title: TLR triggering on tolerogenic dendritic cells results in TLR2 up-regulation and a reduced proinflammatory immune program.
abstract: Tolerogenic dendritic cells (TDC) offer a promising therapeutic potential to ameliorate autoimmune diseases. Reported to inhibit adaptive immune responses, little is known about their innate immunity receptor repertoire. In this study, we compared three types of human TDC (IL-10-DC, dexamethasone (DX)-DC, and 1,25(OH)(2)D(3)-DC) by their TLR expression and response to a set of TLR ligands. TDC are endowed with the same TLR set as standard monocyte-derived dendritic cells but respond differentially to the TLR stimuli Pam3CSK4, polyinosinic-polycytidylic acid, LPS, and flagellin. TDC expressed low or no IL-12-related cytokines and remarkably elevated IL-10 levels. Interestingly, only TDC up-regulated the expression of TLR2 upon stimulation. This boosted the tolerogenic potential of these cells, because IL-10 production was up-regulated in TLR2-stimulated, LPS-primed DX-DC, whereas IL-12 and TNF-alpha secretion remained low. When comparing the TDC subsets, DX-DC and 1,25(OH)(2)D(3)-DC up-regulated TLR2 irrespective of the TLR triggered, whereas in IL-10-DC this effect was only mediated by LPS. Likewise, DX-DC and 1,25(OH)(2)D(3)-DC exhibited impaired ability to mature, reduced allostimulatory properties, and hampered capacity to induce Th1 differentiation. Therefore, both DX-DC and 1,25(OH)(2)D(3)-DC display the strongest tolerogenic and anti-inflammatory features and might be most suitable tools for the treatment of autoimmune diseases.
authors: Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, Amsterdam, The Netherlands.
authors: Sonia
authors: S
authors: Chamorro
authors: Juan J
authors: JJ
authors: García-Vallejo
authors: Wendy W J
authors: WW
authors: Unger
authors: Rosette J
authors: RJ
authors: Fernandes
authors: Sven C M
authors: SC
authors: Bruijns
authors: Sandra
authors: S
authors: Laban
authors: Bart O
authors: BO
authors: Roep
authors: Bert A
authors: BA
authors: 't Hart
authors: Yvette
authors: Y
authors: van Kooyk
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D025461:Feedback, Physiological / Q000276:immunology; D005408:Flagellin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology; D008024:Ligands; D055666:Lipopeptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000096:biosynthesis* / Q000097:blood*; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D008024:Ligands; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D005408:Flagellin; D011070:Poly I-C