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

• Published in: American journal of physiology. Lung cellular and molecular physiology 2007-06, Vol.292 (6), p.L1385
• Main Authors: Tirumurugaan, K. G, Jude, J. A, Kang, B. N, Panettieri, R. A, Walseth, T. F, Kannan, M. S
• Format: Article
• Language: English
• Subjects: Cells; Gene expression; Kinases; Muscular system
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00472.2006

Departments of 1 Veterinary and Biomedical Sciences and 3 Pharmacology, University of Minnesota, St. Paul, Minnesota; and 2 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Submitted 7 December 2006 ; accepted in final form 17 February 2007 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 NF- B 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 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- -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- B and AP-1 activation. EMSAs confirmed the role of p38 and JNK in mediating NF- B 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 NF- B and AP-1 activation, and ERK and p38 MAPKs also regulate expression posttranscriptionally through message stability. extracellular signal-regulated kinase; p38; c-Jun NH 2 -terminal kinase; electrophoretic mobility shift assays; ADP-ribosyl cyclase Address for reprint requests and other correspondence: M. S. Kannan, Dept. of Veterinary and Biomedical Sciences, College of Veterinary Medicine, Univ. of Minnesota, 1971 Commonwealth Ave., St. Paul, MN 55108 (e-mail: kanna001{at}umn.edu )