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13 results on '"MESH : Transforming Growth Factor beta"'

1. Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFβ signaling pathways

Author

Hélène Gilgenkrantz, Cédric Coulouarn, Sébastien Jacques, Anne Audebourg, Catherine Cavard, Florent Dumont, Christine Perret, Pierre-Alexandre Just, Bruno Clément, Benoit Terris, Laura Rubbia-Brandt, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microenvironnement et remodelage, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
MESH: Signal Transduction, Cancer Research, Pathology, MESH : Liver Neoplasms, Cellular differentiation, MESH: beta Catenin, ddc:616.07, Cholangiocarcinoma/etiology/pathology, Cholangiocarcinoma, 0302 clinical medicine, Transforming Growth Factor beta, MESH: Liver Neoplasms, MESH: Carcinoma, Hepatocellular, Wnt Signaling Pathway, beta Catenin, Hepatocyte differentiation, MESH : Prognosis, Tissue microarray, Neoplastic Stem Cells/pathology, Liver Neoplasms, MESH : Extracellular Matrix, MESH: Wnt Signaling Pathway, Wnt signaling pathway, Cell Differentiation, General Medicine, Prognosis, Extracellular Matrix, 3. Good health, Transforming Growth Factor beta/physiology, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, Wnt Signaling Pathway/physiology, Stem cell, MESH: Tissue Array Analysis, MESH : Cell Differentiation, Signal Transduction, MESH : Carcinoma, Hepatocellular, MESH: Cell Differentiation, medicine.medical_specialty, Carcinoma, Hepatocellular, MESH : Wnt Signaling Pathway, Beta Catenin/physiology, MESH: Extracellular Matrix, Biology, MESH: Prognosis, MESH: Gene Expression Profiling, 03 medical and health sciences, MESH : Neoplastic Stem Cells, medicine, Extracellular Matrix/physiology, Humans, Progenitor cell, MESH: Transforming Growth Factor beta, Progenitor, MESH : Signal Transduction, MESH: Humans, Carcinoma, Hepatocellular/etiology/pathology, Signal Transduction/physiology, Gene Expression Profiling, MESH : Gene Expression Profiling, MESH : Humans, Liver Neoplasms/etiology/pathology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Cholangiocarcinoma, MESH : beta Catenin, MESH: Cholangiocarcinoma, MESH: Neoplastic Stem Cells, Gene expression profiling, Bile Ducts, Intrahepatic, MESH : Transforming Growth Factor beta, Bile Duct Neoplasms, Tissue Array Analysis, MESH : Tissue Array Analysis
Abstract

International audience; Intrahepatic malignant tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and combined hepatocholangiocarcinomas (cHCC-CC), a group of rare and poorly characterized tumours that exhibit both biliary and hepatocytic differentiation. The aim of the study was to characterize the molecular pathways specifically associated with cHCC-CC pathogenesis. We performed a genome-wide transcriptional analysis of 20 histologically defined cHCC-CC and compared them with a series of typical HCC and of CC. Data were analysed by gene set enrichment and integrative genomics and results were further validated in situ by tissue microarray using an independent series of 152 tumours. We report that cHCC-CC exhibit stem/progenitor features, a down-regulation of the hepatocyte differentiation program and a commitment to the biliary lineage. TGFβ and Wnt/β-catenin were identified as the two major signalling pathways activated in cHCC-CC. A β-catenin signature distinct from that observed in well-differentiated HCC with mutant β-catenin was found in cHCC-CC. This signature was associated with microenvironment remodelling and TGFβ activation. Furthermore, integrative genomics revealed that cHCC-CC share characteristics of poorly differentiated HCC with stem cell traits and poor prognosis. The common traits displayed by CC, cHCC-CC and some HCC suggest that these tumours could originate from stem/progenitor cell(s) and raised the hypothesis of a potential continuum between intrahepatic CC, cHCC-CC and poorly differentiated HCC.

Published
2012
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2. Type II TGFβ receptor modulates chondrocyte phenotype

Author

Elise Duval, Sylvain Leclercq, Catherine Baugé, Philippe Galéra, Nicolas Girard, Karim Boumediene, David Ollitrault, Normandie Université ( NU ), Microenvironnement cellulaire et pathologie ( MILPAT ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Département de chirurgie orthopédique, Clinique Saint Martin, Normandie Université (NU), Microenvironnement et Pathologies du Cartilage (BioConnecT), Microenvironnement cellulaire et pathologie (MILPAT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Département de chirurgie orthopédique [Hôpital privé Saint Martin Caen], and Hôpital Privé Saint Martin Caen

