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ATP-binding cassette (ABC) transporters are a superfamily proteins that are responsible for expelling various out of the cells. They use ATPhydrolisis as energy source. Some ABC transporters play an important role in cellular detoxification because they transport many xenobiotics out of the cells: they are called MDR (Multi Drug Resistance) transporters. The laboratory is interested in antibiotic efflux. Previous work showed that ciprofloxacin, a fluoroquinolones antibiotic, was substrate for Mrp4 in mouse macrophages, while moxifloxacin, an other fluoroquinolone, was not affected by this transporter.
Because the concentration of antibiotic at its site of action determines its efficacy, the aim of this work was to study the effect of efflux transporters on cellular accumulation of antibiotic in mouse macrophages J774. During this work, I examined in particular two antibiotics: piperacillin, aβ- lactam antibiotic, for which the literature suggests it is substrate for human MRP4, and gemifloxacin, a new fluoroquinolone. Accumulation was determined using cellular models available in the laboratory: namely wild type J774 macrophages and two derived cell-lines that over express or under express Mrp4 transporter, and human THP-1 monocytes.
The results obtained with pipéracilline don’t show any role for Mrp4 in the accumulation of the antibiotic, but they suggest the implication of other transporters: like Bcrp1 and/or P-gp. The results also suggest then evolvement of influx transporters in the cellular accumulation of antibiotics.
With gemifloxacin, we showed a large accumulation in mouse macrophages and human monocytes (2 times higher than for moxifloxacine and about 7 times higher than for ciprofloxacin). Our results also suggest that gemifloxacin is an Mrp4 substrate like ciprofloxacin, because its accumulation is reduced in cells what over express Mrp4. Les transporteurs ABC (ATP Binding Cassette) forment une superfamille de protéines transmembranaires impliquées dans l’efflux de différentes molécules en utilisant l’hydrolyse de l’ATP comme source d’énergie. Certains transporteurs ABC sont particulièrement importants pour la détoxification cellulaire car ils effluent un grand nombre de xénobiotiques : ce sont les transporteurs MDR (Multi Drug Resistance). Le laboratoire s’intéresse en particulier à l’efflux des antibiotiques et a démontré que la ciprofloxacine, un antibiotique de la famille des fluoroquinolones, était substrat du transporteur Mrp4 dans des macrophages de souris alors que la moxifloxacine, une autre fluoroquinolone, n’est pas affectée par ce transporteur.
Sachant que la concentration d’un antibiotique au niveau de son site d’action conditionne son efficacité, ce travail de mémoire a pour but de mettre en évidence l’impact des transporteurs d’efflux sur l’accumulation cellulaire des antibiotiques dans les macrophages de souris J774. Au cours de ce mémoire, je me suis particulièrement intéressée à 2 antibiotiques : la pipéracilline, un antibiotique de la famille des β-lactames pour lequel la littérature suggère qu’elle serait substrat de la pompe MRP4 humaine et la gemifloxacine, une nouvelle fluoroquinolone.
Des expériences d’accumulation d’antibiotiques ont été réalisées sur les modèles cellulaires disponibles au laboratoire : les macrophages J774 sauvages et 2 lignées dérivées qui sur expriment ou sous expriment le transporteur Mrp4, ainsi que sur une lignée de monocytes humains.
Les résultats obtenus concernant la pipéracilline ne permettent pas de mettre en évidence une influence de la pompe Mrp4 de souris sur l’accumulation de cet antibiotique mais suggèrent l’implication d’autres transporteurs : Bcrp1 et/ou P-gp. Les résultats suggèrent également une implication des transporteurs d’influx dans l’accumulation cellulaire de la pipéracilline.
Concernant la gemifloxacine, nous montrons une accumulation importante dans les macrophages de souris et dans les monocytes humains ; 2 fois plus élevée que pour la moxifloxacine et environ 7 fois plus élevée que pour la ciprofloxacine. Nos résultats suggèrent cependant que la gemifloxacine soit substrat de la pompe Prp4 comme la ciproxacine , car son accumulation est réduite dans les cellules qui sur expriment Mrp4

ATP-Binding Cassette Transporters --- Drug Resistance, Multiple --- Macrophages --- ABCC4 protein, mouse --- gemifloxacin --- Piperacillin --- ABCC4 protein, human

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It has only recently been appreciated that the immune and skeletal systems have major interactions. It is now well documented that osteoclasts, which are important cellular mediators of skeletal homeostasis, are derived from hematopoietic precursors that also give rise to immune cells. In addition, numerous cytokines that were first shown to regulate immune cell function have also been demonstrated to regulate bone cells and influence skeletal health. Conversely, products of bone cells appear critical for the engraftment of marrow in bone, the normal development of the hematopoietic and immune systems and provide niche for long-term memory B and T cells. In the past scientists involved in immune and bone cell investigations have rarely interacted in a significant way as these disciplines have developed independently and, for the most part, remain separate. The conference will bring together leading international scientists from both fields to interact so that new collaboration can develop and more rapid progress in understanding the relationships between these fields can be achieved. Short talks will be selected from abstracts from the international community. This conference will have a format to provide an environment of maximum interaction and interchange through lectures, posters, and open discussion.

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