I mRNA expression which was associated with a diminished MF mediated contraction of the gel matrices. These effects were suppressed by simultaneous treatment of cells with a neutralizing IFN-γ antibody. Our experiments confirm the hypothesis that the cytokine IFN-γ is a crucial component of the regulatory network of capsule MFs. IFN-γ notably influences the ability of MFs to contract collagen matrices by suppressing α-SMA gene expression. IFN-γ is toxic for MFs in high concentrations and may negatively regulate the number of pro-fibrotic MFs during the healing process via induction of cell apoptosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  15. Induction of epithelial migration of lymphocytes by intercellular adhesion molecule-1 in a rat model of oral mucosal graft-versus-host disease.

    Science.gov (United States)

    Ohno, Jun; Iwahashi, Teruaki; Ehara, Michiko; Ozasa, Ryuki; Hanada, Hironori; Funakoshi, Tomoyuki; Taniguchi, Kunihisa

    2011-06-01

    To elucidate the involvement of intercellular adhesion molecule-1 (ICAM-1) in the migration of lymphocytes to the oral mucosal epithelium in a rat model of acute graft-versus-host disease (AGVHD), we investigated (1) ICAM-1 and major histocompatibility complex (MHC) class II expression by keratinocytes (KCs) and their role in the epithelial infiltration of CD8+ cells, (2) the tissue expression of interferon-γ (IFN-γ) mRNA and expression of IFN-γ receptor by KCs, and (3) the ability of KCs to direct CD8+ cells into the epithelial layers. We classified the oral mucosal lesions into three consecutive temporal phases on the basis of increased epithelial ICAM-1 expression: basal- (phase I), parabasal- (phase II), and pan-epithelial except for the cornified cell layer (phase III). Basal ICAM-1 expression by KCs preceded that of MHC class II molecules, infiltration of CD8+ cells and epithelial histological changes. Tissue expression of IFN-γ mRNA and expression of IFN-γ receptor on KCs evidenced by immunohistochemistry were detected in early lesions (phase I), indicating that locally produced IFN-γ induced ICAM-1 expression by KCs. CD8+ cells were bound to KCs in frozen sections of epithelial lesions, whereas no lymphocyte attachment was observed in normal KC. Adherence could be inhibited by pretreating CD8+ cells with lymphocyte function-associated antigen-1 (LFA-1) antibody and/or by pretreating sections with ICAM-1 antibody. Our data suggest that in the early phase of acute oral mucosal GVHD, the induction of ICAM-1 expression on KCs leads to the migration of CD8+ cells into the epithelium and that this is mediated in part by the ICAM-1/LFA-1 pathway.

  16. Endotoxin induction of tumor necrosis factor is enhanced by acid-labile interferon-alpha in acquired immunodeficiency syndrome.

    OpenAIRE

    Lau, A S; Livesey, J F

    1989-01-01

    High levels of an acid-labile IFN-alpha have been demonstrated in the sera of patients with symptomatic HIV infection. IFNs have been shown to enhance the cytotoxic and antiproliferative actions of tumor necrosis factor (TNF), which is a potent mediator of inflammation and sepsis. We show that the acid-labile IFN-alpha present in AIDS sera can induce TNF synthesis and sensitize blood monocytes (BM) to endotoxin stimulation resulting in further synthesis of TNF in vitro. TNF production by BM f...