Subjects
Cartilage, Articular, MESH : Bone Marrow, Aging, MESH : RNA, Messenger, MESH : Transcription Factors, MESH : Receptors, Transforming Growth Factor beta, MESH : Chondrogenesis, MESH : Alginates, MESH : Blotting, Western, Osteoarthritis, Hip, 0302 clinical medicine, MESH: Aggrecans, MESH: Osteoarthritis, MESH : Collagen Type II, Cells, Cultured, Regulation of gene expression, Aged, 80 and over, 0303 health sciences, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH: Bone Marrow Cells, Cell Differentiation, General Medicine, MESH: Transcription Factors, Middle Aged, Cell biology, MESH : Phenotype, medicine.anatomical_structure, Phenotype, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 030220 oncology & carcinogenesis, MESH: Alginates, Disease Progression, MESH: Bone Marrow, MESH: Receptors, Transforming Growth Factor beta, MESH : Cell Differentiation, MESH: Chondrogenesis, Signal Transduction, MESH: Cell Differentiation, Blotting, Western, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Phenotype, Real-Time Polymerase Chain Reaction, Chondrocyte, Article, MESH : Chondrocytes, MESH : Cartilage, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, Transforming Growth Factor beta2, Chondrocytes, MESH: Chondrocytes, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH : Aggrecans, Gene silencing, MESH: Blotting, Western, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Aggrecan, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: RNA, Messenger, Aged, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Mesenchymal stem cell, MESH : Humans, MESH: Collagen Type II, Chondrogenesis, Molecular biology, MESH : Osteoarthritis, MESH : Transforming Growth Factor beta, Gene Expression Regulation, MESH: Cartilage, Ectopic expression, Geriatrics and Gerontology, Transforming growth factor, MESH : Bone Marrow Cells
Abstract

International audience; Aging is one of the major risk factors of osteoarthritis. This pathology during which chondrocytes undergo modifications of their phenotype may result from alteration of transforming growth factor β (TGFβ) signaling. This study investigates the role of TGFβ response in the process of chondrocyte dedifferentiation/redifferentiation. Dedifferentiation was induced by successive passages of human articular chondrocytes, whereas their redifferentiation was performed by three-dimensional culture in alginate. Human mesenchymal stem cells were obtained from bone marrow and differentiated into chondrocyte-like phenotype by three-dimensional culture, embedded in the same scaffold. Protein and mRNA levels were analyzed by Western blot and real-time reverse transcription PCR. Regulatory mechanism was investigated using specific inhibitors (mithramycin), mRNA silencing or decoy oligonucleotides, and expression vectors. Chondrocyte dedifferentiation interfered with TGFβ signaling by decreasing TβRII mRNA and protein levels and subsequent TGFβ response. TβRII ectopic expression in passaged chondrocytes permitted to increase the expression of several matrix genes, such as aggrecan or type II collagen. Redifferentiation of passaged chondrocytes permitted to restore, at least in part, TβRII expression and was related to differentiation of human bone marrow mesenchymal stem cells toward chondrocytes, where both specific protein 1 (Sp1) and TβRII mRNA levels were increased. Moreover, Sp1 manipulation by silencing or ectopic expression and pharmacologic inhibition revealed a link between expression levels of this transcriptional factor, which is crucial for constitutive expression of TβRII in cartilage, and TGFβ response. Therefore, these data permit us to suggest an important role of TβRII expression in the maintenance of chondrocyte phenotype, which is altered with age, and bring new insights in our understanding of chondrogenesis process.

Published
2013
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3. Regulatory mechanism of transforming growth factor beta receptor type II degradation by interleukin-1 in primary chondrocytes

Author

Nicolas Girard, Catherine Baugé, Philippe Galéra, Sylvain Leclercq, Karim Boumediene, Microenvironnement et Pathologies du Cartilage ( BioConnecT ), Microenvironnement cellulaire et pathologie ( MILPAT ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Normandie Université ( NU ), Département de chirurgie orthopédique, Clinique Saint Martin, Microenvironnement et Pathologies du Cartilage (BioConnecT), Microenvironnement cellulaire et pathologie (MILPAT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Normandie Université (NU), Département de chirurgie orthopédique [Hôpital privé Saint Martin Caen], and Hôpital Privé Saint Martin Caen

Subjects
Nystatin, MESH : Receptors, Transforming Growth Factor beta, MESH : Caveolae, Caveolin 1, Interleukin-1beta, TGFß receptor, MESH : Blotting, Western, MESH: Down-Regulation, Bortezomib, MESH : Down-Regulation, 0302 clinical medicine, Caveolin-1, MESH: Osteoarthritis, MESH: Interleukin-1beta, Caveolae, Internalization, Lipid raft, MESH : Polymerase Chain Reaction, Cells, Cultured, media_common, Aged, 80 and over, 0303 health sciences, biology, medicine.diagnostic_test, MESH: Proteasome Endopeptidase Complex, Interleukin, Middle Aged, Boronic Acids, Cell biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Biochemistry, MESH: Caveolae, Pyrazines, Turnover regulation, MESH: Receptors, Transforming Growth Factor beta, Proteasome Inhibitors, MESH : Protein-Serine-Threonine Kinases, Proteasome Endopeptidase Complex, media_common.quotation_subject, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: transforming growth factor-beta type II receptor, Protein Serine-Threonine Kinases, MESH: Protein-Serine-Threonine Kinases, MESH : Interleukin-1beta, MESH : Chondrocytes, MESH : Cartilage, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, Chondrocytes, Western blot, MESH: Chondrocytes, Osteoarthritis, medicine, MESH : Proteasome Endopeptidase Complex, MESH: Blotting, Western, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Transforming Growth Factor beta, Aged, 030304 developmental biology, MESH : transforming growth factor-beta type II receptor, Proteasome, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Receptor, Transforming Growth Factor-beta Type II, MESH: Polymerase Chain Reaction, Biological Transport, MESH : Lipids, Cell Biology, Transforming growth factor beta, MESH: Lipids, MESH : Osteoarthritis, MESH : Transforming Growth Factor beta, MESH: Cartilage, Proteolysis, biology.protein, Lysosomes, Receptors, Transforming Growth Factor beta, 030217 neurology & neurosurgery, Interleukin-1
Abstract

