10898490

pubmed:Citation

6

Previous studies from our laboratory have shown that prolonged exposure of mouse macrophages to IFN-beta 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 Stat1alpha (pStat1alpha), and a consequent change in the nuclear ratio of pStat1alpha to non-transactivating pStat1beta. Reduced phosphorylation was observed despite the fact that time-course studies revealed greater than normal quantities of both Stat1alpha and Stat1beta proteins in macrophages that had been pre-exposed to IFN-beta. The decrease in nuclear pStat1alpha was demonstrated to involve an increase in the rate of turnover of phosphorylated protein. The homodimeric form of pStat1alpha 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 pStat1alpha is a means by which down-regulation of genes containing promoter-linked IFN-gamma-activated sites might be achieved.

eng

IM

MEDLINE

0014-2980

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NLM

1551-61

pubmed-meshheading:10898490-Animals, pubmed-meshheading:10898490-Cell Nucleus, pubmed-meshheading:10898490-Cells, Cultured, pubmed-meshheading:10898490-Culture Media, pubmed-meshheading:10898490-Cytotoxicity, Immunologic, pubmed-meshheading:10898490-DNA-Binding Proteins, pubmed-meshheading:10898490-Enhancer Elements, Genetic, pubmed-meshheading:10898490-Interferon Regulatory Factor-1, pubmed-meshheading:10898490-Interferon-beta, pubmed-meshheading:10898490-Interferon-gamma, pubmed-meshheading:10898490-Kinetics, pubmed-meshheading:10898490-Lipopolysaccharides, pubmed-meshheading:10898490-Macrophages, pubmed-meshheading:10898490-Male, pubmed-meshheading:10898490-Mice, pubmed-meshheading:10898490-Mice, Inbred C3H, pubmed-meshheading:10898490-NF-kappa B, pubmed-meshheading:10898490-Nitric Oxide Synthase, pubmed-meshheading:10898490-Nitric Oxide Synthase Type II, pubmed-meshheading:10898490-Phosphoproteins, pubmed-meshheading:10898490-Phosphorylation, pubmed-meshheading:10898490-Promoter Regions, Genetic, pubmed-meshheading:10898490-Recombinant Proteins, pubmed-meshheading:10898490-STAT1 Transcription Factor, pubmed-meshheading:10898490-Time Factors, pubmed-meshheading:10898490-Trans-Activators, pubmed-meshheading:10898490-Transcription, Genetic, pubmed-meshheading:10898490-Tumor Cells, Cultured

Prolonged exposure of mouse macrophages to IFN-beta suppresses transcription of the inducible nitric oxide synthase gene: altered availability of transcription factor Stat1alpha.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't