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Published ahead of print on October 3, 2003, doi:10.1165/rcmb.2003-0295OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 4, April 2004, 555-563

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Submitted on August 11, 2003
Revised on October 2, 2003

Glucocorticoid inhibition of GM-CSF from T cells is independent of control by NF-{kappa}B and CLE0

Martin W Bergmann1, Karl J Staples2, Susan J Smith2, Peter J Barnes2, and Robert Newton3*

1 Franz-Volhard Clinic at Max Delbruck Center, Humboldt University, Berlin, Germany, 2 Thoracic Medicine, Imperial College Faculty of Medicine, London, London, United Kingdom, 3 Biological Sciences, University of Warwick, Coventry, West Midlands, United Kingdom; Thoracic Medicine, Imperial College Faculty of Medicine, London, London, United Kingdom

* To whom correspondence should be addressed. E-mail: robert.newton{at}imperial.ac.uk.

Release of 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 were strongly activated by PMA + PHA. Mutations in either the -85/-76 NF-{kappa}B site or the AP-1 region in the -54/-31 CLE0 site substantially reduced promoter activity. Both GM-CSF promoter and NF-{kappa}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 (ARE) in the GM-CSF 3'-untranslated region was unaffected by dexamethasone and overall ARE binding activity was unaltered. Taken together our data support an important role for the NF-{kappa}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.




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Copyright © 2003 American Thoracic Society.