Submitted on August 28, 2007
Accepted on April 21, 2008
GLUCOCORTICOID REGULATION OF CD38 EXPRESSION IN
HUMAN AIRWAY SMOOTH MUSCLE CELLS:
ROLE OF DUAL SPECIFICITY PHOSPHATASE 1
Bit Na Kang1, Joseph Anthony Jude2, Reynold A Panettieri, Jr3, Timothy F Walseth4, and Mathur S. Kannan5*
1 Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, United States
2 Veterinary and Biomedical Sciences, University of Minnesota, Minnesota, United States
3 Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, United States
4 Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States
5 Veterinary and Biomedical Sciences, University of Minnesota, College of Veterinary Medicine, St. Paul, Minnesota, United States
* To whom correspondence should be addressed. E-mail: kanna001{at}umn.edu.
The enzymatic activity of CD38, ADP-ribosyl cyclase, synthesizes the calcium mobilizing molecule cyclic ADP-ribose from 
-NAD. In human airway smooth muscle (HASM) cells, CD38 expression is augmented by the inflammatory cytokine, tumor necrosis factor-alpha (TNF-
), causing increased intracellular calcium response to agonists. The transcriptional and post-transcriptional regulation of CD38 expression involves signaling through MAP kinases and requires activation of NF-
B and 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 MAPK phosphatase-1 (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 MAP kinases, 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 siRNAs, there was significant attenuation of MKP-1 expression and partial, but non-significant, reversal of dexamethasone inhibition of CD38 expression. These results indicate that regulation of CD38 expression in HASM cells by glucocorticoids involves decreased signaling through MAP kinases and activation of transcription factors. The glucocorticoid effects on decreased CD38 expression and function result from regulation through transcription and transcript stability.