  17. The Use of Recombinant Feline Interferon Omega Therapy as an Immune-Modulator in Cats Naturally Infected with Feline Immunodeficiency Virus: New Perspectives

    Directory of Open Access Journals (Sweden)

    Rodolfo Oliveira Leal

    2016-10-01

    Full Text Available Type I interferons (IFNs are well-known cytokines that, among their main functions, are key components of the host immune response against viral infections. Due to its immune modulation properties, they are commonly used in the therapeutic approach of various retroviral infections, namely human immunodeficiency virus (HIV and feline immunodeficiency virus (FIV. In HIV infection, it has been shown that IFN therapy limits early viral replication, particularly useful on post-exposure prophylaxis. In veterinary medicine, recombinant feline interferon omega (rFeIFN-ω was the first interferon licensed for use in cats. Several studies have recently shown that this compound seems to stimulate the innate immunity, decreasing clinical signs and co-infections in naturally FIV-infected cats. More than summarizing the main conclusions about rFeIFN-ω in cats, this review emphasizes the immune-modulation properties of IFN therapy, opening new perspectives for its use in retroviral infections. Either in FIV-infected cats or in HIV individuals, type I IFNs seem to induce an innate immune-modulation and should not be overlooked as a therapeutic option in retroviral infections.

  18. Combination of interferon alfa-2b and ribavirin in relapsed or nonresponding chronic hepatitis C patients following interferon therapy

    Directory of Open Access Journals (Sweden)

    Laurentius A. Lesmana

    2001-12-01

    Full Text Available Twenty six patients (pts with chronic hepatitis C (CHC who reLapsed or non-responded following.interferon (IFN therapy were given lFN alfa-2b 3   MIU three times a week for 48 weeks in combination with Ribavirin 800-1000 mg daily 2I (80,8% of the 26.pts completed the study consisted of 12 relapsers and 9 non-responders. Five pts dropped out due to drug adverse events in three pts and non-drug related reason in the other two. In the relapsed group complete response, relapse and sustained response rates were obtained in 9/12(75%, 2/2 (16,5% and 7/12(58,3% pts respectively. In the non- responding group, these figures were 3/9 (33,3%, 1/9(I1,1%, and 2/9(22,2% pts, respectively. The most frequent adverse event was flu-like syndrome, which was found in 18 pts (85,7%. Combination therapy of IFN alfa-2b and ribavirin may induce sustained virological response in relapsed and non-responding CHC patients. This combination therapy is more effective for relapsers compared to for non-responders. (Med J Indones 2001; 10: 214-8Keywords: Chronic hepatitis C, combination therapy, interferon, ribavirin

  19. Regulation of interferon pathway in 2-methoxyestradiol-treated osteosarcoma cells

    Directory of Open Access Journals (Sweden)

    Wimbauer Fritz

    2012-03-01

    Full Text Available Abstract Background Osteosarcoma is a bone tumor that often affects children and young adults. Although a combination of surgery and chemotherapy has improved the survival rate in the past decades, local recurrence and metastases still develop in 40% of patients. A definite therapy is yet to be determined for osteosarcoma. Anti- tumor compound and a metabolite of estrogen, 2-methoxyestradiol (2-ME induces cell death in osteosarcoma cells. In this report, we have investigated whether interferon (IFN pathway is involved in 2-ME-induced anti-tumor effects in osteosarcoma cells. Methods 2-ME effects on IFN mRNA levels were determined by Real time PCR analysis. Transient transfections followed by reporter assays were used for investigating 2-ME effects on IFN-pathway. Western blot analyses were used to measure protein and phosphorylation levels of IFN-regulated eukaryotic initiation factor-2 alpha (eIF-2α. Results 2-ME regulates IFN and IFN-mediated effects in osteosarcoma cells. 2 -ME induces IFN gene activity and expression in osteosarcoma cells. 2-ME treatment induced IFN-stimulated response element (ISRE sequence-dependent transcription and gamma-activated sequence (GAS-dependent transcription in several osteosarcoma cells. Whereas, 2-ME did not affect IFN gene and IFN pathways in normal primary human osteoblasts (HOB. 2-ME treatment increased the phosphorylation of eIF-2α in osteosarcoma cells. Furthermore, analysis of osteosarcoma tissues shows that the levels of phosphorylated form of eIF-2α are decreased in tumor compared to normal controls. Conclusions 2-ME treatment triggers the induction and activity of IFN and IFN pathway genes in 2-ME-sensitive osteosarcoma tumor cells but not in 2-ME-resistant normal osteoblasts. In addition, IFN-signaling is inhibited in osteosarcoma patients. Thus, IFN pathways play a role in osteosarcoma and in 2-ME-mediated anti-proliferative effects, and therefore targeted induction of IFN signaling could lead