International audience; Interleukin-1β (IL-1β), a key-cytokine in osteoarthritis, impairs TGFβ signaling through TβRII down-regulation by increasing its degradation. Here, we investigated the molecular mechanism that controls TßRII fate in IL-1ß treated cells. Chondrocytes were treated with IL-1ß in the presence of different inhibitors. TßRII and Cav-1 expression were assayed by Western blot and RT-PCR. We showed that IL-1ß-induced degradation of TßRII is dependent on proteasome and on its internalization in caveolae. In addition, IL-1ß enhances Cav-1 expression, a major constituent of lipid raft. In conclusion, we enlighten a new mechanism by which IL-1ß antagonizes TGFß pathway and propose a model of TßRII turnover regulation upon IL-1ß treatment.

Published
2012
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4. [Regulation of resting follicle activation]

Author

Gougeon , A., Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
MESH: Ovary, MESH: Signal Transduction, MESH : Ovarian Follicle, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Phosphatidylinositol 3-Kinases, Ovarian Follicle, Transforming Growth Factor beta, Humans, MESH : Female, MESH: Transforming Growth Factor beta, MESH : Ovary, MESH : Signal Transduction, MESH: Humans, Ovary, MESH : Humans, Receptor Protein-Tyrosine Kinases, MESH : Phosphatidylinositol 3-Kinases, MESH : Receptor Protein-Tyrosine Kinases, MESH: Ovarian Follicle, MESH : Transforming Growth Factor beta, MESH: Phosphatidylinositol 3-Kinases, Female, MESH: Receptor Protein-Tyrosine Kinases, MESH: Female, Signal Transduction
Abstract

International audience; In humans, folliculogenesis starts when some resting follicles leave the ovarian reserve to enter the growing phase. Activation of resting follicles remains poorly understood, however recent data show existence of a balance between activating and repressing factors. Many molecules, comprised KIT ligand, bind a protein kinase receptor and activate the phosphatidylinositol kinase (PI3K) signaling pathway, which contains enzymes and transcription factors that either stimulate or inhibit activation of resting follicles. Some inhibiting (AMH) or activating (activin, BMPs) molecules belong to the TGF-ß super-family, while others can either stimulate (LIF, androgens) or inhibit (estradiol, progesterone, somatostatin) activation of resting follicles. The understanding of molecular mechanisms controlling activation of resting follicles has significant clinical implications in mobilizing resting follicles in patients suffering from infertility due to ovarian dysfunction either spontaneous or resulting from cancer treatments.

Published
2011
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5. Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay

Author

Agnès Lehuen, Roberto Mallone, Marc Dalod, Lucie Beaudoin, Julien Diana, Anna Tafuri, Vedran Brezar, Christian Boitard, Andrew L. Mellor, Matthias von Herrath, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medical College of Georgia, Immunotherapy Center, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), La Jolla Institute for Immunology [La Jolla, CA, États-Unis], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), CHU Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), La Jolla Institute for Allergy and Immunology (LIA), La Jolla Institute for Allergy & Immunology, Université Paris Descartes - Paris 5 ( UPD5 ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and La Jolla Institute for Allergy and Immunology ( LIA )

Subjects
MESH: Interleukin-10, endocrine system diseases, Programmed Cell Death 1 Receptor, MESH: Membrane Glycoproteins, MESH : Membrane Glycoproteins, MESH: Lymph Nodes, Cell Communication, CD8-Positive T-Lymphocytes, Lymphocyte Activation, T-Lymphocytes, Regulatory, B7-H1 Antigen, MESH : Diabetes Mellitus, Type 1, MESH : T-Lymphocytes, Regulatory, Interleukin 21, Mice, 0302 clinical medicine, Transforming Growth Factor beta, immune system diseases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, IL-2 receptor, MESH : Antigens, CD80, MESH : Lymph Nodes, 0303 health sciences, Membrane Glycoproteins, MESH: Dendritic Cells, MESH : Peptides, MESH: Peptides, FOXP3, hemic and immune systems, MESH : CD8-Positive T-Lymphocytes, Natural killer T cell, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Interleukin-10, MESH: Virus Diseases, medicine.anatomical_structure, Virus Diseases, Antigens, Surface, B7-1 Antigen, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Diabetes Mellitus, Type 1, MESH : Apoptosis Regulatory Proteins, MESH : Antigens, Surface, endocrine system, MESH : Cell Communication, MESH: Antigens, Surface, T cell, Immunology, macromolecular substances, Biology, Article, 03 medical and health sciences, Islets of Langerhans, MESH: Antigens, CD80, MESH : Interleukin-10, MESH : Mice, MESH: Cell Communication, medicine, Animals, MESH : Islets of Langerhans, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH: Mice, MESH : Lymphocyte Activation, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Apoptosis Regulatory Proteins, MESH: T-Lymphocytes, Regulatory, MESH: Islets of Langerhans, Dendritic cell, Dendritic Cells, MESH : Virus Diseases, MESH : Natural Killer T-Cells, MESH : Transforming Growth Factor beta, Diabetes Mellitus, Type 1, MESH: Natural Killer T-Cells, MESH : Dendritic Cells, Natural Killer T-Cells, MESH : Animals, Lymph Nodes, Apoptosis Regulatory Proteins, Peptides, 030215 immunology
Abstract

iNKT cell and pDC cross talk prevents type 1 diabetes by inducing T reg cells in the pancreatic lymph node during viral infection., Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell–mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell–plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β–producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3+ CD4+ regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8+ T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.

