TNF- induced CD38 expression in human airway smooth muscle cells: role of MAP kinases and transcription factors NF- B and AP-1

Tirumurugaan KG, Jude JA, Kang BN, Panettieri RA, Walseth TF, Kannan MS. TNFinduced CD38 expression in human airway smooth muscle cells: role of MAP kinases and transcription factors NFB and AP-1. Am J Physiol Lung Cell Mol Physiol 292: L1385–L1395, 2007. First published February 23, 2007; doi:10.1152/ajplung.00472.2006.—In human airway smooth muscle (HASM) cells, the expression of CD38, which synthesizes the calcium-mobilizing molecule cyclic ADP-ribose, is augmented by TNF, a cytokine implicated in asthma. We determined the role of mitogen-activated protein kinase (MAPK) in the activation of NFB and AP-1 in the regulation of CD38 expression in HASM cells. In HASM cells exposed to TNF(40 ng/ml), the inhibitors of extracellular signal-regulated kinase (ERK), p38, or c-Jun NH2-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-induced CD38 expression. Electrophoretic mobility shift assays (EMSAs) were performed using nuclear proteins and consensus sequences to detect the effect of the MAPKs on NFB and AP-1 activation. EMSAs confirmed the role of p38 and JNK in mediating NFB and AP-1 activation. Transfection of a dominant negative c-Jun decreased TNF-induced CD38 expression indicating involvement of AP-1. Stability of TNF-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 NFB and AP-1 activation, and ERK and p38 MAPKs also regulate expression posttranscriptionally through message stability.