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1. The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development

Author

Arlette Hammann, Eric Solary, Oleg N. Demidov, Gaëtan Jego, Robinet E, A. Seignez, Sarah Richaud, Anastasia R. Goloudina, Evelyne Kohli, Magali Svrcek, Carmen Garrido, Eric Fourmaux, Deepti A, Anne-Laure Joly, Sophie Hébrard, Ada Collura, Elise Schmitt, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)

Subjects
0301 basic medicine, X-Box Binding Protein 1, Cancer Research, Lactams, Macrocyclic, RNA Splicing, T-Cells, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Hsp90 inhibitor, 03 medical and health sciences, Mice, Sensitivity, Inflammatory-Bowel-disease, Genetics, medicine, Benzoquinones, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neural progenitor cells, HSP90 Heat-Shock Proteins, Intestinal Mucosa, Stem Cell Niche, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Leukemia, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Bone-Marrow-Transplantation, Molecules, medicine.disease, Stem cell niche, 3. Good health, Ire1-Alpha, Intestines, Mice, Inbred C57BL, 030104 developmental biology, Graft-versus-host disease, Er Stress, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cytoprotection, Immunology, Multiple-Myeloma, Female
Abstract

IF 7.932; International audience; Graft versus host disease (GvHD), which is the primary complication of allogeneic bone marrow transplantation, can alter the intestinal barrier targeted by activated donor T-cells. Chemical inhibition of the stress protein HSP90 was demonstrated in vitro to inhibit T-cell activation and to modulate endoplasmic reticulum (ER) stress to which intestinal cells are highly susceptible. Since the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17AAG) is developed in clinics, we explored here its ability to control intestinal acute GvHD in vivo in two mouse GvHD models (C57BL/6 -> BALB/c and FVB/N -> Lgr5-eGFP), ex vivo in intestine organoids and in vitro in intestinal epithelial cultures. We show that 17AAG decreases GvHD-associated mortality without impairing graft versus leukemia effect. While 17AAG effect in T-cell activation is just moderate at the dose used in vivo, we observe a striking intestinal integrity protection. At the intestine level, the drug promotes the splicing of the transcription factor X-box binding protein 1 (XBP1), which is a key component of the ER stress. This effect is associated with a decrease in intestinal damage and an increase in Lgr5(+) stem cells, Paneth cells and defensins production. The importance of XBP1 splicing control is further confirmed in cultured cells and organoids of primary intestinal epithelium where XBP1 is either shRNA depleted or inhibited with toyocamycin. In conclusion, 17AAG has a protective effect on the epithelial intestinal barrier in mouse models of acute GvHD. This compound deserves to be tested in the therapeutic control of acute GvHD.

Published
2016
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2. Human T cells require IL-2 but not G1/S transition to acquire susceptibility to Fas-mediated apoptosis

Author

Sylvie Fournel, Genestier, L., Robinet, E., Flacher, M., and Revillard, J. P.

Subjects
Immunology, Immunology and Allergy
Abstract

The interaction between Fas ligand and Fas, both expressed on activated T cells, is the major pathway in the regulation of activation-induced cell death. However, activated T cells that express membrane Fas are initially resistant to anti-Fas-induced apoptosis and become susceptible only after proliferation in vitro. Since IL-2 is known to regulate activation-induced cell death, we studied the effect of IL-2 on anti-Fas-mediated apoptosis. Interference with the IL-2 pathway was achieved by 1) inhibition of cytokine synthesis using cyclosporin A or FK506, 2) neutralization of IL-2 by anti-IL-2 Ab, 3) inhibition of binding to IL-2R by CD25 mAb, and 4) blocking of IL-2R signaling by rapamycin. We show that Fas expression is independent of the IL-2 pathway, whereas Fas-mediated apoptosis does not develop in the presence of inhibitors of IL-2 production or signaling. While the addition of rIL-2 reversed the inhibitory effect of cyclosporin A and FK506, the addition of rIL-4, rIL-7, or rIFN-gamma did not, although these cytokines induced progression into the S phase of the cell cycle. Aphidicolin-treated activated T cells that do not progress into the S phase were susceptible to Fas-mediated apoptosis. Therefore, Fas-mediated apoptosis is controlled by signals generated by IL-2 in agreement with the reported alteration of apoptosis in mice deficient in IL-2 or IL-2R.

Published
1996
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3. A noncomitogenic CD2R monoclonal antibody induces apoptosis of activated T cells by a CD95/CD95-L-dependent pathway

Author

Fournel, S., Robinet, E., Nathalie Bonnefoy, Assossou, O., Flacher, M., Waldmann, H., Bismuth, G., and Revillard, Jp

Subjects
Fas Ligand Protein, Membrane Glycoproteins, T-Lymphocytes, Immunology, CD2 Antigens, Antibodies, Monoclonal, chemical and pharmacologic phenomena, hemic and immune systems, Apoptosis, Lymphocyte Activation, biological factors, hemic and lymphatic diseases, Immunology and Allergy, Humans, fas Receptor, biological phenomena, cell phenomena, and immunity, Cells, Cultured, Signal Transduction
Abstract