Published
2011
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6. Genotype-phenotype correlations of TGFBI p.Leu509Pro, p.Leu509Arg, p.Val613Gly, and the allelic association of p.Met502Val-p.Arg555Gln mutations

Author

Niel-Butschi F, Kantelip B, Iwaszkiewicz J, Zoete V, Boimard M, Delpech M, Jl, Bourges, Renard G, D'Hermies F, Pj, Pisella, Hamel C, Delbosc B, Sophie Valleix, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Hôtel-Dieu, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Gui De Chaulliac, Service d'ophtalmologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Laboratoire de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), 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), Service d'Anatomie pathologique [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Service d'ophtalmologie [CHRU Besançon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Viala, Pascale, Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) ( CEF2P / CARCINO ), and Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté [COMUE] ( UBFC ) -Université de Franche-Comté ( UFC )

Subjects
Male, Models, Molecular, MESH: Extracellular Matrix Proteins, MESH : Molecular Sequence Data, MESH : Algeria, Genetic Linkage, MESH : Genotype, MESH: Amino Acid Sequence, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, MESH: Aged, 80 and over, Gene Frequency, Transforming Growth Factor beta, MESH : Gene Frequency, MESH : Female, Bowman Membrane, MESH: Genetic Association Studies, Aged, 80 and over, Corneal Dystrophies, Hereditary, Extracellular Matrix Proteins, MESH: Middle Aged, MESH : Amino Acid Sequence, MESH : Infant, Middle Aged, MESH : Adult, MESH: Infant, Pedigree, MESH : Phenotype, Phenotype, Female, France, MESH : Mutation, MESH: Algeria, MESH: Models, Molecular, Research Article, Adult, MESH: Mutation, Genotype, MESH: Pedigree, MESH : Models, Molecular, MESH : Bowman Membrane, MESH : Male, Molecular Sequence Data, MESH: Genetic Linkage, MESH: Corneal Dystrophies, Hereditary, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Phenotype, MESH : Extracellular Matrix Proteins, [SDV.CAN] Life Sciences [q-bio]/Cancer, Algeria/ethnology, Alleles, Amino Acid Sequence, Bowman Membrane/metabolism, Bowman Membrane/pathology, Corneal Dystrophies, Hereditary/classification, Corneal Dystrophies, Hereditary/epidemiology, Corneal Dystrophies, Hereditary/ethnology, Corneal Dystrophies, Hereditary/genetics, Corneal Dystrophies, Hereditary/pathology, Extracellular Matrix Proteins/genetics, Extracellular Matrix Proteins/metabolism, France/epidemiology, Genetic Association Studies, Humans, Infant, Mutation, Transforming Growth Factor beta/genetics, Transforming Growth Factor beta/metabolism, MESH: Gene Frequency, MESH : Middle Aged, MESH : Aged, 80 and over, MESH : France, MESH: Transforming Growth Factor beta, MESH: Humans, MESH: Molecular Sequence Data, MESH: Alleles, MESH : Humans, MESH: Adult, MESH : Genetic Association Studies, MESH : Genetic Linkage, MESH: Male, eye diseases, MESH: France, MESH : Transforming Growth Factor beta, Algeria, MESH : Pedigree, MESH : Corneal Dystrophies, Hereditary, MESH : Alleles, MESH: Female, MESH: Bowman Membrane
Abstract

International audience; PURPOSE: Investigate the genotype-phenotype correlations for five TGFBI (transforming growth factor, beta-induced) mutations including one novel pathogenic variant and one complex allele affecting the fourth FAS1 domain of keratoepithelin, and their potential effects on the protein's structure. METHODS: Three unrelated families were clinically diagnosed with lattice corneal dystrophy (CD) and one with an unclassified CD of Bowman's layer. Mutations in the TGFBI gene were detected by direct sequencing, and the functional impact of each variant was predicted using in silico algorithms. Corneal phenotypes, including histological examinations, were compared with the literature data. Furthermore, molecular modeling studies of these mutations were performed. RESULTS: Two distinct missense mutations affecting the same residue at position 509 of keratoepithelin: p.Leu509Pro (c.1526T>C) and p.Leu509Arg (c.1526T>G) were found to be associated with a lattice-type CD. The novel p.Val613Gly (c.1828T>G) TGFBI mutation was found in a sporadic case of an Algerian individual affected by lattice CD. Finally, the Bowman's layer CD was linked to the association in cis of the p.Met502Val and p.Arg555Gln variants, leading to the reclassification of this CD as atypical Thiel-Behnke CD. Structural modeling of these TGFBI mutations argues in favor of these mutations being responsible for instability and/or incorrect folding of keratoepithelin, predictions that are compatible with the clinical diagnoses. CONCLUSIONS: Description of a novel TGFBI mutation and a complex TGFBI allele further extends the mutational spectrum of TGFBI. Moreover, we show convincing evidence that TGFBI mutations affecting Leu509 are linked to the lattice phenotype in two unrelated French families, contrasting with findings previously reported. The p.Leu509Pro was reported to be associated with both amyloid and non-amyloid aggregates, whereas p.Leu509Arg has been described as being responsible for Epithelial Basement Membrane Dystrophy (EBMD).

