Prolonged exposure of mouse macrophages to IFN‐β suppresses transcription of the inducible nitric oxide synthase gene: altered availability of transcription factor Stat1α

• Published in: European journal of immunology Vol. 30; no. 6; pp. 1551 - 1561
• Main Authors: Gao, Jian Jun, Filla, Michael B., Lorsbach, Robert B., Pace, Judith L., Crespo, Ana, Russell, Stephen W., Murphy, William J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag GmbH 01-06-2000
• Subjects: b-Interferon; Cellular activation; Gene regulation; Inflammatory mediator; Lipopolysaccharide; Molecular biology; Stat1^a protein
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/1521-4141(200006)30:6<1551::AID-IMMU1551>3.0.CO;2-Y

Previous studies from our laboratory have shown that prolonged exposure of mouse macrophages to IFN‐β interferes with their subsequent ability to become activated for tumor cell killing. Data reported here show that such inhibition is due to reduced production of NO, resulting from decreased transcription of the gene that encodes inducible NO synthase (iNOS; EC 1.14.13.39). The molecular basis for such suppression was shown to be, at least in part, decreased nuclear accumulation of tyrosine‐phosphorylated Stat1α (pStat1α), and a consequent change in the nuclear ratio of pStat1α to non‐transactivating pStat1β. Reduced phosphorylation was observed despite the fact that time‐course studies revealed greater than normal quantities of both Stat1α and Stat1β proteins in macrophages that had been pre‐exposed to IFN‐β. The decrease in nuclear pStat1α was demonstrated to involve an increase in the rate of turnover of phosphorylated protein. The homodimeric form of pStat1α is essential for the expression of both the iNOS and IFN‐regulatory factor‐1 genes (the product of the latter is necessary for full expression of the iNOS gene). These results have broad implications, because they suggest that limiting the availability of homodimeric pStat1α is a means by which down‐regulation of genes containing promoter‐linked IFN‐γ‐activated sites might be achieved.