title: Regulation of dectin-1-mediated dendritic cell activation by peroxisome proliferator-activated receptor-gamma ligand troglitazone.
abstract: Dectin-1 is the major receptor for fungal β-glucans. The activation of Dectin-1 leads to the up-regulation of surface molecules on dendritic cells (DCs) and cytokine secretion. Furthermore, Dectin-1 is important for the recruitment of leukocytes and the production of inflammatory mediators. Peroxisome proliferator-activated receptor-γ (PPAR-γ) and its ligands, cyclopentenone prostaglandins or thiazolidinediones, have modulatory effects on B-cell, T-cell, and DC function. In the present study, we analyzed the effects of troglitazone (TGZ), a high-affinity synthetic PPAR-γ ligand, on the Dectin-1-mediated activation of monocyte-derived human DCs. Dectin-1-mediated activation of DCs was inhibited by TGZ, as shown by down-regulation of costimulatory molecules and reduced secretion of cytokines and chemokines involved in T-lymphocyte activation. Furthermore, TGZ inhibited the T-cell-stimulatory capacity of DCs. These effects were not due to a diminished expression of Dectin-1 or to a reduced phosphorylation of spleen tyrosine kinase; they were mediated by the inhibition of downstream signaling molecules such as mitogen-activated protein kinases and nuclear factor-κB. Furthermore, curdlan-mediated accumulation of caspase recruitment domain 9 (CARD9) in the cytosol was inhibited by TGZ. Our data demonstrate that the PPAR-γ ligand TGZ inhibits Dectin-1-mediated activation by interfering with CARD9, mitogen-activated protein kinase, and nuclear factor-κB signaling pathways. This confirms their important role as negative-feedback regulators of potentially harmful inflammatory responses.
authors.affiliation: Department of Hematology and Oncology, University of Bonn, Wilhelmstrasse 35-37, Bonn, Germany.
authors.forename: Grethe
authors.initials: G
authors.lastname: Kock
authors.forename: Anita
authors.initials: A
authors.lastname: Bringmann
authors.forename: Stefanie Andrea Erika
authors.initials: SA
authors.lastname: Held
authors.forename: Solveig
authors.initials: S
authors.lastname: Daecke
authors.forename: Annkristin
authors.initials: A
authors.lastname: Heine
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
mesh_terms: D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D037181:Lectins, C-Type; D008024:Ligands; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D000072377:Syk Kinase; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D000099181:Dectin-1
chemical_list: D053468:CARD Signaling Adaptor Proteins; D018925:Chemokines; D002839:Chromans; D016207:Cytokines; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D045162:Thiazolidinediones; D000077288:Troglitazone; D000099181:Dectin-1; C505855:CARD9 protein, human; C000606896:SYK protein, human