Glucocorticoid inhibition of granulocyte macrophage–colony-stimulating factor from T cells is independent of control by nuclear factor-?B and conserved lymphokine element 0

Bergmann, Martin W., Staples, Karl J., Smith, Susan J., Barnes, Peter J. and Newton, Robert (2004) Glucocorticoid inhibition of granulocyte macrophage–colony-stimulating factor from T cells is independent of control by nuclear factor-?B and conserved lymphokine element 0. American Journal of Respiratory Cell and Molecular Biology, 30 (4), 555-563. (doi:10.1165/rcmb.2003-0295OC).

Abstract

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

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Contributors

Author: Karl J. Staples

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