In human airway smooth muscle (HASM) cells, the expression of CD38, which synthesizes the
calcium-mobilizing molecule
cyclic ADP-ribose, is augmented by
TNF-alpha, a
cytokine implicated in
asthma. We determined the role of
mitogen-activated protein kinase (MAPK) in the activation of
NF-kappaB and
AP-1 in the regulation of CD38 expression in HASM cells. In HASM cells exposed to
TNF-alpha (40 ng/ml), the inhibitors of
extracellular signal-regulated kinase (ERK), p38, or c-Jun NH(2)-terminal
kinase (JNK) decreased CD38 expression and
ADP-ribosyl cyclase activity. Transfection of HASM cells with a dominant negative
MEK decreased while a wild-type ERK increased
TNF-alpha-induced CD38 expression. Electrophoretic mobility shift assays (EMSAs) were performed using
nuclear proteins and consensus sequences to detect the effect of the MAPKs on
NF-kappaB and
AP-1 activation. EMSAs confirmed the role of p38 and JNK in mediating
NF-kappaB and
AP-1 activation. Transfection of a dominant negative c-Jun decreased
TNF-alpha-induced CD38 expression indicating involvement of
AP-1. Stability of
TNF-alpha-induced CD38 transcripts were determined in the presence of MAPK inhibitors after arresting the transcription with
actinomycin D. Transcript stability decreased in the presence of ERK and
p38 MAPK, but not the JNK, inhibitors. These results indicate that regulation of CD38 expression through p38 and JNK MAPKs involves
NF-kappaB and
AP-1 activation, and ERK and p38 MAPKs also regulate expression posttranscriptionally through message stability.