Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NFκB

J Innate Immun. 2017;9(6):546-560. doi: 10.1159/000477211. Epub 2017 Jun 29.

Abstract

Sepsis is a severe systemic inflammatory response to infection. Endothelial activation and dysfunction play a critical role in the pathophysiology of sepsis and represent an important therapeutic target to reduce sepsis mortality. Interferon regulatory factor 1 (IRF-1) was recently identified as a downstream target of TNF-α-mediated signal transduction in endothelial cells. The aim of this study was to explore the importance of IRF-1 as a regulator of lipopolysaccharide (LPS)-induced endothelial proinflammatory activation. We found that renal IRF-1 was upregulated by LPS in vivo as well as in LPS-stimulated endothelial cells in vitro. Furthermore, we identified intracellular retinoic acid inducible gene-I (RIG-I) as a regulator of LPS-mediated IRF-1 induction. IRF-1 depletion specifically resulted in diminished induction of VCAM-1 in response to LPS, but not of E-selectin or ICAM-1, which was independent of NFκB signaling. When both IRF-1 and the RIG-I adapter protein mitochondrial antiviral signaling (MAVS) were absent, VCAM-1 induction was not additionally inhibited, suggesting that MAVS and IRF-1 reside in the same signaling pathway. Surprisingly, E-selectin and IL-6 induction were no longer inhibited by MAVS knockdown when IRF-1 was also absent, revealing a redundant endothelial activation pathway. In summary, we report an IRF-1-mediated proinflammatory signaling pathway that specifically regulates LPS-mediated VCAM-1 expression, independent of NFκB.

Keywords: Endothelial cells; Inflammation; Interferon regulatory factor 1; Lipopolysaccharide; NFκB signaling; Sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endothelium / metabolism*
  • Endothelium / pathology
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Kidney / physiology*
  • Lipopolysaccharides / immunology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • RNA, Small Interfering / genetics
  • Sepsis / immunology*
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism*

Substances

  • Interferon Regulatory Factor-1
  • Lipopolysaccharides
  • Membrane Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Robo3 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1