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Received for publication April 2, 2004.
Revised May 13, 2004.
Accepted for publication May 14, 2004.
differentially regulates the expression of pro-inflammatory genes in human airway smooth muscle cells by activation of IFN
-dependent CD38 pathway
Recent evidence suggests that CD38, an ectoenzyme that converts NAD+ to cyclic ADP-ribose (cADPr), may play a role in cytokine-induced airway smooth muscle (ASM) cell hyper-responsiveness, a key feature associated with chronic asthma. In the present study, we investigated the major signaling pathways by which TNF
induces CD38 expression as well as its role in regulating gene expression in human ASM cells. Using flow cytometry analyses, TNF enhanced CD38 expression in a manner that was time (0-24hr), concentration (0.1-40 ng/ml) and protein synthesis (cycloheximide blockade) dependent. A selective agonistic antibody against TNFR1 also augmented CD38 expression while anti-TNFR2 antagonistic antibody did not prevent the TNF response. Inhibition of the JAK/STAT pathways using a soluble inhibitor ((2-(1,1-Dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz-[h]imidaz[4,5f]isoquinolin-7-one) or with neutralizing antibody against IFN
completely abrogated TNF-induced CD38 expression at both protein and mRNA levels. Combining TNF (0.1 and 1 ng/ml) and IFN(100 IU/ml), at concentrations alone that had little effect on CD38 expression, induced a robust synergistic induction of CD38 mRNA and protein levels. 8-bromo-cADPr, a cADPr antagonist, significantly augmented TNF-induced IL-6 secretion, while RANTES secretion was suppressed. 8-bromo-cADPr, however, did not affect TNF-induced cell surface expression of ICAM-1. Together, our study is the first to demonstrate that IFN-dependent activation of CD38 pathway is a novel component by which TNF differentially regulates the expression of inflammatory genes in ASM cells.
Key words:
Tumor necrosis factor, Stat activated transcriptional events
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