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

Am J Respir Cell Mol Biol. 2004 Apr;30(4):555-63. doi: 10.1165/rcmb.2003-0295OC. Epub 2003 Oct 3.

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)-kappaB 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-kappaB-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-kappaB 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Antigens, Surface / drug effects
  • Antigens, Surface / metabolism
  • Base Sequence
  • Cells, Cultured
  • Conserved Sequence
  • DNA-Binding Proteins*
  • Dexamethasone / pharmacology
  • ELAV Proteins
  • ELAV-Like Protein 1
  • Glucocorticoids / pharmacology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Half-Life
  • Humans
  • Immediate-Early Proteins / drug effects
  • Immediate-Early Proteins / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Lymphokines / genetics*
  • Molecular Sequence Data
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism*
  • Phytohemagglutinins / pharmacology
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / drug effects
  • RNA-Binding Proteins / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Time Factors
  • Tristetraprolin

Substances

  • 3' Untranslated Regions
  • Antigens, Surface
  • DNA-Binding Proteins
  • ELAV Proteins
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • Glucocorticoids
  • Immediate-Early Proteins
  • Lymphokines
  • NF-kappa B
  • Phytohemagglutinins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Tristetraprolin
  • ZFP36 protein, human
  • Dexamethasone
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Tetradecanoylphorbol Acetate