Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 292, Issue 6, Pages L1385-L1395Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00472.2006
Keywords
extracellular signal-regulated kinase; p38; c-Jun NH2-terminal kinase; electrophoretic mobility shift assays; ADP-ribosyl cyclase
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Funding
- NHLBI NIH HHS [R01 HL081824, HL-081824, R01 HL057498, HL-057498] Funding Source: Medline
- NIDA NIH HHS [DA-11806, P50 DA011806] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL057498, R01HL081824] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [P50DA011806] Funding Source: NIH RePORTER
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In human airway smooth muscle ( HASM) cells, the expression of CD38, which synthesizes the calciummobilizing 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-kappa B 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 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-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-kappa B and AP-1 activation. EMSAs confirmed the role of p38 and JNK in mediating NF-kappa B 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-kappa B and AP-1 activation, and ERK and p38 MAPKs also regulate expression posttranscriptionally through message stability.
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