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Glucocorticoid Inhibition of Granulocyte Macrophage–Colony-Stimulating Factor from T cells Is Independent of Control by Nuclear Factor-B and Conserved Lymphokine Element 0

Department of Thoracic Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom

Address correspondence to: Dr. Robert Newton, BioMedical Research Institute, Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK. E-mail: robert.newton{at}imperial.ac.uk

Release of granulocyte macrophage–colony-stimulating factor (GM-CSF) from T cells is important in the differentiation, maturation, and survival of inflammatory cells. Here the induction of GM-CSF expression from T cells was dependent on transcription and translation and was prevented by dexamethasone. In primary human CD3⁺ T cells, up to 3.3 kb of human GM-CSF promoter was strongly activated by PMA + PHA. Mutations in either the -85/-76 nuclear factor (NF)-B site or the activator protein-1 region in the -54/-31 conserved lymphokine element 0 (CLE0) site substantially reduced promoter activity. Both GM-CSF promoter and NF-B–dependent constructs were unresponsive to dexamethasone whereas the release of GM-CSF was potently repressed. Analysis of GM-CSF mRNA and protein expression at various time points and the effect of adding dexamethasone after the stimulus revealed the existence of potent mechanisms of inhibition acting at a translational level. The expression of tristetraproline and HuR, proteins that bind the AU-rich element in the GM-CSF 3'-untranslated region was unaffected by dexamethasone and overall AU-rich element binding activity was unaltered. Taken together our data support an important role for the NF-B and CLE0 sites in the transcriptional control of GM-CSF expression in primary human T cells and suggest that post-transcriptional/translational mechanisms are key mediators of glucocorticoid-dependent repression.

Abbreviations: activator protein-1, AP-1 • adenosine/uridine (AU)-rich element, ARE • conserved lymphokine element 0, CLE0 • enzyme-linked immunosorbent assay, ELISA • glyceraldehyde phosphate dehydrogenase, GAPDH • granulocyte macrophage–colony-stimulating factor, GM-CSF • glucocorticoid receptor, GR • nuclear factor-B, NF-B • peripheral blood mononuclear cells, PBMC • phytohemaglutinin, PHA • phorbol 12-myristate 12-acetate, PMA • tristetraproline • untranslated region, UTR

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