Molecular mechanisms of iNOS induction by IL-1β and IFN-γ in rat aortic smooth muscle cells

Xingwu Teng, Hanfang Zhang, Connie Snead, And John D. Catravas

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

In rat aortic smooth muscle cells (RASMC), interferon (IFN)-γ enhanced nitrite accumulation and type II nitric oxide synthase (iNOS) protein expression induced by interleukin (IL)-1β. IFN-γ alone had no effect on nitrite accumulation or iNOS protein. IL-1β, but not IFN-γ, induced nuclear factor (NF)-κB and CCAAT box/enhancer binding protein (C/EBP) nuclear binding. Conversely, IFN-γ, but not IL-1β, induced signal transducer and activator of transcription (STAT) 1 and interferon regulatory factor (IRF)-1 binding. In a -1.4-kb rat iNOS promoter segment, deletion of an IFN-γ-activated site (GAS) increased IL-1β-induced activity but inhibited IFN-γ-enhanced activity, suggesting a two-way effect of the GAS site on iNOS induction: enhancing induction through STAT1 activation and inhibiting induction through a non-IFN-γ-mediated mechanism. Deletion of both an IRF and a C/EBP site reduced the IL-1β-induced and the IFN-γ-enhanced activities. However, IRF site mutations decreased the IFN-γ-enhanced activity without affecting the IL-1β-induced activity. Insertion of two IRF sites increased the IFN-γ-enhanced, but not the IL-1β-induced, activity. Mutations of a reverse NF-κB site did not significantly change IFN-γ-enhanced activity. We conclude that in RASMC, NF-κB and C/EBP mediate the IL-1β-induced iNOS expression, whereas IRF-1 and STAT1 mediate the IFN-γ-enhanced iNOS induction.

Original languageEnglish (US)
Pages (from-to)C144-C152
JournalAmerican Journal of Physiology - Cell Physiology
Volume282
Issue number1 51-1
Publication statusPublished - Jul 2 2002

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Keywords

  • CCAAT box/enhancer binding protein
  • Interferon regulatory factor-1
  • Interferon-γ activation site
  • Nuclear factor-κB
  • Signal transducer and activator of transcription 1

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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