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Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NF kappa B

Yan, R., van Meurs, M., Popa, E. R., Jongman, R. M., Zwiers, P. J., Niemarkt, A. E., Kuiper, T., Kamps, J. A., Heeringa, P., Zijlstra, J. G., Molema, G. & Moser, J., Nov-2017, In : Journal of innate immunity. 9, 6, p. 546-560 15 p.

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

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DOI

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
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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