IFN-gamma inhibits AP-1 binding activity in human brain-derived cells through a nitric oxide dependent mechanism.
It has been demonstrated that CNS levels of the cytokine IFN-gamma are elevated in association with a number of neuro-inflammatory diseases. In the present study, we have examined the effect of this cytokine on human brain derived cells. We show that prolonged treatment (22 h) of such cells with IFN-gamma inhibits the DNA binding activity of transcription factor AP-1. Furthermore, we show that this effect can be reversed by either N(G)-monomethyl-L-arginine (L-NMMA) or L-N5-(1-iminoethyl)ornithine (L-NIO), competitive inhibitors of nitric oxide synthase activity [Rees et al., 1990]. In addition, we show that treatment of brain-derived cells with the nitric oxide donor 3-morpholinosydnonimine, HCl (SIN-1), or [N-(b-D-glucopyranosyl)-N2-acetyl-S-nitroso-D,L-penicillaminamide] (glyco-SNAP-1), also inhibits the binding activity of AP-1. Together, these results suggest that IFN-gamma can inhibit AP-1 binding activity through a nitric oxide dependent mechanism.
Laboratory of Molecular Medicine and Neuroscience, National Institutes of Health, Bethesda, MD 20892, USA. conant@codon.nih.gov
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Conant
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Ahmed
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JP
Schwartz
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Major
D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018808:Transcription Factor AP-1; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D007371:Interferon-gamma; D008981:Molsidomine; D010396:Penicillamine