  20. Tratamento de hemangioma gigante com interferon alfa: relato de dois casos Treatment of giant hemangioma with interferon-alpha: report of two cases

    Directory of Open Access Journals (Sweden)

    Ana Julia Balau

    2007-12-01

    Full Text Available O objetivo do trabalho é descrever o uso de interferon alfa no tratamento de pacientes com hemangioma gigante. Os autores relatam e analisam dois casos de hemangioma gigante em tratamento com interferon alfa. IBS, 3 anos, em acompanhamento no Ambulatório de Hematologia desde um ano de idade com quadro de lesão angiomatosa em praticamente toda hemiface direita, acompanhada de sangramentos gengivais importantes. Após a realização de exames complementares (Angiorressonância magnética e feito o diagnóstico de hemangioma gigante em face, foi iniciado tratamento com prednisona e, posteriormente, associação com interferon alfa e observada importante melhora do quadro, resultando na diminuição dos episódios de sangramento e no tamanho do tumor. C.N.P., 12 anos, apresentando nódulo em região lateral de joelho esquerdo há 2 anos, com aumento progressivo do tamanho e dor local. Fez uso de prednisona e, sem melhora do quadro, introduzido interferon alfa com regressão importante do tamanho do tumor. O tratamento com interferon alfa deve ser considerado no tratamento de hemangiomas, pois apresenta bons resultados em relação à diminuição do tamanho do tumor e, conseqüentemente, reduz as intercorrências clínicas associadas à sua presença, principalmente os sangramentos.The aim of this study is to describe the treatment using interferon-alpha of giant hemangiomas in children. The authors report two cases of children presenting with giant hemangiomas treated using interferon-alpha and analyze the results. IBS, 3 years-old, has been followed up in Famema Hemathology Service since she was 1 year-old with a tumor on the face and persistent bleeding. After clinical and radiologic evaluations and suggested the diagnosis of giant hemangioma, she started treatment with interferon-alpha. A great clinical improvement was observed a reducing of the number of episodes of bleedings and a decrease in of the tumor size. CNP, 12 years-old, came to

  1. Control of influenza infection is impaired by diminished interferon-γ secretion by CD4 T cells in the lungs of toddler mice.

    Science.gov (United States)

    Verhoeven, David; Perry, Sheldon; Pryharski, Karin

    2016-07-01

    Respiratory viral infections, such as influenza, can lead to delayed viral clearance in toddlers, possibly exacerbating disease morbidity. We hypothesized that defective CD4 T cells in toddlers may contribute to a failure to clear virus at a similar rate to adults. Thus, we developed a young mouse model to examine potential divergent responses between toddlers and adults. We determined that young mice (toddler mice, 21 d old) were actively generating and recruiting effector/memory T cells, whereas memory populations were firmly established in older, adult mice (8-10 wk old). We infected toddler and adult mice with influenza A/PR8/34 (H1N1) and found young mice had elevated morbidity, as measured by enhanced weight loss and lower partial pressure of oxygen levels, throughout the infection, thus, modeling the higher morbidity observed in children (infection. Early viral loads were comparable to adult mice, but toddler mice failed to clear virus by 10 d postinfection. This delayed clearance corresponded to poor lung recruitment of CD4 T cells, lower antiviral T cell responses, and lower B cell/antibodies in the lungs. Mechanistically, diminished interferon-γ was detected in the lungs of toddler mice throughout the infection and corresponded to intrinsic, rather than extrinsic, CD4 T cell limitations in interferon-γ transcription. Moreover, defects in interferon-γ production appeared downstream from signal transducer and activator of transcription 4 in the interleukin-12 signaling pathway, suggesting maturational delays different from neonates. Importantly, recombinant interferon-γ supplementation rescued CD4 T cell numbers in the lungs and influenza-specific antibody formation. This study highlights the intrinsic limitations in CD4 T cell effector functions that may arise in toddlers and contribute to disease pathology. © Society for Leukocyte Biology.

