Transforming growth factor-β impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line

Salem, S. and Harris, T. and Mok, S.L. and Li, M.Y. and Keenan, C.R. and Schuliga, M.J. and Stewart, A.G. (2012) Transforming growth factor-β impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line. British Journal of Pharmacology. ISSN 0007-1188, DOI PMID: 22300324.

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Background and purpose.  The lung adenocarcinoma cell line, A549, undergoes epithelial mesenchymal cell transition (EMT) in response to transforming growth factor-β (TGF-β). Glucocorticoids did not prevent the EMT response, but TGF-β induced resistance to the cytokine-regulatory action of glucocorticoids. We sought to characterise the impairment of glucocorticoid response in A549 cells. Experimental approach.  A549 cells were exposed to TGF-β for up to 96 h before glucocorticoid treatment and challenge with IL-1α to ascertain the extent of glucocorticoid regulation of interleukin-6 (IL-6) and CXCL8 production. Nuclear localisation of glucocorticoid receptor (GR) α was ascertained by immunofluorescence and Western blotting. Glucocorticoid-response element (GRE) transactivation was measured with a transfected GRE-SEAP reporter. Key Results.  TGF-β (40-400 pM) reduced the maximum inhibitory effect of dexamethasone on IL-1α-induced IL-6 and CXCL8 production. The impaired glucocorticoid response was detected with 4 h of TGF-β (40 pM) exposure (and 4 h IL-1α to induce CXCL8 expression) and therefore was not secondary to EMT, a process that requires longer incubation periods and higher concentrations of TGF-β. TGF-β also impaired dexamethasone regulation of granulocyte-macrophage colony-stimulating factor in thrombin-stimulated BEAS-2B epithelial cells. Impaired regulation of CXCL8 was associated with markedly reduced GRE transactivation and reduced induction of IκBα mRNA, glucocorticoid-inducible leucine zipper (GILZ) and the epithelial sodium channel (SCNN1A). The expression, cellular levels and nuclear localisation of glucocorticoid receptor α were reduced by TGF-β. Conclusions and Implications.  We have identified that TGF-β impairs glucocorticoid responses in the A549 and BEAS-2B cell lines. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Item Type: Article
Additional Information: Department of Pharmacology, University of Melbourne, Grattan St., Parkville Victoria Australia. Current address: Department of Pharmacology, University of Malaya, Kuala Lumpur, Malaysia
Uncontrolled Keywords: Pharmacology
Subjects: R Medicine
Depositing User: Mr. Faizal Hamzah
Date Deposited: 25 Feb 2012 02:21
Last Modified: 16 Dec 2014 06:23

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