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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

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


1044-1549
555-563
Bergmann, Martin W.
569898b9-1e22-497d-964b-85bb6741f48c
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Smith, Susan J.
7bdf3bab-5523-473b-a20a-33ff71b7e5ac
Barnes, Peter J.
6cbf850c-3499-4e23-983c-4442643c0004
Newton, Robert
4a2c2a99-b7ad-4373-8840-96fbb5b5313e
Bergmann, Martin W.
569898b9-1e22-497d-964b-85bb6741f48c
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Smith, Susan J.
7bdf3bab-5523-473b-a20a-33ff71b7e5ac
Barnes, Peter J.
6cbf850c-3499-4e23-983c-4442643c0004
Newton, Robert
4a2c2a99-b7ad-4373-8840-96fbb5b5313e

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).

Record type: Article

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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Published date: April 2004
Organisations: Faculty of Medicine

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Local EPrints ID: 374403
URI: https://eprints.soton.ac.uk/id/eprint/374403
ISSN: 1044-1549
PURE UUID: f341844a-4569-43f2-9045-b70b9ce86de2
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 16 Feb 2015 12:02
Last modified: 20 Jul 2019 00:53

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Contributors

Author: Martin W. Bergmann
Author: Karl J. Staples ORCID iD
Author: Susan J. Smith
Author: Peter J. Barnes
Author: Robert Newton

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