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Citation
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HERO ID
2792670
Reference Type
Journal Article
Title
Glucocorticoid receptor nitration leads to enhanced anti-inflammatory effects of novel steroid ligands
Author(s)
Paul-Clark, MJ; Roviezzo, F; Flower, RJ; Cirino, G; Del Soldato, P; Adcock, IM; Perretti, M
Year
2003
Is Peer Reviewed?
Yes
Journal
Journal of Immunology
ISSN:
0022-1767
EISSN:
1550-6606
Volume
171
Issue
6
Page Numbers
3245-3252
Language
English
PMID
12960354
DOI
10.4049/jimmunol.171.6.3245
Web of Science Id
WOS:000185247300064
Abstract
It has recently emerged that posttranslational modification of proteins via nitration of tyrosine residues can alter their function. In this study, we describe that specific nitration of the glucocorticoid receptor (GR) by NCX-1015, a novel NO-donating prednisolone derivative (prednisolone 21-[4'-(nitrooxymethyl)benzoate), results in an enhancement of GR-mediated events. Incubation of PBMC and U937 cells with 1-10 micro M NCX-1015 caused faster activation of GR as assessed by augmented 1) binding to [(3)H]dexamethasone, 2) dissociation from heat shock protein 90, and 3) nuclear translocation. PBMCs treated with NCX-1015 contained GR that had undergone tyrosine nitration. The chemistry facilitating the increase in steroid binding capacity observed with NCX-1015 is specific, because changing the position of the NO-donating group or ubiquitous nitration by addition of an NO donor was unable to mimic this event. In vivo treatment with NCX-1015 provoked GR nitration and faster heat shock protein 90 dissociation as assessed in peritoneal cells. Accordingly, NCX-1015, but not prednisolone or other derivatives, produced a rapid inhibition of the early neutrophil recruitment and mediator generation in a model of peritonitis. In conclusion, we report here for the first time that posttranslational modification of GR by this novel nitrosteroid is associated with its enhanced anti-inflammatory activity.
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