  2. Hypnosis for induction of labour.

    Science.gov (United States)

    Nishi, Daisuke; Shirakawa, Miyako N; Ota, Erika; Hanada, Nobutsugu; Mori, Rintaro

    2014-08-14

    Induction of labour using pharmacological and mechanical methods can increase complications. Complementary and alternative medicine methods including hypnosis may have the potential to provide a safe alternative option for the induction of labour. However, the effectiveness of hypnosis for inducing labour has not yet been fully evaluated. To assess the effect of hypnosis for induction of labour compared with no intervention or any other interventions. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2014), handsearched relevant conference proceedings, contacted key personnel and organisations in the field for published and unpublished references. All published and unpublished randomised controlled trials (RCTs) and cluster-RCTs of acceptable quality comparing hypnosis with no intervention or any other interventions, in which the primary outcome is to assess whether labour was induced. Two review authors assessed the one trial report that was identified (but was subsequently excluded). No RCTs or cluster-RCTs were identified from the search strategy. There was no evidence available from RCTs to assess the effect of hypnosis for induction of labour. Evidence from RCTs is required to evaluate the effectiveness and safety of this intervention for labour induction. As hypnosis may delay standard care (in case standard care is withheld during hypnosis), its use in induction of labour should be considered on a case-by-case basis.Future RCTs are required to examine the effectiveness and safety of hypnotic relaxation for induction of labour among pregnant women who have anxiety above a certain level. The length and timing of the intervention, as well as the staff training required, should be taken into consideration. Moreover, the views and experiences of women and staff should also be included in future RCTs.

  3. Estimation of physical parameters in induction motors

    DEFF Research Database (Denmark)

    Børsting, H.; Knudsen, Morten; Rasmussen, Henrik

    1994-01-01

    Parameter estimation in induction motors is a field of great interest, because accurate models are needed for robust dynamic control of induction motors......Parameter estimation in induction motors is a field of great interest, because accurate models are needed for robust dynamic control of induction motors...

  4. 14 CFR 25.1091 - Air induction.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Air induction. 25.1091 Section 25.1091... STANDARDS: TRANSPORT CATEGORY AIRPLANES Powerplant Induction System § 25.1091 Air induction. (a) The air induction system for each engine and auxiliary power unit must supply— (1) The air required by that engine...

  5. 14 CFR 27.1091 - Air induction.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Air induction. 27.1091 Section 27.1091... STANDARDS: NORMAL CATEGORY ROTORCRAFT Powerplant Induction System § 27.1091 Air induction. (a) The air induction system for each engine must supply the air required by that engine under the operating conditions...

  6. 14 CFR 29.1091 - Air induction.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Air induction. 29.1091 Section 29.1091... STANDARDS: TRANSPORT CATEGORY ROTORCRAFT Powerplant Induction System § 29.1091 Air induction. (a) The air induction system for each engine and auxiliary power unit must supply the air required by that engine and...

  7. Mechanism of Interferon Uptake in Parental and Somatic Monkey-Mouse Hybrid Cells

    Science.gov (United States)

    Chany, C.; Grégoire, A.; Vignal, M.; Lemaitre-Moncuit, J.; Brown, P.; Besançon, F.; Suarez, H.; Cassingena, R.

