Dl. Feinstein, SUPPRESSION OF ASTROGLIAL NITRIC-OXIDE SYNTHASE EXPRESSION BY NOREPINEPHRINE RESULTS FROM DECREASED NOS-2 PROMOTER ACTIVITY, Journal of neurochemistry, 70(4), 1998, pp. 1484-1496
We previously demonstrated that norepinephrine (NE) inhibits induction
of the calcium-independent isoform of nitric oxide synthase (NOS-2) i
n primary rat astrocyte cultures. However, the molecular mechanisms un
derlying this effect are unknown. In C6 cells and astrocytes, NE suppr
essed both cytokine- and lipopolysaccharide (LPS)-dependent nitrite ac
cumulation, an index of NOS-2 activity, NE reduced the steady-state le
vels of NOS-2 mRNA induced by LPS plus cytokines but did not decrease
NOS-2 mRNA stability or inhibit activation or subunit composition of t
ranscription factor nuclear factor KB, which is necessary for NOS-2 in
duction. In C6 cells stably transfected with a 1,588-bp mouse NOS-2 pr
omoter, NE reduced LPS plus cytokine-induced reporter gene expression,
suggesting inhibition of NOS-2 promoter activity. in contrast, suppre
ssion was lost when a truncated 85-bp NOS-2 promoter was used, and in
these cells NE potentiated reporter gene expression, alone or in the p
resence of LPS and cytokines. These results suggest that the suppressi
ve effects of NE are due to modification of transcription factor activ
ity in a region located between -1,588 and -85 of the NOS-2 promoter a
nd may help explain observations that in some cells cyclic AMP can pot
entiate, rather than suppress, NOS-2 expression.