11 Citations (Scopus)

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-alpha-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 NF kappa B 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 NF kappa B. (C) 2017 S. Karger AG, Basel.

Original languageEnglish
Pages (from-to)546-560
Number of pages15
JournalJournal of innate immunity
Volume9
Issue number6
Early online date29-Jun-2017
DOIs
Publication statusPublished - Nov-2017

Keywords

  • Interferon regulatory factor 1
  • Sepsis
  • Lipopolysaccharide
  • Endothelial cells
  • Inflammation
  • NF kappa B signaling
  • FACTOR-I
  • SEVERE SEPSIS
  • SEPTIC SHOCK
  • CELL-ADHESION
  • TNF-ALPHA
  • INFLAMMATION
  • IRF-1
  • GENE
  • DEFINITIONS
  • MOLECULES

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