    1973-01-01

    Dose-response curves of interferons in different sensitive cells are regularly sigmoidal. In somatic monkey-mouse hybrid cells, however, a significant decrease in the slope of the curve for primate interferon was observed, while the dose-response effect was unaltered for mouse interferon. High concentrations of primate interferon were 10- to 100-times less effective in hybrid clones than in parental monkey CV-1 cells; at low concentrations the antiviral effect was 10- to 20-times higher in hybrid clones than in the parental cells. The receptor(s) for primate interferon located on the cell membrane was destroyed by trypsin but not by EDTA. Similarly, acid pH inactivated these receptor sites. We, thus, postulate that the antiviral effect is, at least partially, related to the amount of interferon taken up by the cells. Uptake could be conditioned by active cooperation of two cell-specific factors: a receptor and an activator. The activator might be missing or inactivated for primate interferon in the hybrid cells. We suggest that the putative antiviral protein is not cell-species specific, and that information for its synthesis in the hybrid cells might be located on a mouse rather than a monkey chromosome. PMID:4346894

  8. Role of Leptin and SOCS3 in Inhibiting the Type I Interferon Response During Obesity.

    Science.gov (United States)

    Terán-Cabanillas, Elí; Hernández, Jesús

    2017-02-01

    Obesity provokes an imbalance in the immune system, including an aberrant type I interferon response during some viral infections and after TLR stimulation. SOCS3 overexpression and altered systemic leptin levels could be responsible for the reduced type I interferon production in people with obesity and, eventually, significantly increase the risk of viral infection. The aim of this study was to determine whether SOCS3- and leptin-induced tolerance are responsible for the reduced type I interferon production in people with obesity. SOCS3 overexpression in PBMCs from people with obesity was inhibited with the small interfering RNA (siRNA) assay, and leptin-induced tolerance was evaluated in PBMCs from non-obese volunte\\ers and U937 cells treated with TLR ligands. SOCS3, but not SOCS1, gene silencing via siRNA increased the type I interferon response in PBMCs obtained from people with obesity. On the other hand, leptin induced SOCS3 expression and inhibited type I interferons in PBMCs from healthy donors and in U937 monocytes stimulated with TLR ligands. Taken together, these results demonstrate that reduced type I interferon production in obesity is caused by SOCS3 overexpression as well as tolerance induced by leptin. Here, we demonstrate a key role of leptin and SOCS3 in inhibiting the type I interferon response during obesity.

  9. Oxidative Modification of Blood Serum Proteins in Multiple Sclerosis after Interferon Beta and Melatonin Treatment

    Directory of Open Access Journals (Sweden)

    Monika Adamczyk-Sowa

    2017-01-01

    Full Text Available Multiple sclerosis (MS is a disease involving oxidative stress (OS. This study was aimed at examination of the effect of melatonin supplementation on OS parameters, especially oxidative protein modifications of blood serum proteins, in MS patients. The study included 11 control subjects, 14 de novo diagnosed MS patients with the relapsing-remitting form of MS (RRMS, 36 patients with RRMS receiving interferon beta-1b (250 μg every other day, and 25 RRMS patients receiving interferon beta-1b plus melatonin (5 mg daily. The levels of N′-formylkynurenine, kynurenine, dityrosine, carbonyl groups, advanced glycation products (AGEs, advanced oxidation protein products (AOPP, and malondialdehyde were elevated in nontreated RRSM patients. N′-Formylkynurenine, kynurenine, AGEs, and carbonyl contents were decreased only in the group treated with interferon beta plus melatonin, while dityrosine and AOPP contents were decreased both in the group of patients treated with interferon beta and in the group treated with interferon beta-1b plus melatonin. These results demonstrate that melatonin ameliorates OS in MS patients supporting the view that combined administration of interferon beta-1b and melatonin can be more effective in reducing OS in MS patients than interferon beta-1b alone.

