title: Mutated cylindromatosis gene affects the functional state of dendritic cells.
abstract: Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-κB signaling pathway and attenuates NF-κB and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLD(ex7/8)), display a higher content of nuclear RelB and express elevated levels of NF-κB family members as well as of known NF-κB-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLD(ex7/8) DC exhibited a significantly higher primary allogenic T-cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated CYLD(ex7/8) DC with relB-specific shRNA reduced their T-cell stimulatory capacity. Treatment with the synthetic glucocorticoid dexamethasone known to inhibit NF-κB and AP-1 activity reverted the pro-immunogenic phenotype and function of CYLD(ex7/8) DC and re-established their tolerogenic function. DC derived from CYLD knockout mice showed no functional alterations compared with WT DC. Therefore, although complete loss of CYLD may be compensated for by other endogenous NF-κB inhibitors, CYLD(ex7/8) acts in a dominant negative manner. Our findings raise the question of whether genetic defects associated with increased NF-κB activity may result in disturbed maintenance of peripheral tolerance.
authors.affiliation: Clinical Research Unit Allergology, Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. mbros@uni-mainz.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Bros
authors.forename: Nadine
authors.initials: N
authors.lastname: Dexheimer
authors.forename: Verena
authors.initials: V
authors.lastname: Besche
authors.forename: Joumana
authors.initials: J
authors.lastname: Masri
authors.forename: Stefanie
authors.initials: S
authors.lastname: Trojandt
authors.forename: Nadine
authors.initials: N
authors.lastname: Hövelmeyer
authors.forename: Sonja
authors.initials: S
authors.lastname: Reissig
authors.forename: Ramin
authors.initials: R
authors.lastname: Massoumi
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Angelika B
authors.initials: AB
authors.lastname: Reske-Kunz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology; D007108:Immune Tolerance / Q000276:immunology; D007527:Isoenzymes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D018808:Transcription Factor AP-1 / Q000276:immunology*; D051841:Transcription Factor RelB / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000276:immunology*
chemical_list: D005938:Glucocorticoids; D007527:Isoenzymes; D016328:NF-kappa B; C497594:Relb protein, mouse; D018808:Transcription Factor AP-1; D025521:Tumor Suppressor Proteins; D051841:Transcription Factor RelB; D012313:RNA; D003907:Dexamethasone