Airway epithelial IL-15 transforms monocytes into dendritic cells.

IL-15 has recently been shown to induce the differentiation of functional dendritic cells (DCs) from human peripheral blood monocytes. Since DCs lay in close proximity to epithelial cells in the airway mucosa, we investigated whether airway epithelial cells release IL-15 in response to inflammatory stimuli and thereby induce differentiation and maturation of DCs. Alveolar (A549) and bronchial (BEAS-2B) epithelial cells produced IL-15 spontaneously and in a time- and dose-dependent manner after stimulation with IL-1beta, IFN-gamma, or TNF-alpha. Airway epithelial cell supernatants induced an increase of IL-15Ralpha gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15Ralpha gene expression up to 300-fold. Airway epithelial cell-conditioned media induced the differentiation of ex vivo monocytes into partially mature DCs (HLA-DR+, DC-SIGN+, CD14+, CD80-, CD83+, CD86+, CCR3+, CCR6(+), CCR7-). Based on their phenotypic (CD123+, BDCA2+, BDCA4+, BDCA1(-), CD1a-) and functional properties (limited maturation upon stimulation with LPS and limited capacity to induce T cell proliferation), these DCs resembled plasmacytoid DCs. The effects of airway epithelial cell supernatants were largely blocked by a neutralizing monoclonal antibody to IL-15. Thus, our results demonstrate that airway epithelial cell-conditioned media have the capacity to differentiate monocytes into functional DCs, a process substantially mediated by epithelial-derived IL-15.

Type I IFN-mediated regulation of IL-1 production in inflammatory disorders.

Although contributing to inflammatory responses and to the development of certain autoimmune pathologies, type I interferons (IFNs) are used for the treatment of viral, malignant, and even inflammatory diseases. Interleukin-1 (IL-1) is a strongly pyrogenic cytokine and its importance in the development of several inflammatory diseases is clearly established. While the therapeutic use of IL-1 blocking agents is particularly successful in the treatment of innate-driven inflammatory disorders, IFN treatment has mostly been appreciated in the management of multiple sclerosis. Interestingly, type I IFNs exert multifaceted immunomodulatory effects, including the reduction of IL-1 production, an outcome that could contribute to its efficacy in the treatment of inflammatory diseases. In this review, we summarize the current knowledge on IL-1 and IFN effects in different inflammatory disorders, the influence of IFNs on IL-1 production, and discuss possible therapeutic avenues based on these observations.

La fortuna di Luciano nel Rinascimento : il volgarizzamento del manoscritto Vaticano Chigiano L.VI.215 : edizione critica dei volgarizzamenti delle "Storie vere"

