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Received for publication October 7, 2005.
Revised November 2, 2005.
Accepted for publication November 16, 2005.
and IFN
by a mechanism involving the upregulation of glucocorticoid receptor 
isoform
Evidence shows that the CD38 molecule, recently involved in the two main features of asthma, bronchial hyper-responsiveness and airway inflammation, could represent a new potential therapeutic target for asthma. Here, we investigated whether glucocorticoid (GC), the most effective treatment for lung diseases, can affect CD38 expression in human airway smooth muscle (ASM) cells treated with different pro-inflammatory cytokines such as TNF
and IFNs. We found that CD38 expression induced by TNF alone was completely abrogated by fluticasone (100 nM), dexamethasone (1 µM) or budesonide (100 nM). In contrast, the synergistic induction of CD38 by the combination of TNF with IFN
or IFN
, but not with IL-1 or IL-13, was completely insensitive to the GC inhibitory effects. We also found that TNF and IFN impaired GC responsiveness by inhibiting steroid induced both i) GR-DNA binding activity, and ii) GC-Responsive-Elements-(GRE)-dependent gene transcription. While levels of GC receptor (GR) alpha isoform remained unchanged, expression of GR, the dominant negative GR isoform, was synergistically increased by TNF and IFN with a GR/GR ratio of 1 to 3. More importantly, fluticasone failed to induce GRE-dependent gene transcription and to suppress TNF-induced CD38 expression in ASM cells transfected with constitutively active GR. We conclude that, upon pro-inflammatory cytokine stimulation, CD38 expression becomes insensitive to GC action by a mechanism involving the upregulation of GR isoform, thus providing a novel in vitro cellular model to dissect GC resistance in primary cells.
Key words:
Interferons, Interleukins, Tumor necrosis factor, Glucorticoids/Mineralocorticoids, Regulation of gene expression, Regulation - xenobiotic, Protein targets, Overexpression, Resistance
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