Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-kappaB binding to DNA.
Treatment of astroglial cells with interleukin 1beta and interferon gamma transcriptionally activates the nitric oxide synthase (NOS)-2 gene. The duration of mRNA expression is brief because of transcript instability. In addition, NO donors reduce the expression of NOS-2 mRNA dramatically by reducing the rate of transcription. In this study we observed that the NO donor, spermine NONOate did not inhibit the activation and translocation of NF-kappaB, a key transcription factor in the induction of NOS-2, but inhibited formation of the NF-kappaB-DNA complex. This effect was reversed by methaemoglobin (acting as an NO trap) and by the reducing agent dithiothreitol. Formation of the interferon-regulatory factor-DNA complex was unaffected by NO. These results suggest that NO can modulate its own production by interfering with NF-kappaB interaction with the promoter region of the NOS gene, a negative feedback effect that may be important for limiting NO production in vivo.
Park
S K
SK
Department of Pharmacology, University of Iowa College of Medicine, Iowa City 52242, U.S.A.
Lin
H L
HL
Murphy
S
S
D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001692:Biological Transport; D002451:Cell Compartmentation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D008706:Methemoglobin / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
D016328:NF-kappa B; D009569:Nitric Oxide; D008706:Methemoglobin; D019001:Nitric Oxide Synthase