Published
2011

7. iNKT cell development is orchestrated by different branches of TGF-beta signaling

Author

Sylvie Martel, C Garcia, Régine Losson, Jean-Marc Doisne, Farhan S. Cyprian, Nadia Duarte, Kamel Benlagha, Kai-Ping Yan, Jean-Benoît Le Luduec, Laurent Bartholin, Julien C. Marie, Branka Horvat, David F. Vincent, Ruth Rimokh, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Immunologie, génétique et traitement des maladies métaboliques et du diabète ( UMR_S 561 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), École normale supérieure - Lyon ( ENS Lyon ) -IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunité infection vaccination ( I2V ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), and Peney, Maité

Subjects
MESH: Signal Transduction, MESH : Transcription Factors, MESH : Receptors, Transforming Growth Factor beta, MESH: Spleen, Cellular differentiation, Apoptosis, MESH: T-Lymphocyte Subsets, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, Transforming Growth Factor beta, MESH: Smad4 Protein, Immunology and Allergy, MESH: Animals, Smad4 Protein, 0303 health sciences, biology, Stem Cells, Cell Differentiation, MESH: Transcription Factors, Natural killer T cell, MESH : Mice, Transgenic, Cell biology, MESH: Interleukin-2 Receptor beta Subunit, MESH : Stem Cells, MESH: Receptors, Transforming Growth Factor beta, Stem cell, Signal transduction, MESH : Cell Differentiation, Signal Transduction, MESH : Spleen, MESH: Cell Differentiation, MESH: T-Box Domain Proteins, MESH: Mice, Transgenic, Immunology, MESH : Cell Lineage, Mice, Transgenic, MESH: Stem Cells, Article, 03 medical and health sciences, MESH : Mice, TGF beta signaling pathway, Animals, Cell Lineage, Transcription factor, MESH: Mice, MESH: Transforming Growth Factor beta, MESH : Interleukin-2 Receptor beta Subunit, 030304 developmental biology, MESH : Signal Transduction, Cell growth, MESH: Apoptosis, MESH : Smad4 Protein, Transforming growth factor beta, MESH: Cell Lineage, MESH : Natural Killer T-Cells, MESH : T-Lymphocyte Subsets, Interleukin-2 Receptor beta Subunit, MESH : T-Box Domain Proteins, MESH : Transforming Growth Factor beta, MESH: Natural Killer T-Cells, biology.protein, Natural Killer T-Cells, MESH : Animals, T-Box Domain Proteins, Receptors, Transforming Growth Factor beta, Spleen, MESH : Apoptosis, Transcription Factors, 030215 immunology
Abstract

International audience; Invariant natural killer T (iNKT) cells constitute a distinct subset of T lymphocytes exhibiting important immune-regulatory functions. Although various steps of their differentiation have been well characterized, the factors controlling their development remain poorly documented. Here, we show that TGF-beta controls the differentiation program of iNKT cells. We demonstrate that TGF-beta signaling carefully and specifically orchestrates several steps of iNKT cell development. In vivo, this multifaceted role of TGF-beta involves the concerted action of different pathways of TGF-beta signaling. Whereas the Tif-1gamma branch controls lineage expansion, the Smad4 branch maintains the maturation stage that is initially repressed by a Tif-1gamma/Smad4-independent branch. Thus, these three different branches of TGF-beta signaling function in concert as complementary effectors, allowing TGF-beta to fine tune the iNKT cell differentiation program.

Published
2009
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8. [Role of the Regulatory T lymphocytes in hepatitis C fibrosis progression]

Author

Delhem, Nadira, Cottrez, Françoise, Carpentier, Arnaud, Miroux, Céline, Moralès, Olivier, François, Violaine, Groux, Hervé, Auriault, Claude, Pancré, Véronique, Institut de Biologie de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Immunosearch, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Liver Cirrhosis, MESH : Liver Neoplasms, MESH: Interleukin-10, MESH : Cytokines, Biopsy, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, MESH : Aged, MESH : T-Lymphocytes, Helper-Inducer, Hepacivirus, T-Lymphocytes, Regulatory, MESH : Hepacivirus, MESH : T-Lymphocytes, Regulatory, MESH: Biopsy, Transforming Growth Factor beta, MESH: Liver Neoplasms, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Hepacivirus, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, MESH: Carcinoma, Hepatocellular, MESH: Antigens, CD, MESH: Aged, MESH: Cytokines, MESH: Middle Aged, MESH : Immune Tolerance, Liver Neoplasms, T-Lymphocytes, Helper-Inducer, MESH : Adult, Middle Aged, Hepatitis C, Interleukin-10, MESH: Hepatitis C, Chronic, Liver, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Disease Progression, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA Primers, MESH: Disease Progression, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH: Liver Cirrhosis, MESH : Carcinoma, Hepatocellular, Adult, MESH: DNA Primers, Carcinoma, Hepatocellular, MESH: Immune Tolerance, MESH : Hepatitis C, Chronic, Antigens, CD, MESH : Interleukin-10, MESH : Antigens, CD, Immune Tolerance, MESH : Liver Cirrhosis, Humans, MESH : Middle Aged, MESH: T-Lymphocytes, Helper-Inducer, MESH: Transforming Growth Factor beta, Aged, DNA Primers, MESH: Hepatitis C, MESH: Humans, MESH: T-Lymphocytes, Regulatory, MESH : Humans, MESH : Liver, MESH: Adult, MESH : Disease Progression, MESH : Hepatitis C, Hepatitis C, Chronic, MESH : Transforming Growth Factor beta, MESH : Biopsy, MESH: Liver
Abstract

