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Molecular Medicine

, Volume 18, Issue 2, pp 201–208 | Cite as

Interferon Regulatory Factor-1 Regulates the Autophagic Response in LPS-Stimulated Macrophages through Nitric Oxide

  • Lemeng Zhang
  • Jon S. Cardinal
  • Runalia Bahar
  • John Evankovich
  • Hai Huang
  • Gary Nace
  • Timothy R. Billiar
  • Matthew R. Rosengart
  • Pinhua Pan
  • Allan Tsung
Research Article

Abstract

The pathogenesis of sepsis is complex and, unfortunately, poorly understood. The cellular process of autophagy is believed to play a protective role in sepsis; however, the mechanisms responsible for its regulation in this setting are ill defined. In the present study, interferon regulatory factor 1 (IRF-1) was found to regulate the autophagic response in lipopolysaccharide (LPS)-stimulated macrophages. In vivo, tissue macrophages obtained from LPS-stimulated IRF-1 knockout (KO) mice demonstrated increased autophagy and decreased apoptosis compared to those isolated from IRF-1 wild-type (WT) mice. In vitro, LPS-stimulated peritoneal macrophages obtained from IRF-1 KO mice experienced increased autophagy and decreased apoptosis. IRF-1 mediates the inhibition of autophagy by modulating the activation of the mammalian target of rapamycin (mTOR). LPS induced the activation of mTOR in WT peritoneal macrophages, but not in IRF-1 KO macrophages. In contrast, overexpression of IRF-1 alone increased the activation of mTOR and consequently decreased autophagic flux. Furthermore, the inhibitory effects of IRF-1 mTOR activity were mediated by nitric oxide (NO). Therefore, we propose a novel role for IRF-1 and NO in the regulation of macrophage autophagy during LPS stimulation in which IRF-1/NO inhibits autophagy through mTOR activation.

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Authors and Affiliations

  • Lemeng Zhang
    • 1
    • 2
  • Jon S. Cardinal
    • 1
  • Runalia Bahar
    • 1
  • John Evankovich
    • 1
  • Hai Huang
    • 1
  • Gary Nace
    • 1
  • Timothy R. Billiar
    • 1
  • Matthew R. Rosengart
    • 1
  • Pinhua Pan
    • 1
    • 2
  • Allan Tsung
    • 1
    • 3
  1. 1.Department of SurgeryUniversity of PittsburghPittsburghUSA
  2. 2.Department of Pulmonology, Xiangya HospitalCentral South UniversityChangshaChina
  3. 3.Montefiore HospitalUPMC Liver Cancer CenterPittsburghUSA

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