Résumé II lavoro verte sui volgarizzamenti quattro-cinquecenteschi di Luciano di Samosata, importante capitolo nella fortuna dell'autore greco, che diede l'avvio a quel vasto fenomeno chiamato "lucianesimo", esteso in Europa fino al XIX sec. In particolare fornisco l'edizione critica e commentata delle Storie vere volgarizzate, contenute nella prima, assai ampia (41 opuscoli), e per molto tempo unica, silloge lucianea in volgare, che ho datato a poco prima del 1480. Essa ci è giunta tramite un unico manoscritto, il Vaticano Chigiano L.VI.215, confezionato a Ferrara per Ercole I d'Este, nonché in almeno otto edizioni veneziane apparse fra il 1525 e il 1551. La princeps, da cui dipendono in vario modo tutte le edizioni successive, è pubblicata da Niccolò Zoppino. I1 ms. e le prime due edizioni (1525; 1527 Bindoni e Pasini) tacciono il nome del traduttore, che compare solo nell'edizione del 1529 (Zoppino): Niccolò Leoniceno (1428-1524), medico umanista e valente grecista, attivo a Ferrara dal 1464 al 1524, studioso e traduttore di Ippocrate e Galeno, editore di Aristotele e volgarizzatore di storici per Ercole d'Este. L'edizione ha richiesto uno studio preliminare sulle numerose traduzioni in latino e in volgare di Luciano, per valutare meglio le modalità della sua fortuna umanistica. Confrontando ms. e stampe, per le Storie vere si hanno due volgarizzamenti totalmente diversi, fin dal titolo: La vera historia nel ms., Le vere narrazioni nelle cinquecentine. Ma per l'ultimo quarto di testo, ms. e stampe in sostanza coincidono. La collazione ha coinvolto anche il testo greco (con gli apparati delle edizioni critiche) e la versione latina dell'umanista umbro Lilio Tifernate (1417/18-1486) risalente al 1439-43 ca., intitolata De veris narrationibus, di cui si hanno almeno tre redazioni d'autore; una quarta è invece dovuta probabilmente a Benedetto Bordon, che la inserì nella sua silloge latina di Luciano del 1494. Ho cosa stabilito che il volgarizzamento del ms. Chigiano, La vera historia, è stato eseguito direttamente dal greco, fatto eccezionale nel panorama delle traduzioni umanistiche, mentre quello a stampa, Le vere narrazioni, deriva dalla redazione Bordon del De veris narrationibus. La diversità dei titoli dipende dalle varianti dei codici greci utilizzati dai traduttori: il Vat. gr. 1323, o una sua copia, è utilizzato sia dal volgarizzatore del Chigiano, sia da Bordon, indipendentemente l'uno dall'altro; il Marc. gr. 434, o una sua copia, dal Tifernate. Il titolo latino mantenuto da Bordon risale al Tifernate. Per quanto riguarda l'attribuzione dei due volgarizzamenti, come già per altri due testi della silloge da me studiati (Lucio 01 Asino e Timone), anche per La vera historia del Chigiano è accettabile il nome di Niccolò Leoniceno, poiché: 1) essa è tradotta direttamente dal greco, correttamente e con buona resa in volgare, 2) Paolo Giovio -che conobbe di persona il Leoniceno -, negli Elogia veris clarorum virorum imaginibus apposita ricorda che i volgarizzamenti di Luciano e di Dione eseguiti dal Leoniceno piacquero molto ad Ercole d'Este, 3) nessuno nella prima metà del sec. XVI rivendica, per sé o per un suo maestro, il volgarizzamento di Luciano. Le vere narrazioni a stampa, tradotte dal latino del Bordon, dopo il 1494 e prima del 1525, per la parte che diverge dalla Vera historia rimangono invece anonime. Dato che si tratta di due volgarizzamenti distinti, ho allestito l'edizione a fronte dei due testi fin dove essi divergono, seguendo per l'uno il ms., per l'altro la princeps; per la parte finale, in cui confluiscono, mi baso invece sul manoscritto e relego in apparato le varianti più vistose della princeps (non è emerso un chiaro rapporto di dipendenza fra i due testimoni). Oltre all'apparato critico con le lezioni rifiutate, fornisco un commento con la giustificazione delle scelte e il confronto con i corrispondenti passi greci e latini.

Fallait-il le rêver pour oser le réaliser?

(Résumé de l'ouvrage) La question du rêve est part intégrante de la question de la religion et intéresse de ce fait au plus haut point l'histoire comparée des religions. Non seulement les rêves ont-ils souvent été à l'origine d'une religion, mais ils sont fréquemment un de ses vecteurs principaux. En incluant la dimension onirique comme un élément constitutif du religieux et en développant des méthodes pour l'investiguer, le présent ouvrage se propose de montrer le lien consubstantiel entre religion et rêve. Les études réunies sont issues du colloque Rêves, visions révélatrices: réception et interprétation des songes dans le contexte religieux qui a eu lieu à Lausanne les 7 et 8 décembre 2000. Elles offrent des réflexions et des visions sur les rêves portant sur différentes traditions religieuses et faisant recours à des approches méthodologiques variées. L'ensemble des contributions tente de répondre à la double exigence de l'histoire des religions qui, tout en investissant un contexte religieux spécifique, se donne les moyens de réfléchir le rêve en lien à la religion dans une perspective comparative.

Prescription de statines en prévention primaire: quel score de risque cardiovasculaire faut-il utiliser en Suisse? [Statin prescription in primary prevention: which cardiovascular risk score should be used in Switzerland?]

La prévention primaire des maladies cardiovasculaires par les médecins s'effectue par une prise en charge individualisée des facteurs de risque. L'indication à un traitement par statines se base sur une estimation du risque de survenue d'une maladie cardiovasculaire et sur le taux de LDL-cholestérol. Trois scores de risque sont couramment utilisés: le score PROCAM, le score Framingham, et le SCORE européen. En Suisse, le Groupe Suisse Lipides et Athérosclérose (GSLA) recommande en première instance l'utilisation du score PROCAM avec une adaptation du niveau de risque pour la Suisse. Une enquête a aussi montré que c'est le score le plus utilisé en Suisse. Dans cet article, les particularités de ces scores et leurs applications pratiques en ce qui concerne la prescription de statines en prévention primaire sont discutées. Les conséquences et les bénéfices potentiels de l'application de ces scores en Suisse sont également abordés. [Abstract] Primary prevention of cardiovascular disease by physicians is achieved by management of individual risk factors. The eligibility for treatment with statins is based on both an estimate of the risk of developing cardiovascular disease and the LDL-cholesterol. Three risk scores are commonly used : the PROCAM score, the Framingham score, and the European score. In Switzerland, the Swiss Group Lipids and Atherosclerosis (GSLA) recommends to use the PROCAM score with an adjustment of the level of risk for Switzerland. A survey also showed that PROCAM is the most used in Switzerland. In this article, the differences of these scores and their practical applications regarding the prescription of statins in primary prevention are discussed. The consequences and potential benefits of applying these scores in Switzerland are also discussed.