  10. Reversible silencing of cytomegalovirus genomes by type I interferon governs virus latency.

    Directory of Open Access Journals (Sweden)

    Franziska Dağ

    2014-02-01

    Full Text Available Herpesviruses establish a lifelong latent infection posing the risk for virus reactivation and disease. In cytomegalovirus infection, expression of the major immediate early (IE genes is a critical checkpoint, driving the lytic replication cycle upon primary infection or reactivation from latency. While it is known that type I interferon (IFN limits lytic CMV replication, its role in latency and reactivation has not been explored. In the model of mouse CMV infection, we show here that IFNβ blocks mouse CMV replication at the level of IE transcription in IFN-responding endothelial cells and fibroblasts. The IFN-mediated inhibition of IE genes was entirely reversible, arguing that the IFN-effect may be consistent with viral latency. Importantly, the response to IFNβ is stochastic, and MCMV IE transcription and replication were repressed only in IFN-responsive cells, while the IFN-unresponsive cells remained permissive for lytic MCMV infection. IFN blocked the viral lytic replication cycle by upregulating the nuclear domain 10 (ND10 components, PML, Sp100 and Daxx, and their knockdown by shRNA rescued viral replication in the presence of IFNβ. Finally, IFNβ prevented MCMV reactivation from endothelial cells derived from latently infected mice, validating our results in a biologically relevant setting. Therefore, our data do not only define for the first time the molecular mechanism of IFN-mediated control of CMV infection, but also indicate that the reversible inhibition of the virus lytic cycle by IFNβ is consistent with the establishment of CMV latency.

  11. Re-emergence of interferon-α in the treatment of chronic myeloid leukemia

    Science.gov (United States)

    Talpaz, M; Hehlmann, R; Quintás-Cardama, A; Mercer, J; Cortes, J

    2013-01-01

    Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML. PMID:23238589

  12. Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.

    Science.gov (United States)

    Blohmke, Christoph J; Darton, Thomas C; Jones, Claire; Suarez, Nicolas M; Waddington, Claire S; Angus, Brian; Zhou, Liqing; Hill, Jennifer; Clare, Simon; Kane, Leanne; Mukhopadhyay, Subhankar; Schreiber, Fernanda; Duque-Correa, Maria A; Wright, James C; Roumeliotis, Theodoros I; Yu, Lu; Choudhary, Jyoti S; Mejias, Asuncion; Ramilo, Octavio; Shanyinde, Milensu; Sztein, Marcelo B; Kingsley, Robert A; Lockhart, Stephen; Levine, Myron M; Lynn, David J; Dougan, Gordon; Pollard, Andrew J

    2016-05-30

    Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever. © 2016 Blohmke et al.

  13. Interferon-gamma response of PBMC indicates productive pseudorabies virus (PRV) infection in swine.

    Science.gov (United States)

    Hoegen, Bärbel; Saalmüller, Armin; Röttgen, Marlene; Rziha, Hanns-Joachim; Geldermann, Hermann; Reiner, Gerald; Pfaff, Eberhard; Büttner, Mathias

    2004-12-28

    In Chinese Meishan/German Landrace cross-bred swine F2 generation interferon gamma (IFN-gamma) production by peripheral blood mononuclear cells (PBMC) was determined directly ex vivo at different time points after survival of a virulent pseudorabies virus (PRV) infection. This reactivity was compared with the reactivity of naïve PBMC. Significant IFN-gamma production was determined in ELISA and ELISPOT only after in vitro PBMC re-stimulation with PRV and not with the closely related bovine herpesvirus BHV-1. The PRV-specific IFN-gamma secretion from re-stimulated PBMC showed high levels 6 days after infection, before the presence of serum antibodies, and it persisted at a high level over a 3 months period. The response of a group of eight piglets infected intranasally with PRV varied. Only two animals showed the expected typical fever response. PRV specific IFN-gamma production by PBMC clearly indicated that infection had occurred. Early significant IFN-gamma production by primed PBMC turned out to be a reliable and specific ex vivo marker for cellular response against productive PRV infection in swine before antibody formation.

