Advanced

Mutated cylindromatosis gene affects the functional state of dendritic cells

Bros, Matthias; Dexheimer, Nadine; Besche, Verena; Masri, Joumana; Trojandt, Stefanie; Hoevelmeyer, Nadine; Reissig, Sonja; Massoumi, Ramin LU ; Grabbe, Stephan and Waisman, Ari, et al. (2010) In European Journal of Immunology 40(10). p.2848-2857
Abstract
Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-kappa B signaling pathway and attenuates NF-kappa B and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLDex7/8), display a higher content of nuclear RelB and express elevated levels of NF-kappa B family members as well as of known NF-kappa B-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLDex7/8 DC exhibited a significantly higher primary allogenic T-cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated... (More)
Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-kappa B signaling pathway and attenuates NF-kappa B and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLDex7/8), display a higher content of nuclear RelB and express elevated levels of NF-kappa B family members as well as of known NF-kappa B-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLDex7/8 DC exhibited a significantly higher primary allogenic T-cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated CYLDex7/8 DC with relB-specific shRNA reduced their T-cell stimulatory capacity. Treatment with the synthetic glucocorticoid dexamethasone known to inhibit NF-kappa B and AP-1 activity reverted the pro-immunogenic phenotype and function of CYLDex7/8 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-kappa B inhibitors, CYLDex7/8 acts in a dominant negative manner. Our findings raise the question of whether genetic defects associated with increased NF-kappa B activity may result in disturbed maintenance of peripheral tolerance. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Transgenic/knockout mice, Tolerance, DC, Autoimmunity, Costimulation
in
European Journal of Immunology
volume
40
issue
10
pages
2848 - 2857
publisher
John Wiley & Sons
external identifiers
  • wos:000283387500023
  • scopus:77957172335
ISSN
1521-4141
DOI
10.1002/eji.200939285
language
English
LU publication?
yes
id
6a84d0cd-031f-4d26-b562-f58acb60ce8a (old id 1720926)
date added to LUP
2010-12-03 13:21:41
date last changed
2018-05-29 12:17:49
@article{6a84d0cd-031f-4d26-b562-f58acb60ce8a,
  abstract     = {Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-kappa B signaling pathway and attenuates NF-kappa B and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLDex7/8), display a higher content of nuclear RelB and express elevated levels of NF-kappa B family members as well as of known NF-kappa B-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLDex7/8 DC exhibited a significantly higher primary allogenic T-cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated CYLDex7/8 DC with relB-specific shRNA reduced their T-cell stimulatory capacity. Treatment with the synthetic glucocorticoid dexamethasone known to inhibit NF-kappa B and AP-1 activity reverted the pro-immunogenic phenotype and function of CYLDex7/8 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-kappa B inhibitors, CYLDex7/8 acts in a dominant negative manner. Our findings raise the question of whether genetic defects associated with increased NF-kappa B activity may result in disturbed maintenance of peripheral tolerance.},
  author       = {Bros, Matthias and Dexheimer, Nadine and Besche, Verena and Masri, Joumana and Trojandt, Stefanie and Hoevelmeyer, Nadine and Reissig, Sonja and Massoumi, Ramin and Grabbe, Stephan and Waisman, Ari and Reske-Kunz, Angelika B.},
  issn         = {1521-4141},
  keyword      = {Transgenic/knockout mice,Tolerance,DC,Autoimmunity,Costimulation},
  language     = {eng},
  number       = {10},
  pages        = {2848--2857},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Immunology},
  title        = {Mutated cylindromatosis gene affects the functional state of dendritic cells},
  url          = {http://dx.doi.org/10.1002/eji.200939285},
  volume       = {40},
  year         = {2010},
}