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Plos One : Pro-asthmatic Cytokines Regulate Unliganded and Ligand-dependent Glucocorticoid Receptor Signaling in Airway Smooth Muscle, Volume 8

By Bolego, Chiara

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Book Id: WPLBN0003965207
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos One : Pro-asthmatic Cytokines Regulate Unliganded and Ligand-dependent Glucocorticoid Receptor Signaling in Airway Smooth Muscle, Volume 8  
Author: Bolego, Chiara
Volume: Volume 8
Language: English
Subject: Journals, Science, Medical Science
Collections: Periodicals: Journal and Magazine Collection (Contemporary)
Historic
Publication Date:
Publisher: Plos

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Bolego, C. (n.d.). Plos One : Pro-asthmatic Cytokines Regulate Unliganded and Ligand-dependent Glucocorticoid Receptor Signaling in Airway Smooth Muscle, Volume 8. Retrieved from http://worldebookfair.com/


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Description : To elucidate the regulation of glucocorticoid receptor (GR) signaling under pro-asthmatic conditions, cultured human airway smooth muscle (HASM) cells were treated with proinflammatory cytokines or GR ligands alone and in combination, and then examined for induced changes in ligand-dependent and -independent GR activation and downstream signaling events. Ligand stimulation with either cortisone or dexamethsone (DEX) acutely elicited GR translocation to the nucleus and, comparably, ligand-independent stimulation either with the Th2 cytokine, IL-13, or the pleiotropic cytokine combination, IL- 1b/TNFa, also acutely evoked GR translocation. The latter response was potentiated by combined exposure of cells to GR ligand and cytokine. Similarly, treatment with either DEX or IL-13 alone induced GR phosphorylation at its serine-211 residue (GRSer211), denoting its activated state, and combined treatment with DEX+IL-13 elicited heightened and sustained GRSer211 phosphorylation. Interestingly, the above ligand-independent GR responses to IL-13 alone were not associated with downstream GR binding to its consensus DNA sequence or GR transactivation, whereas both DEX-induced GR:DNA binding and transcriptional activity were significantly heightened in the presence of IL-13, coupled to increased recruitment of the transcriptional co-factor, MED14. The stimulated GR signaling responses to DEX were prevented in IL-13-exposed cells wherein GRSer211 phosphorylation was suppressed either by transfection with specific serine phosphorylation-deficient mutant GRs or treatment with inhibitors of the MAPKs, ERK1/2 and JNK. Collectively, these novel data highlight a heretofore-unidentified homeostatic mechanism in HASM cells that involves pro-asthmatic cytokine-driven, MAPKmediated, non-ligand-dependent GR activation that confers heightened glucocorticoid ligand-stimulated GR signaling. These findings raise the consideration that perturbations in this homeostatic cytokine-driven GR signaling mechanism may be responsible, at least in part, for the insensirtivity to glucocorticoid therapy that is commonly seen in individuals with severe asthma

 

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