  14. Antiviral Type I and Type III Interferon Responses in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Thomas Michiels

    2013-03-01

    Full Text Available The central nervous system (CNS harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i preventing neuroinvasion and infection of CNS cells; ii the identity of IFN-producing cells in the CNS; iii the antiviral activity of ISGs; and iv the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  15. Interferon gamma response to Mycobacterium avium subsp. paratuberculosis specific lipopentapeptide antigen L5P in cattle.

    Science.gov (United States)

    Holbert, Sébastien; Branger, Maxime; Souriau, Armel; Lamoureux, Bérénice; Ganneau, Christelle; Richard, Gaëlle; Cochard, Thierry; Tholoniat, Christophe; Bay, Sylvie; Winter, Nathalie; Moyen, Jean Louis; Biet, Franck

    2015-10-01

    After Mycobacterium avium subsp. paratuberculosis (Map) infection the cell-mediated immune (CMI) response indicative of early Th1 activation may be detected using interferon-gamma release assay (IGRA). Currently, the purified protein derivatives (PPDs), i.e., the total extract of mycobacteria antigens are used to recall CMI responses against Map. This study aimed to assess the ability of the chemically synthesized Map specific cell wall lipopentapeptide L5P to induce CMI response in cows infected by Map compared to PPD. L5P and PPD elicited an IFN-γ response in 12 and 35 animals from two Map infected herds respectively, but IFN-γ was not detected in the 13 cows recruited from a non-infected herd. Levels of IFN-γ detected were higher with PPD than with L5P. There was no correlation between the IFN-γ response and the humoral response to Map or faecal culture. Copyright © 2015. Published by Elsevier Ltd.

  16. Potential role of type I interferon in the pathogenic process leading to type 1 diabetes.

    Science.gov (United States)

    Qaisar, Natasha; Jurczyk, Agata; Wang, Jennifer P

    2018-01-24

    Understanding the relationship between viral infections and the development of type 1 diabetes (T1D) is essential for T1D prevention. Virus-induced innate immune responses, specifically type I interferon (IFN-I) and the IFN gene signature, orchestrate early events of β-cell dysfunction preceding islet autoimmunity. We summarize recent advances in how IFN-I and the IFN gene signature can drive T1D development. IFN-I, particularly IFN-α, and the IFN gene signature have been detected in islets and peripheral blood of T1D patients. T1D risk genes in the IFN-I signaling pathway regulate antiviral responses in β cells driven by IFN-I and proinflammatory cytokines. Polymorphisms in these genes may cause chronic dysregulated IFN signaling in islets, characterized by hyperexpression of IFN-I, the IFN gene signature, and major histocompatibility complex class I during viral infection. Islet-cell inflammation mediated by aberrant IFN signaling drives β-cell apoptosis by initiating autoreactivity against β-cell antigens. The profound elevation in IFN-I and the IFN gene signature observed in some forms of T1D are also seen in a novel group of human autoimmune and autoinflammatory diseases called interferonopathies. Despite significant advances, further studies are required to functionally dissect the mechanisms by which excessive IFN-I contributes to the evolution of autoimmunity that destroys β cells.

  17. Diagnostic performance of interferon-γ release assay for lymph node tuberculosis.

    Science.gov (United States)

    Jia, Hongyan; Pan, Liping; Du, Boping; Sun, Qi; Wei, Rongrong; Xing, Aiying; Du, Fengjiao; Sun, Huishan; Zhang, Zongde

    2016-05-01

    The aim of the study was to evaluate the performance of interferon-γ (IFN-γ) release assay (IGRA) (T-SPOT.TB) for patients with suspected lymph node tuberculosis (TB). Of the 405 patients with suspected lymph node TB, enrolled from Beijing Chest Hospital between July 2011 and April 2015, 83 (20.5%) were microbiologically/histopathologically confirmed lymph node TB, and 282 (69.6%) did not have active TB. The remaining 21 inconclusive TB and 19 clinical TB were excluded from the final analysis (9.9%). T-SPOT.TB using peripheral blood mononuclear cells was performed to examine the IFN-γ response to the Mycobacterium tuberculosis-specific antigens early secretory antigenic target 6 and culture filtrate protein 10. The overall sensitivity and specificity for T-SPOT.TB were 90.4% and 70.5%, respectively. Spot-forming cells in the lymph node TB group (184 [48-596/10(6) peripheral blood mononuclear cells {PBMCs}]) were significantly higher than that in the nonactive TB group (0 [0-41]/10(6) PBMCs) (Plymph node TB. Copyright © 2016. Published by Elsevier Inc.

