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Molecular regulation of granulocyte macrophage colony-stimulating factor in human lung epithelial cells by interleukin (IL)-1beta, IL-4, and IL-13 involves both transcriptional and post-transcriptional mechanisms.

Abstract
Interleukin (IL)-1beta stimulates the release of granulocyte macrophage colony-stimulating factor (GM-CSF) from lung epithelial cells. To investigate the molecular mechanisms underlying GM-CSF regulation, we studied GM-CSF production, messenger RNA (mRNA) expression levels, and GM-CSF promoter activity in A549 human alveolar carcinoma cells stimulated with IL-1beta. Coincubation with IL-4 or IL-13 dose-dependently inhibited IL-1beta-induced GM-CSF release. Time-course studies of intracellular and extracellular protein release and mRNA expression indicated tight coupling of protein and mRNA synthesis within 6 h after stimulation. IL-4 and IL-13 both inhibited expression of GM-CSF mRNA and protein by 2 h after stimulation. Stable transfection of A549 cells, with GM-CSF promoter/ enhancer constructs containing up to 3.3 kb upstream of the transcription start site, revealed maximal activation by IL-1beta and phorbol 12-myristate 13-acetate (PMA) with a reporter containing the proximal promoter (-627 to +35). This excludes sequences further upstream from a major regulatory role in GM-CSF promoter activation by IL-1beta or PMA in these cells. IL-4 and IL-13 downregulated promoter activation but had no effect on GM-CSF mRNA half-life. However, IL-1beta activation of all constructs was far less pronounced than in Jurkat T cells, suggesting a requirement for additional mechanisms, possibly post-transcriptional, to potentiate the observed transcriptional induction.
AuthorsM Bergmann, P J Barnes, R Newton
JournalAmerican journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 22 Issue 5 Pg. 582-9 (May 2000) ISSN: 1044-1549 [Print] United States
PMID10783130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Interleukin-1
  • Interleukin-13
  • Interleukins
  • RNA, Messenger
  • Dactinomycin
  • Interleukin-4
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Cycloheximide
  • Tetradecanoylphorbol Acetate
Topics
  • Cycloheximide (pharmacology)
  • Dactinomycin (pharmacology)
  • Gene Expression Regulation (drug effects)
  • Genes, Reporter
  • Granulocyte-Macrophage Colony-Stimulating Factor (genetics, metabolism)
  • Humans
  • Interleukin-1 (pharmacology)
  • Interleukin-13 (pharmacology)
  • Interleukin-4 (pharmacology)
  • Interleukins (pharmacology)
  • Jurkat Cells
  • Lung (metabolism)
  • Promoter Regions, Genetic
  • RNA, Messenger (metabolism)
  • Tetradecanoylphorbol Acetate (pharmacology)
  • Time Factors
  • Transcription, Genetic (drug effects)
  • Transfection
  • Tumor Cells, Cultured

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