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Differentially Regulates the Expression of Proinflammatory Genes in Human Airway Smooth Muscle Cells by Activation of Interferon-
–Dependent CD38 Pathway
Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania (O.T., R.A.P., S.T., Y.A.); and Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota (T.F.W.)
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 tumor necrosis factor-
(TNF) induces CD38 expression and its role in regulating gene expression in human ASM cells. Using flow cytometry analyses, TNF enhanced CD38 expression in a manner that was time-(0–24 h), concentration-(0.1–40 ng/ml), and protein synthesis-(cycloheximide blockade) dependent. A selective agonistic antibody against tumor necrosis factor receptor (TNFR) 1 also augmented CD38 expression, whereas anti-TNFR2 antagonistic antibody did not prevent the TNF response. Inhibition of the Janus activated kinase/signal transducer and activator of transcription pathways using the soluble inhibitor 2-(1,1-dimethylethyl)-9-fluoro-3,6-dihydro-7H-benz-[h]imidaz[4,5-f]isoquinolin-7-one (DBI) or with neutralizing antibody against interferon 
(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 interleukin-6 secretion, whereas regulated on activation normal T cell expressed and secreted secretion was suppressed. 8-Bromo-cADPr, however, did not affect TNF-induced cell surface expression of intercellular adhesion molecule-1. 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.
Address correspondence to: Dr. Yassine Amrani, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, 421 Curie Boulevard, 848 BRB II/III, Philadelphia, PA 19104-6160. E-mail: amrani{at}mail.med.upenn.edu
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