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Glucocorticoid regulation of CD38 expression in human airway smooth muscle cells: role of dual specificity phosphatase 1

Departments of ¹Veterinary and Biomedical Sciences, ³Pharmacology, and ⁴Pediatrics, University of Minnesota, St. Paul, Minnesota; and ²Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Submitted 28 August 2007 ; accepted in final form 21 April 2008

The enzymatic activity of CD38, ADP-ribosyl cyclase, synthesizes the calcium mobilizing molecule cyclic ADP-ribose from β-NAD. In human airway smooth muscle (HASM) cells, CD38 expression is augmented by the inflammatory cytokine, TNF-, causing increased intracellular calcium response to agonists. The transcriptional and posttranscriptional regulation of CD38 expression involves signaling through MAPKs and requires activation of NF-B and activator protein-1 (AP-1). The cytokine-augmented CD38 expression is decreased by anti-inflammatory glucocorticoids due to inhibition of NF-B activation and other mechanisms. In this study, we investigated glucocorticoid regulation of CD38 expression in HASM cells through the MKP-1. In HASM cells, dexamethasone and TNF- induced MKP-1 expression (both mRNA and protein) rapidly. Dexamethasone decreased TNF--induced phosphorylation of the major MAPKs, i.e., ERK, p38, and JNK, and decreased the activation of NF-B and AP-1. Dexamethasone also decreased CD38 expression induced by TNF-, and part of this effect was attributable to decreased transcript stability. In cells transfected with MKP-1-specific small interfering RNAs (siRNAs), there was significant attenuation of MKP-1 expression and partial, but nonsignificant, reversal of dexamethasone inhibition of CD38 expression. These results indicate that regulation of CD38 expression in HASM cells by glucocorticoids involves decreased signaling through MAPKs and activation of transcription factors. The glucocorticoid effects on decreased CD38 expression and function result from regulation through transcription and transcript stability.

mitogen-activated protein kinases; nuclear factor-B; activator protein-1; adenosine 5'-diphosphate-ribosyl cyclase; tumor necrosis factor-

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