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Vol. 54, Issue 2, 258-263, August 1998

Expressional Down-Regulation of Neuronal-Type Nitric Oxide Synthase I by Glucocorticoids in N1E-115 Neuroblastoma Cells

Petra M. Schwarz, Birgit Gierten, Jean-Paul Boissel, and Ulrich Förstermann

Department of Pharmacology, Johannes Gutenberg University, 55101 Mainz, Germany

Neuronal-type nitric oxide synthase (NOS I) is involved in ischemia-induced brain damage, and glucocorticoids have been reported to protect from brain damage. This prompted us to investigate if the activity or expression of NOS I was influenced by glucocorticoids. We used the murine neuroblastoma cell line N1E-115 as our experimental model. Short-term incubation (30 min) of the N1E-115 cells with dexamethasone (10 nM to 1 µM) or hydrocortisone (100 nM to 10 µM) did not change the enzymatic activity of NOS I. However, the glucocorticoids inhibited NOS I mRNA expression in a concentration-dependent fashion (down to 53.3 ± 2.5% of control). In time-course experiments with 100 nM dexamethasone, maximum down-regulation of NOS I mRNA was seen after 24 hr (55.6 ± 6.3% of control). Similar effects were seen with 10 µM hydrocortisone. The effect of 100 nM dexamethasone was completely reversed by 1 µM of the glucocorticoid receptor antagonist mifepristone. In experiments with actinomycin D (10 µg/ml), the half-life of the NOS I mRNA was determined to be approximately 12 hr and remained unchanged after glucocorticoid incubation. Nuclear run-on analyses indicated that the decrease in NOS I mRNA was the result of a glucocorticoid-induced inhibition of NOS I gene transcription. In Western blots, the 160-kDa NOS I protein band was down-regulated to 68.5 ± 8.4% of control after an incubation of the N1E-115 cells with 100 nM dexamethasone for 26 hr. Similarly, NO production was down-regulated to 57.8 ± 8.7% of control. These data demonstrate that glucocorticoids reduce the expression of NOS I without changing its activity.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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