Clonal expansion of activated T and B cells is controlled by homeostatic mechanisms resulting in apoptosis of a large proportion of activated cells, mostly through interaction between CD95 (Fas or Apo-1) receptor and its ligand CD95-L. CD2, which is considered as a CD3/TCR alternative pathway of T cell activation, may trigger activation-induced cell death, but the role of CD95/CD95-L interaction in CD2-mediated apoptosis remains controversial. We show here that the CD2R mAb YTH 655.5, which does not induce comitogenic signals when associated with another CD2 mAb, triggers CD95-L expression by preactivated but not resting T cells, resulting in CD95/CD95-L-mediated apoptosis. The critical role of CD95/CD95-L interaction was supported by complete inhibition in the presence of the antagonist CD95 mAb ZB4 and by blocking CD95-L synthesis and surface expression by cycloheximide, cyclosporin A, EGTA, or cytochalasin B. YTH 655.5 was shown to stimulate p56lck phosphorylation and enzymatic activity. However, p56lck activation is not sufficient to trigger apoptosis, because other CD2R and CD4 mAbs that activate p56lck do not induce apoptosis. In conclusion, CD2 can mediate nonmitogenic signals, resulting in CD95-L expression and apoptosis of CD95+ cells.

Published
1998

5. The bacterial cytolethal distending toxin: a nuclease inducing indirect DNA double-strand breaks into eukaryotic cells

Author

Bezine, E., Fedor, Y., Julien Vignard, Boutet-Robinet, E., Salles, B., Mirey, G., ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Génotoxicité & Signalisation (ToxAlim-GS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Contaminants & Stress Cellulaire (ToxAlim-COMICS), and EMBO. DEU.

Subjects
[SDV]Life Sciences [q-bio]
Abstract

National audience; The cytolethal distending toxin (CDT) is produced by many pathogenic Gram-minus bacteria like Escherichia coli, Helicobacter hepaticus, Haemophilus ducreyi, Salmonella typhi and others. In vivo, the production of CDT by Helicobacter hepaticus induces the development of dysplastic liver nodules, thus defining CDT as a potential carcinogen. Ex vivo, CdtB, the catalytic sub-unit of CDT, is relocated into the eukaryotic cell nucleus. There, CDT induces DNA double-stranded breaks (DSBs), leading to cell cycle arrest and cell death. However, after years of study, the CDT mode of action only begins to be unrevealed and many aspects remain to be studied. To better characterize the CDT-induced DNA lesions, we are studying the biochemistry of CDT, specifically regarding its catalytic nuclease activity and relate these aspects to the overall cellular effects of the toxin. Based on the literature and on the structural homology of CdtB with the DNase I, we developed several CDT mutants for specific residues involved in the catalytic activity. The DNA binding and the nuclease activities of CdtB are studied by in vitro tests, like Supercoiled DNA cleavage and DNA binding assay. Ex vivo, CDT-induced DNA damage and the activation of specific DNA damage response (DDR) pathways have been characterized. Thanks to comet assay and immunofluorescence staining, we have shown that, depending on the CDT dose, DSBs (high doses) or SSBs (moderate doses) will be induced, the later degenerating into DSBs following the replication. In fact, after a treatment with moderate doses, CDT-induced DNA damages cause the activation of the DDR involving the RPA, ATR and CHK1 proteins, characteristic of a replicative stress. The activation of the ATM pathway, due to DSBs induction, occurs later during CDT treatment. The importance of the S-phase passage for the CDT cytotoxicity suggests that proliferating cells are more sensitive to CDT than quiescent cells. The presence of unrepaired damage can lead to cell death, whereas effective repair will allow cells to resume cell cycle. However, improper repair of DNA damage can induce genetic instability and lead to cancer. Bacterial niches containing CDT producing strains are located at epithelia that are quick renewal tissues. Understanding the effects of CDT at the cellular level is an essential step in order to understand these effects at the tissue and/or organism level as well as CDT’s involvement in bacteria pathogenicity.

6. Serum interleukin-12 levels in patients undergoing allogeneic or autologous bone marrow transplantation

Author

bernard bonnotte, Am, Burdiles, Chehimi J, Carayol G, Pardoux C, Py, Dietrich, Kubin M, Jy, Blay, Caignard A, Ibrahim A, Robinet E, Hayat M, Jl, Pico, Jh, Bourhis, and Chouaib S

Subjects
Adult, Male, Adolescent, Hepatic Veno-Occlusive Disease, Graft vs Host Disease, Middle Aged, Infections, Interleukin-12, Transplantation, Autologous, Methotrexate, Child, Preschool, Cyclosporine, Humans, Transplantation, Homologous, Female, Child, Immunosuppressive Agents, Bone Marrow Transplantation
Abstract

Cytokines may be helpful in promoting hematopoietic reconstitution but have also an impact on the cellular interactions that contribute to GvHD and immunologic graft rejection. Because IL-12 is emerging as a central cytokine in immune response, we have investigated its levels in serum samples of patients undergoing bone marrow transplantation and transplant-related events. A double-antibody radioimmunoassay method for monitoring levels of endogenous IL-12, before and after allogeneic (27 patients) or autologous (19 patients) bone marrow transplantation, was used. The serum levels of IL-12 after allogeneic BMT were found to be relatively low (140-300 pg/ml) and similar to the IL-12 levels in the healthy donors (183 pg/ml). Seric IL-12 levels following autologous BMT (350 pg/ml) were higher than those observed in patients receiving an allogeneic BMT and in healthy donors. Our data indicate that the occurrence of GvHD and the development of infection after allogeneic BMT are not associated with IL-12 induction which suggests a possible down-regulation due to immunosuppressive treatment.

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