International audience; Hepatitis C virus (HCV) becomes chronic in about 85 % of infected individuals, whereas only 15 % of infected people clear spontaneously the virus. The progression of hepatitis C to chronic status is associated to a profound down-regulation of CD4 and CD8 multispecific immune response. This immune defect may participate to the immune tolerance of VHC and consequently to its persistence. Recent findings indicate that T regulatory cells as Tr1 play an inhibitory role on T helper responses notably in the context of auto-immune or inflammatory disorders. The existence of immunosuppressive mechanisms supported by Tr1 lymphocytes and their IL-10 production represent an attractive hypothesis. We have previously evaluated the existence of regulatory T cells (Tr1) via high production of IL-10, in liver biopsies of three well-defined cohorts of HCV-1b infected patients. To this purpose, we compared liver biopsies of chronically infected patients including patients without liver lesions, with cirrhosis and with hepatocellular carcinoma (HCC). Using quantitative real time PCR, the results obtained demonstrate, an increased expression of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta)_, in liver biopsies with more severe fibrosis. This observation was correlated with an increased expression during the pathogenesis progression, of the three specific markers of the Tr1 cells sub-population, recently described and confirming the Tr1 phenotype. Evidence of regulatory T cells installation in the liver of chronically infected patient and increased frequency in cirrhosis and HCC suggest a main role of these cells in the aggravation of the liver pathology. This study should bring insight of T regulatory cell implications in VHC persistence and in the pathology progression.

Published
2008
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9. Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites?

Author

Solange Bresson-Hadni, Sophie Hue, Sophie Caillat-Zucman, Shaoling Zhang, Damien Sène, Dominique A. Vuitton, Bernadette Kantelip, Alfred Penfornis, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Service d'Anatomie pathologique [CHRU Besançon], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, SERF Unit, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Université de Franche-Comté ( UFC ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), and Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)

Subjects
MESH : Host-Parasite Interactions, Genes, MHC Class I, MESH : Hepatocytes, MESH : Echinococcus multilocularis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Histocompatibility Antigens Class I, MESH: Hepatocytes, 0302 clinical medicine, Transforming Growth Factor beta, MESH : Receptors, Immunologic, Immunology and Allergy, MESH: Animals, Receptors, Immunologic, [ SDV.MP.MYC ] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 0303 health sciences, MESH: Echinococcosis, Hepatic, MESH: Genes, MHC Class I, 3. Good health, Infectious Diseases, medicine.anatomical_structure, Liver, NK Cell Lectin-Like Receptor Subfamily K, Receptors, Natural Killer Cell, MESH: NK Cell Lectin-Like Receptor Subfamily K, MESH : Histocompatibility Antigens Class I, Echinococcosis, Hepatic, T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Major histocompatibility complex, MESH: Host-Parasite Interactions, MESH : Genes, MHC Class I, Natural killer cell, Host-Parasite Interactions, MESH: Receptors, Natural Killer Cell, 03 medical and health sciences, MESH : Receptors, Natural Killer Cell, MHC class I, medicine, MESH : NK Cell Lectin-Like Receptor Subfamily K, Animals, Humans, MESH: Receptors, Immunologic, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Echinococcus multilocularis, MESH: Humans, Histocompatibility Antigens Class I, MESH : Humans, MESH : Liver, NKG2D, Molecular biology, stomatognathic diseases, MESH : Transforming Growth Factor beta, Giant cell, Immunology, biology.protein, Hepatocytes, Echinococcus multilocularis, MESH : Animals, MESH : Echinococcosis, Hepatic, CD8, 030215 immunology, Transforming growth factor, MESH: Liver
Abstract

International audience; BACKGROUND: Echinococcus multilocularis growth and persistent granuloma, which lead to the development of the severe parasitic disease alveolar echinococcosis (AE), might be caused by abnormal expression of stress-induced proteins, with subsequent abnormalities in T cell activation. Similar to its involvement in tumors, the NKG2D-major histocompatability complex class I chain-related molecules A and B (MICA/B) signaling system could be involved in host-parasite interactions; however, its involvement in helminthic diseases has never been studied. METHODS: We studied MICA/B, NKG2D, and transforming growth factor-beta (TGF-beta) expression on liver sections and measured levels of soluble MICA in serum samples obtained from patients with progressive AE. Livers from healthy and cirrhotic subjects were studied as controls. RESULTS: Expression of MICA/B proteins was strongly enhanced in the hepatocytes and endothelial and bile duct cells; in the CD68+ cells of the periparasitic infiltrate, especially epithelioid and giant cells; and, also, in the metacestode germinal layer. Strong expression of MICA/B in the liver contrasted with low numbers of NK cells and lack of expression of NKG2D on the numerous CD8+ T lymphocytes of the periparasitic infiltrate, as well as with the absence of soluble MICA in serum. TGF-beta was strongly expressed by most of the infiltrating lymphocytes. CONCLUSIONS: Sustained expression of MICA/B molecules and TGF-beta might lead to modulation of NKG2D with subsequent inhibition of NKG2D-dependent cytotoxicity. Abnormalities of this signaling system could contribute to parasitic evasion of the host's immunity.

