IκBα glutathionylation and reduced histone H3 phosphorylation inhibit eotaxin and RANTES

Seidel, P. and Roth, M. and Ge, Q. and Merfort, I. and S'Ng C, T. and Ammit, A. J.. (2011) IκBα glutathionylation and reduced histone H3 phosphorylation inhibit eotaxin and RANTES. The European respiratory journal, Vol. 38, H. 6. pp. 1444-1452.

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Official URL: http://edoc.unibas.ch/dok/A6007097

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Airway smooth muscle cells (ASMCs) secrete eotaxin and RANTES (regulated on activation, normal T-cell expressed and secreted) in response to tumour necrosis factor (TNF)-?, which is inhibited by the nuclear factor (NF)-?B inhibitor dimethylfumarate (DMF). NF-?B/I?B (inhibitor of NF-?B) glutathionylation and changes in chromatin remodelling can inhibit NF-?B activity. In this study, we determined whether NF-?B/I?B glutathionylation and reduced histone H3 phosphorylation might underlie the inhibitory effect of DMF on NF-?B activity, and eotaxin and RANTES secretion. Primary human ASMCs were treated with DMF, diamide and/or glutathione (GSH) ethylester (OEt) prior to TNF-? stimulation and were subsequently analysed by ELISA, electrophoretic mobility shift assay, immunofluorescence, co-immunoprecipitation or immunoblotting. DMF reduced intracellular GSH and induced I?B? glutathionylation (I?B?-SSG), which inhibited I?B? degradation, NF-?B p65 nuclear entry and NF-?B/DNA binding. In addition, DMF inhibited the phosphorylation of histone H3, which was possibly mediated by the inhibitory effect of DMF on mitogen- and stress-activated protein kinase (MSK)-1. However, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase MAPK and MAPK phosphatase-1, upstream of MSK-1, were not inhibited by DMF. Importantly, DMF-mediated effects on NF-?B, histone H3, eotaxin and RANTES were reversed by addition of GSH-OEt. Our data suggest that DMF inhibits NF-?B-dependent eotaxin and RANTES secretion by reduction of GSH with subsequent induction of I?B?-SSG and inhibition of histone H3 phosphorylation. Our findings offer new potential drug targets to reduce airway inflammation in asthma.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Pulmonary Cell Research (Roth/Tamm)
UniBasel Contributors:Roth-Chiarello, Michael
Item Type:Article, refereed
Article Subtype:Research Article
Note:Variant title: IkappaBalpha glutathionylation and reduced histone H3 phosphorylation inhibit eotaxin and RANTES -- Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 May 2015 08:45
Deposited On:27 Feb 2014 15:45

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