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NF-κB-dependent synergistic regulation of CXCL10 gene expression by IL-1β and IFN-γ in human intestinal epithelial cell lines
No full textBackground and aims Little is known about the intestinal epithelial expression and secretion of CXCL10 (IP-10), a chemokine involved in recruiting T cells and monocytes. We aimed to study CXCL10 gene expression and regulation by the pro-inflammatory cytokines interleukin (IL)-1 beta, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in intestinal epithelial cell lines. Materials and methods CXCL10 expression and secretion kinetics were assessed in Caco-2, HT-29 and DLD1 human colon epithelial cells, treated with IL-1 beta, TNF-alpha, IFN-gamma alone or in combination with each other by real-time polymerase chain reaction (PCR), Northern blotting and enzyme-linked immunoabsorbent assay (ELISA). Transient transfections with TGL-IP10 (CXCL10 promoter) and TGL-IP10-kappa B2 mutant promoter and gelshifts and supershifts for nuclear factor (NF)-kappa B were also performed. Results Real-time PCRs and ELISA experiments revealed that IL-1 beta was the strongest and earliest inducer of CXCL10 messenger ribonucleic acid (mRNA) expression and protein secretion in Caco-2 cell line, whereas INF-gamma had a delayed kinetics. There was a strong synergistic effect of either TNF-alpha or IL-1 beta with IFN-gamma both on CXCL10 mRNA expression and protein secretion in all three cell lines. Real-time PCR and ELISA experiments using a specific NF-kappa B inhibitor and transfection experiments with a NF-kappa B-binding defective CXCL10 promoter construct revealed that the induction of CXCL10 by IL-1 beta and its synergism with IFN-gamma is NF-kappa B dependent. Conclusion These data demonstrate that in colonic epithelial cells, depending on the cellular context and utilizing the NF-kappa B pathway, IL-1 beta alone and/or in synergism with IFN-gamma may play a major role in the induction of CXCL10
Quantitative gene expression of cytokines in peripheral blood leukocytes stimulated in vitro: modulation by the anti-tumor nerosis factor-alpha antibody infliximab and comparison with the mucosal cytokine expression in patients with ulcerative colitis
No full textEmerging data indicate that alterations in cytokine synthesis play a role in inflammatory bowel disease (IBD)) pathogenesis. In this study, we quantified mRNA expression of the main acute-phase cytokines and T-cell cytokines in biopsies from patients with established ulcerative colitis (UC) and compared it with that obtained in biopsies from normal controls. Quantification of cytokine gene expression was also evaluated in in vitro phytohemagglutinin (PHA)-treated peripheral blood leukocytes (PBLs) at the RNA and protein levels. The in vitro influence of the anti-tumor necrosis factor-alpha (TNF-alpha) antibody infliximab (INFL) on PHA-treated PBLs was also evaluated. Analyzing inflamed specimens from UC patients compared with control samples, interleukin (IL)-6 was sharply the most induced cytokine. Interestingly, similar results were found in activated PBLs, where acute-phase cytokines were more abundantly expressed compared with T-cell cytokines. IL-6 was confirmed to be the most induced with a maximum increase of 1110-fold after 4 h of PHA stimulation, followed by TNF-alpha and IL-1 beta as well as interferon-gamma (IFN-gamma). Surprisingly, analyzing cytokine-mRNA expression from activated PBLs, the time kinetics and quantity of IFN-gamma was more similar to that of the acute-phase proteins than to that of the T-cell cytokines, which were upregulated after I h. The upregulation of cytokine-mRNA was translated into protein as demonstrated by enzyme-linked immunosorbent assay. IFN-,gamma was also strongly expressed in the RNA from UC biopsies. TNF-a protein was not detectable at all in INFL-treated cultures. INFL did not induce a reduction of TNF-alpha-mRNA nor of IL-1 beta-mRNA, but it reduced IFN-gamma-mRNA and, to a lesser extent, IL-6-mRNA; it also reduced the T-cell-derived cytokine IL-2. The in vitro model of PHA-stimulated PBLs may mimic inflammation processes observed in vivo. INFL may reduce inflammation in vivo through inhibition of both monocyte and T-cell activation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Untersuchungen zur Rolle des Darmepithels bei chronisch entzündlichen Darmerkrankungen: Über den Einfluss von Zytokinen und Glucocorticoiden auf die Expression der Chemokine CXCL8 und CXCL10 und den NF-kB Signalweg in intestinalen Epithel-Zelllinien
No full textIntestinale Epithelzellen werden entweder
direkt durch luminale Antigene oder durch inflammatorische Signale
aus der unmittelbaren Umgebung aktiviert. Durch Sekretion von
Chemokinen trägt das intestinale Epithel zur mukosalen Infiltration
von Entzündungszellen bei chronisch entzündlichen Darmerkrankungen
(CEDE) bei. Über die intestinale Expression und Sekretion des
Chemokins CXCL10 (IP-10), das bei der Rekrutierung von T-Zellen und
Monozyten maßgeblich ist, ist bisher wenig bekannt. Insbesondere
existieren bisher keine Daten über die Rolle von Interleukin 1β
des am häufigsten exprimierten Zytokins in der Darmschleimhaut bei
chronisch entzündlichen Darmerkrankungen. Das Ziel der Arbeit war
die Expression und Regulation der Chemokine CXCL8 (IL-8) und CXCL10
(IP-10), (in epithelialen Zelllinien zu untesuchen durch
proinflammatorischen Zytokinen IL-1β Interferon gamma und
TNF-alpha). Der Transkriptionsfaktor NF-κB spielt eine tragende
Rollein der Pathophysiologie der chronisch entzündlichen
Darmerkrankung. Er stellt daher ein potentielles pharmakologisches
Ziel in der Behandlung dieser Erkrankung dar. Ein weiteres Ziel der
Arbeit bestand daher darin, die Effekte von zwei NF-κB-Inhibitoren
auf die Interleukin-1-induzierte CXCL8- und CXCL10-Expression in
intestinalen Epithelzellen zu untersuchen. Glukokortikoide sind
potente Inhibitoren der Chemokin-Gen-Expression in Immunzellen.
