TY - JOUR
T1 - Glucocorticoid regulation of CD38 expression in human airway smooth muscle cells
T2 - Role of dual specificity phosphatase 1
AU - Kang, Bit Na
AU - Jude, Joseph A.
AU - Panettieri, Reynold A.
AU - Walseth, Timothy F.
AU - Kannan, Mathur S.
PY - 2008/7
Y1 - 2008/7
N2 - 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-α, causing increased intracellular calcium response to agonists. The transcriptional and posttranscriptional regulation of CD38 expression involves signaling through MAPKs and requires activation of NF-κB and activator protein-1 (AP-1). The cytokine-augmented CD38 expression is decreased by anti-inflammatory glucocorticoids due to inhibition of NF-κB 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-α induced MKP-1 expression (both mRNA and protein) rapidly. Dexamethasone decreased TNF-α-induced phosphorylation of the major MAPKs, i.e., ERK, p38, and JNK, and decreased the activation of NF-κB and AP-1. Dexamethasone also decreased CD38 expression induced by TNF-α, 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.
AB - 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-α, causing increased intracellular calcium response to agonists. The transcriptional and posttranscriptional regulation of CD38 expression involves signaling through MAPKs and requires activation of NF-κB and activator protein-1 (AP-1). The cytokine-augmented CD38 expression is decreased by anti-inflammatory glucocorticoids due to inhibition of NF-κB 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-α induced MKP-1 expression (both mRNA and protein) rapidly. Dexamethasone decreased TNF-α-induced phosphorylation of the major MAPKs, i.e., ERK, p38, and JNK, and decreased the activation of NF-κB and AP-1. Dexamethasone also decreased CD38 expression induced by TNF-α, 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.
KW - Activator protein-1
KW - Adenosine 5′-diphosphate-ribosyl cyclase
KW - Mitogen-activated protein kinases
KW - Nuclear factor-κB
KW - Tumor necrosis factor-α
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U2 - 10.1152/ajplung.00352.2007
DO - 10.1152/ajplung.00352.2007
M3 - Article
C2 - 18441094
AN - SCOPUS:49049091227
SN - 1040-0605
VL - 295
SP - L186-L193
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 1
ER -