Published
2008
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10. Transforming growth factor beta controls the directional migration of hepatocyte cohorts by modulating their adhesion to fibronectin

Author

Urszula Hibner, Fabien Binamé, Patrice Lassus, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
rac1 GTP-Binding Protein, MESH : Cell Line, MESH : Protein Subunits, Apoptosis, Cell Communication, Integrin alpha5, MESH : Hepatocytes, Epithelium, Mesoderm, MESH: Hepatocytes, Mice, 0302 clinical medicine, Cell Movement, Transforming Growth Factor beta, MESH: Fibronectins, MESH : Cell Movement, MESH : Fibronectins, MESH: Animals, MESH: Cell Movement, MESH: Mesoderm, 0303 health sciences, MESH : Gene Expression Regulation, MESH: Cell Surface Extensions, MESH : Mesoderm, Articles, Adhesion, MESH: Protein Subunits, MESH: Gene Expression Regulation, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hepatocyte, MESH: Integrin alpha5, MESH : Cell Communication, MESH : Cell Membrane, MESH : Cell Surface Extensions, Biology, Cell Line, MESH: Cell Adhesion, MESH: Gene Expression Profiling, 03 medical and health sciences, MESH : rac1 GTP-Binding Protein, MESH : Integrin alpha5, MESH: Cell Communication, MESH : Mice, Cell Adhesion, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Humans, MESH: rac1 GTP-Binding Protein, Gene Expression Profiling, MESH: Apoptosis, MESH : Gene Expression Profiling, Cell Membrane, MESH : Humans, Cell Biology, MESH : Epithelium, Fibronectins, MESH: Cell Line, Fibronectin, Protein Subunits, MESH: Epithelium, MESH : Cell Adhesion, MESH : Transforming Growth Factor beta, Gene Expression Regulation, Hepatocytes, biology.protein, Cell Surface Extensions, MESH : Animals, MESH : Apoptosis, MESH: Cell Membrane, Transforming growth factor
Abstract

International audience; Transforming growth factor beta (TGF-beta) has a strong impact on liver development and physiopathology, exercised through its pleiotropic effects on growth, differentiation, survival, and migration. When exposed to TGF-beta, the mhAT3F cells, immortalized, highly differentiated hepatocytes, maintained their epithelial morphology and underwent dramatic alterations of adhesion, leading to partial or complete detachment from a culture plate, followed by readhesion and spreading. These alterations of adhesive behavior were caused by sequential changes in expression of the alpha5beta1 integrin and of its ligand, the fibronectin. The altered specificity of anchorage to the extracellular matrix gave rise to changes in cells' collective motility: cohorts adhering to fibronectin maintained a persistent, directional motility, with ezrin-rich pathfinder cells protruding from the tips of the cohorts. The absence of adhesion to fibronectin prevented the appearance of polarized pathfinders and lead to random, oscillatory motility. Our data suggest a novel role for TGF-beta in the control of collective migration of epithelial cohorts.

Published
2008
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11. Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis

Author

E. Racadot, D. Wendling, Jean-Pierre Cedoz, Gilles Dumoulin, Agents pathogènes et inflammation - UFC (EA 4266) ( API ), Université de Franche-Comté ( UFC ), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Agents pathogènes et inflammation - UFC (EA 4266) (API), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC)

Subjects
Male, MESH : Bone Morphogenetic Protein 7, Pathology, MESH: Bone Morphogenetic Protein 7, MESH: Bone Morphogenetic Proteins, MESH: Interleukin-17, Bone Morphogenetic Protein 7, MESH : Spondylitis, Ankylosing, Bone remodeling, MESH : Bone Morphogenetic Proteins, 0302 clinical medicine, Transforming Growth Factor beta, MESH : Female, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Interleukin-17, MESH : Adult, MESH: Spondylitis, Ankylosing, MESH : Bone Remodeling, Bone morphogenetic protein 7, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Bone Morphogenetic Proteins, Female, Interleukin 17, Bone Remodeling, Adult, medicine.medical_specialty, MESH : Male, MESH : Interleukin-17, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, 03 medical and health sciences, Rheumatology, MESH: Bone Remodeling, medicine, Humans, In patient, Spondylitis, Ankylosing, Spondylitis, MESH: Transforming Growth Factor beta, 030304 developmental biology, 030203 arthritis & rheumatology, Ankylosing spondylitis, MESH: Humans, business.industry, MESH : Humans, MESH: Biological Markers, MESH: Adult, medicine.disease, MESH: Male, MESH : Biological Markers, MESH : Transforming Growth Factor beta, business, MESH: Female, Biomarkers
Abstract

International audience

Published
2007
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12. Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

