Am. J. Respir. Cell Mol. Biol., Volume 22, Number 5, May, 2000 582-589

Molecular Regulation of Granulocyte Macrophage Colony-Stimulating Factor in Human Lung Epithelial Cells by Interleukin (IL)-1, IL-4, and IL-13 Involves Both Transcriptional and Post-Transcriptional Mechanisms

Martin Bergmann, Peter J. Barnes, and Robert Newton

Franz-Volhard Clinic at Max-Delbrück Center, Charité, Humboldt University, Berlin, Germany; and Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom

Interleukin (IL)-1 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-1. Coincubation with IL-4 or IL-13 dose-dependently inhibited IL-1-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-1 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-1 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-1 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.

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