CD38 expression is insensitive to steroid action in cells treated with tumor necrosis factor-α and interferon-γ by a mechanism involving the up-regulation of the glucocorticoid receptor β 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. In this study, 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 tumor necrosis factor-alpha (TNF alpha) and interferons ( IFNs). We found that CD38 expression induced by TNF alpha alone was completely abrogated by fluticasone ( 100 nM), dexamethasone ( 1 mu M), or budesonide ( 100 nM). In contrast, the synergistic induction of CD38 by the combination of TNF alpha with IFN gamma or IFN beta, but not with IL-1 beta or IL-13, was completely insensitive to the GC inhibitory effects. We also found that TNF alpha and IFN gamma impaired GC responsiveness by inhibiting steroid induced both 1) GR alpha-DNA binding activity and 2) GC-responsive element-( GRE)-dependent gene transcription. Although levels of the GC receptor ( GR) alpha isoform remained unchanged, expression of GR beta, the dominant-negative GR isoform, was synergistically increased by TNF alpha and IFN gamma with a GR alpha/GR beta ratio of 1 to 3. More importantly, fluticasone failed to induce GRE-dependent gene transcription and to suppress TNF alpha-induced CD38 expression in ASM cells transfected with constitutively active GR beta. We conclude that, upon pro-inflammatory cytokine stimulation, CD38 expression becomes insensitive to GC action by a mechanism involving the up-regulation of GR beta isoform, thus providing a novel in vitro cellular model to dissect GC resistance in primary cells.