Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon-γ and lipopolysaccharide

R. B. Lorsbach, W. J. Murphy, C. J. Lowenstein, S. H. Snyder, S. W. Russell

Research output: Contribution to journalArticlepeer-review

Abstract

Macrophages can become activated to kill both tumor cells and a variety of microbes. Results here show that synthesis of nitric oxide (NO), a mediator of many macrophage cytotoxic functions, was greatly increased when cells of the mouse macrophage cell line RAW 264.7 were costimulated with bacterial lipopolysaccharide (LPS) and interferon-γ (IFN-γ), compared to LPS alone. This increase paralleled increases in cytotoxicity. Northern analysis showed that increased production of NO was preceded by markedly enhanced expression of mRNA for the inducible form of macrophage NO synthase (mac-NOS), which catalyzes the synthesis of NO. Cycloheximide inhibited the induction of mac- NOS mRNA by IFN-γ and LPS, indicating that expression of this mRNA required de novo protein synthesis. Elevated expression of mac-NOS mRNA was not due to an increase in its stability. Rather, the combination of IFN-γ and LPS induced a much higher rate of transcription of the mac-NOS gene than did stimulation with LPS alone. These results provide one explanation of why priming and triggering stimuli, such as IFN-γ and LPS, respectively, synergistically activate macrophages and may be applicable to explaining how IFN-γ augments NO-dependent microbicidal activity in macrophages as well.

Original languageEnglish (US)
Pages (from-to)1908-1913
Number of pages6
JournalJournal of Biological Chemistry
Volume268
Issue number3
StatePublished - 1993

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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