Indice forensique incriminant: l'accusé a-t-il intérêt à se taire ?

Quel défenseur ne s'est pas senti désarmé par les résultats d'une¦expertise ADN rapportant une correspondance entre une trace¦trouvée sur une scène de crime et son client? Ce sentiment est¦largement répandu auprès des avocats pénalistes. Souvent, la bataille¦n'est pourtant pas perdue à ce stade, comme l'illustrent¦deux arrêts récents du Tribunal pénal fédéral, et l'accusé n'a pas¦toujours intérêt à se taire face à des indices forensiques incriminants.

The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis.

The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell-dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6-dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.

Carriers of the fragile X mental retardation 1 (FMR1) premutation allele present with increased levels of cytokine IL-10.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited late-onset neurodegenerative disorder, characterized both by neurological and cognitive deficits. It is caused by the expansion of CGG repeats (55 to 200 repeats) in the noncoding region of the fragile X mental retardation 1 (FMR1) gene. Abnormal immunological patterns are often associated with neurodegenerative disorders and implicated in their etiology. We therefore investigated the immune status of FXTAS patients, which had not been assessed prior to this study. METHOD: Peripheral blood mononuclear cells (PBMCs) were collected from 15 asymptomatic FMR1 premutation carriers and 20 age-matched controls. Concentrations of three cytokines (IL-6, IL-8, IL-10) were measured in PBMC supernatants using ELISA assays. RESULTS: We found a significant increase in the concentration of the major anti-inflammatory cytokine IL-10 in supernatants of PBMCs derived from premutation carriers, when compared with controls (P = 0.019). This increase correlated significantly with the number of CGG repeats (P = 0.002). CONCLUSIONS: Elevated IL-10 levels were observed in all premutation carriers, before appearance of the classical neurological symptoms; therefore, IL-10 may be one of the early biomarkers of FXTAS.

Interleukins (IL)-1 and IL-2 control IL-2 receptor alpha and beta expression in immature thymocytes.

Functional high-affinity interleukin-2 receptors (IL-2R) contain three transmembrane proteins, IL-2R alpha, beta and gamma. We have investigated the expression of IL-2R alpha and beta genes in immature mouse thymocytes. Previous work has shown that during differentiation these cells transiently express IL-2R alpha on their surface. Stimulation of IL-2R alpha+ and IL-2R alpha- immature thymocytes with phorbol 12-myristate 13-acetate and calcium ionophore induces synthesis of IL-2R alpha and IL-2R beta mRNA. Most of this response depends on autocrine stimulation by IL-2. IL-1 synergizes with IL-2 to induce a 120-fold increase in IL-2R alpha mRNA and a 14-fold increase in IL-2R beta mRNA levels. A large proportion of the stimulated cells contains both transcripts. These interleukins do not induce any differentiation to more mature phenotypes. Collectively, these results show that IL-2 plays a major role in the regulation of IL-2R expression in normal immature thymocyte. We suggest that this response to interleukins may be part of a homeostatic mechanism to increase the production of immature thymocytes during stress.

[Phot. des membres de la mission envoyée à l'île Saint-Paul pour y observer le passage de Vénus en 1874, don de Charles Vélain. Il s'agit en réalité de la reproduction d'un cliché offert par Ernest Mouchez à Auguste Daubrée]

Donateur : Daubrée, Auguste (1814-1896)

Enhanced excitation-coupled Ca(2+) entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease.

Prolonged depolarization of skeletal muscle cells induces entry of extracellular calcium into muscle cells, an event referred to as excitation-coupled calcium entry. Skeletal muscle excitation-coupled calcium entry relies on the interaction between the 1,4-dihydropyridine receptor on the sarcolemma and the ryanodine receptor on the sarcoplasmic reticulum membrane. In this study, we directly measured excitation-coupled calcium entry by total internal reflection fluorescence microscopy in human skeletal muscle myotubes harbouring mutations in the RYR1 gene linked to malignant hyperthermia (MH) and central core disease (CCD). We found that excitation-coupled calcium entry is strongly enhanced in cells from patients with CCD compared with individuals with MH and controls. Furthermore, excitation-coupled calcium entry induces generation of reactive nitrogen species and enhances nuclear localization of NFATc1, which in turn may be responsible for the increased IL-6 released by myotubes from patients with CCD.