1. Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs)
- Author
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Françoise Raynaud, Vassili Soumelis, Yong-Jun Liu, Réda Hadj-Slimane, Raphaël Zollinger, Yves Lepelletier, Cristina Ghirelli, Antonio Cappuccio, Olivier Hermine, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacochimie Moléculaire et Cellulaire (PMC - UMR_S 648), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), The University of Texas M.D. Anderson Cancer Center [Houston], R.Z. was supported by the European Community Sixth Framework Program (grant EXT 014162 to V.S.) and by a fellowship from the Fondation pour la Recherche Médicale (FRM). C.G. was supported by a fellowship from Association pour la Recherche contre le Cancer (ARC). A.C. was supported by a grant from Agence National pour la Recherche (ANR). Y.L. is the recipient of a grant from Association pour la Recherche contre le Cancer., We thank Zofia Maciorowski and Annick Viguier for cell sorting, and Dr J. A. Ribeil (Department of Biotherapy, Hospital Necker-Enfants Malades) for providing us with blood samples., Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Department of Immunology (FONDATION OSWALDO CRUZ), Fundação Oswaldo Cruz (FIOCRUZ), and Réseau International des Instituts Pasteur (RIIP) - Fundação Oswaldo Cruz (FIOCRUZ) - Réseau International des Instituts Pasteur (RIIP) - Fundação Oswaldo Cruz (FIOCRUZ)
- Subjects
Small interfering RNA ,[SDV]Life Sciences [q-bio] ,Immunology ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Caspase 8 ,Biochemistry ,CFLAR ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Humans ,Autocrine signalling ,Glucocorticoids ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Toll-like receptor ,Innate immune system ,Tumor Necrosis Factor-alpha ,Toll-Like Receptors ,Interferon-alpha ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Dendritic Cells ,Cell Biology ,Hematology ,Cell biology ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Proto-Oncogene Proteins c-bcl-2 ,Toll-Like Receptor 7 ,Toll-Like Receptor 9 ,Tumor necrosis factor alpha ,030215 immunology - Abstract
Microbial infection triggers the endogenous production of immunosuppressive glucocorticoid (GC) hormones and simultaneously activates innate immunity through toll-like receptors (TLRs). How innate immune cells integrate these 2 opposing signals in dictating immunity or tolerance to infection is not known. In this study, we show that human plasmacytoid predendritic cells (pDCs) were highly sensitive to GC-induced apoptosis. Strikingly, they were protected by microbial stimulation through TLR-7 and TLR-9, but not by microbial-independent stimuli, such as interleukin-3, granulocyte macrophage colony-stimulating factor, or CD40-ligand. This protection was dependent on TLR-induced autocrine tumor necrosis factor-α and interferon-α, which collectively increased the expression ratio between antiapoptotic genes (Bcl-2, Bcl-xL, BIRC3, CFLAR) versus proapoptotic genes (Caspase-8, BID, BAD, BAX). In particular, virus-induced Bcl-2 up-regulation was dependent on autocrine interferon-α. Using small interfering RNA technology, we demonstrated that Bcl-2 and CFLAR/c-flip were essential for TLR-induced protection of pDCs from GC-induced caspase-8–mediated apoptosis. Our results demonstrate a novel property of the TLR pathway in regulating the interface between GC and innate immunity and reveal a previously undescribed mechanism of GC resistance.
- Published
- 2010