  18. Interferon beta-1b reduces black holes in a randomised trial of clinically isolated syndrome.

    Science.gov (United States)

    Nagtegaal, Gijsbert J A; Pohl, Christoph; Wattjes, Mike P; Hulst, Hanneke E; Freedman, Mark S; Hartung, Hans-Peter; Miller, David; Montalban, Xavier; Kappos, Ludwig; Edan, Gilles; Pleimes, Dirk; Beckman, Karola; Stemper, Brigitte; Polman, Christoph H; Sandbrink, Rupert; Barkhof, Frederik

    2014-02-01

    Multiple sclerosis (MS) is characterised by inflammatory lesions of the central nervous system. Interferon beta-1b (IFNB-1b) has been shown to improve clinical and magnetic resonance imaging (MRI) measures for patients with MS. To evaluate whether IFNB-1b in patients presenting with clinically isolated syndromes (CIS) prevented persisting T1 hypointensities on MRI (persistent black holes (PBHs)). In the placebo-controlled phase, patients (n = 468) were initially randomised to IFNB-1b (n = 292) or placebo (n = 176) for two years or clinically definite MS (CDMS). In the open-label phase (n = 418), both groups were offered IFNB-1b for up to five years. Lesions were classified as PBHs if T1 hypointensity persisted throughout the last available scan (minimum time one year). A total of 435 patients were evaluable for analysis. The number of PBHs/patient was lower in the early rather than the delayed treatment arm during both phases (.42 vs .71, p = .0102 and .70 vs 1.17, p = .0121). Exploratory analyses identified baseline characteristics that affected rate of conversion. Although the rate of lesions that converted to PBH showed no significant differences between groups, the numbers of PBHs per patient out of new lesions was significantly lower in IFNB-1b patients compared to patients on placebo. NCT00544037.

  19. Antiviral type I and type III interferon responses in the central nervous system.

    Science.gov (United States)

    Sorgeloos, Frédéric; Kreit, Marguerite; Hermant, Pascale; Lardinois, Cécile; Michiels, Thomas

    2013-03-15

    The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  20. Induction of formaldehyde contact sensitivity

    DEFF Research Database (Denmark)

    Andersen, Klaus Ejner; Boman, A; Vølund, A

    1985-01-01

    The sensitizing potential of aqueous formaldehyde was evaluated with the guinea pig maximization test (GPMT) in two laboratories (Copenhagen and Stockholm) using different guinea pig strains. Six intradermal (0.01%-3%), and 6 topical (0.5%-20%) concentrations were used for induction, and formalde......The sensitizing potential of aqueous formaldehyde was evaluated with the guinea pig maximization test (GPMT) in two laboratories (Copenhagen and Stockholm) using different guinea pig strains. Six intradermal (0.01%-3%), and 6 topical (0.5%-20%) concentrations were used for induction......, and formaldehyde 1% and 0.1% was used for challenge. The incidence of contact sensitivity depended on the intradermal, but not on the topical induction dose. Statistical analyses showed a non-monotonous (non-linear) dose response relationship. The estimated maximal sensitization rate in Copenhagen was 80% after...... intradermal induction with 0.65% formaldehyde; in Stockholm it was 84% after induction with 0.34%. The data from the two laboratories could be described by parallel displaced dose response curves suggesting that the guinea pig strain used in Stockholm was significantly more susceptible to formaldehyde than...