Author

Nicola Marziliano, H. Plauchu, Peter N. Robinson, Catherine Boileau, Bert Callewaert, Uta Francke, P Comeglio, Christine Binquet, J. De Backer, Guillaume Jondeau, Dorothy Halliday, Christophe Béroud, Paul Coucke, A. De Paepe, Katherine Holman, Kenneth H. Mayer, B. Benetts, Andrew Biggin, Eloisa Arbustini, Hal Dietz, Anne H. Child, Gwenaëlle Collod-Béroud, Christine Muti, Laurence Faivre, Mireille Claustres, A Kiotsekoglou, Lesley C. Adès, Mine Arslan-Kirchner, Maggie Brett, Bart Loeys, Claire Bonithon-Kopp, Elodie Gautier, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Medical Genetics [Ghent], Ghent University Hospital, Howard Hughes Medical Institute (HHMI), Sonalee Laboratory for Marfan syndrome and related disorders, Department of Cardiological Sciences, St. George's Hospital Medical School, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Department of Biochemistry [Oxford], University of Oxford [Oxford], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de Génétique, Hôtel Dieu, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Discipline of Paediatrics and Child Health, The University of Sydney, Department of Molecular Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Cardiological Sciences, Saint George's Hospital Medical School, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Universitätsmedizin Charité, The Children's Hospital at Westmead, The University of Sydney [Sydney], The Children's Hospital ant Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and COLLOD-BEROUD, Gwenaëlle

Subjects
Marfan syndrome, Proband, Male, MESH: Epidermal Growth Factor, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Bioinformatics, Severity of Illness Index, Marfan Syndrome, MESH: Protein Structure, Tertiary, MESH : Exons, 0302 clinical medicine, Transforming Growth Factor beta, Genotype, Missense mutation, MESH : Female, Genetics(clinical), Ectopia lentis, Genetics (clinical), MESH : Epidermal Growth Factor, Genetics, 0303 health sciences, MESH : Prognosis, Microfilament Proteins, Exons, MESH : Adult, Prognosis, 3. Good health, MESH : Phenotype, Phenotype, Mutation (genetic algorithm), MESH : Severity of Illness Index, Female, MESH : Mutation, Haploinsufficiency, MESH : Protein Structure, Tertiary, Adult, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, MESH : Male, Biology, MESH: Phenotype, Fibrillins, MESH: Prognosis, Article, MESH: Marfan Syndrome, MESH: Microfilament Proteins, 03 medical and health sciences, MESH : Adolescent, MESH: Severity of Illness Index, medicine, Humans, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, Epidermal Growth Factor, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, Protein Structure, Tertiary, MESH : Transforming Growth Factor beta, Inframe Mutation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Exons, MESH: Female
Abstract

International audience; Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

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13. Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression

Author

Bernhard Ryffel, Simon C. Robson, Sylvain Ladoire, Jean René Pallandre, François Ghiringhelli, Lionel Apetoh, Frédérique Végran, Aziz Hichami, Angélique Chevriaux, Gérard Eberl, Christophe Borg, Julie Vincent, Cédric Rébé, Grégoire Mignot, David Masson, Fanny Chalmin, Valentin Derangère, Mélanie Bruchard, 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 ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Department of Medicine and Surgery, Harvard Medical School [Boston] ( HMS ) -Beth Israel Deaconess Medical Centre-Liver Center and Transplantation Institute, Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Immunologie et embryologie moléculaires ( IEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), 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), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Centre-Liver Center and Transplantation Institute, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Adoptive cell transfer, MESH : Transcription Factors, Cellular differentiation, MESH: Th17 Cells, T-Lymphocytes, Cell, MESH : Promoter Regions, Genetic, MESH : RNA, Small Interfering, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Transforming Growth Factor beta, MESH: RNA, Small Interfering, MESH : STAT3 Transcription Factor, Immunology and Allergy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Ectonucleotidase, MESH: Animals, RNA, Small Interfering, STAT3, MESH: Lymphocytes, Tumor-Infiltrating, Promoter Regions, Genetic, MESH: Antigens, CD, 5'-Nucleotidase, Regulation of gene expression, Mice, Knockout, 0303 health sciences, MESH : Gene Expression Regulation, Apyrase, MESH: STAT3 Transcription Factor, MESH: Transcription Factors, MESH: Gene Expression Regulation, MESH : Mice, Transgenic, Cell biology, MESH : Lymphocytes, Tumor-Infiltrating, DNA-Binding Proteins, MESH : Apyrase, Infectious Diseases, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : DNA-Binding Proteins, MESH: Apyrase, STAT3 Transcription Factor, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : Interleukin-6, MESH: Mice, Transgenic, T cell, Immunology, Mice, Transgenic, MESH : Mice, Inbred C57BL, Biology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, MESH: Mice, Inbred C57BL, Antigens, CD, MESH: Promoter Regions, Genetic, MESH : 5'-Nucleotidase, MESH : Mice, medicine, MESH : Antigens, CD, MESH : Th17 Cells, Animals, Transcription factor, MESH: Mice, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH : T-Lymphocytes, Binding Sites, Interleukin-6, MESH: Interleukin-6, Mice, Inbred C57BL, MESH: T-Lymphocytes, MESH : Transforming Growth Factor beta, MESH: Binding Sites, Gene Expression Regulation, biology.protein, MESH : Mice, Knockout, Th17 Cells, MESH : Animals, MESH: 5'-Nucleotidase, MESH: DNA-Binding Proteins, MESH : Binding Sites, 030215 immunology, Transcription Factors
Abstract

International audience; Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.

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