Bisher existieren keine Daten über den Einfluß von Glukokortikoiden
auf die Chemokin-Expression in intestinalen Epithelzellen, so daß
auch der Effekt von Glukokortikoiden auf die Zytokin-induzierte
Expression von CXCL8 und CXCL10 untersucht wurde.
Die oben genannten Daten zeigten, daß IL-1β ein starker und
unmittelbarer Stimulus für die CXCL8- und CXCL10-Genexpression
sowohl auf RNA- als auch Proteinebene in Darmepithelzelllinien
darstellt. Die differentielle Expression von CXCL10 durch
proinflammatorische Zytokine unterstreicht die Bedeutung des
Zusammenspiels epithelialer Zellen und Immunzellen im Rahmen einer
intestinalen Entzündungsreaktion. Interleukin-1 spielt abhängig vom
zellulären Kontext unter Nutzung des NF-κB-Signalweges eine große
Rolle bei der Induktion der CXCL10-Genexpression in epithelialen
Zelllinien, so daß dieses Zytokin z. B. im Falle versagender
Anti-TNF-Strategien ein lohnendes Ziel für die Entwicklung
zukünftiger Therapieformen darstellt. Eine pharmakologische
Inhibitition von NF-κB durch unspezifische Inhibitoren wie PDTC als
zukünftige Therapieoption muß kritisch hinterfragt werden, da sie
im hier vorliegenden Zellmodell zu einer Verstärkung der
Interleukin-1-induzierten CXCL8-Genexpression führte, ein Phänomen,
das möglicherweise mit einer Aktivierung alternativer
inflammatorischer Signalwege gedeutet werden kann. Die Tatsache,
daß Glukokortikoide offenbar nicht wie in klassischen Immunzellen
zu einer Inhibitition von Zytokinen-stimulierter
Chemokin-Genexpression führen, trägt möglicherweise zum Phänomen
der Steroidresistenz bei Patienten mit chronisch entzündlichen
Darmerkrankungen bei.Activation of intestinal epithelial cells
(IEC) may occur either by luminal antigens stimulation or by
inflammatory signals deriving from immune cells in the close
vicinity. Production of chemokines by the intestinal epithelium
contributes to mucosal infiltration of inflammatory cells in
inflammatory bowel disease (IBD). Little is known about the
intestinal epithelial expression and secretion of CXCL10 (IP-10)
involved in recruiting T-cells and monocytes. Especially, the role
of IL-1β, one of the most abundant cytokines in IBD mucosa, has not
been established yet. We therefore aimed to evaluate the expression
and regulation of CXCL8/Interleukin-8 (IL-8) and CXCL10/Interferon
gamma regulated protein 10 kda (IP-10), two of the most abundant
chemokines in inflammatory bowel disease (IBD), in epithelial cell
lines stimulated with proinflammatory cytokines (IL-1β, IFN γ and
TNF-α). NF-κB is known to play a major role in the pathophysiology
of IBD. This makes NF-κB a potential phamocological target to treat
IBD. So we aimed at studying the effects of two inhibitors of NF-κB
on IL-1β induced CXCL8 and CXCL10 gene expression in IECs.
Glucocorticoids are known to be effective in regulating the
cytokine mediated chemokine gene expression in immune cells. These
kinds of study were lacking in relation to IECs. So we also aimed
at evaluating the role of glucocorticoids in cytokine mediated
CXCL8 and CXCL10 gene expression in IECs.
Our data demonstrate that IL-1β is a strong and early inducer of
CXCL8 gene expression and protein secretion in colonic epithelial
cells. CXCL10 gene expression can be differentially regulated by
proinflammatory cytokines and underline that the interplay between
epithelial cells and immune cells is important in intestinal
inflammation. Depending on the cellular context and utilizing the
NF-κB pathway, IL-1β alone and/or in synergism with IFNγ, may play
a major role in the induction of CXCL10 gene in IECs, suggesting
IL-1β to be a promising target in treating IBD (e.g. in case of
failing anti-TNF alpha strategies). Usage of pharmacological
inhibitors to NF-κB should be given attention, as we show that the
non specific inhibitor of NF-κB, PDTC, inhibits IL-1β induced NF-κB
activity and enhances IL-1β induced CXCL8 gene expression in a cell
specific manner, a phenomenon which might be explained by the
activation of alternative proinflammatory pathways.
Glucocorticoids, which are known to be anti-inflammatory in
function, were ineffective in inhibiting cytokine mediated CXCL8
and CXCL10 gene expression in IECs, a phenomenon which might
contribute to the known steroid unresponsiveness that occur in many
patients with IBD
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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