Endothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NF kappa BYan, 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.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||15|
|Journal||Journal of innate immunity|
|Early online date||29-Jun-2017|
|Publication status||Published - Nov-2017|
- 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