Open AccessEndothelial Interferon Regulatory Factor 1 Regulates Lipopolysaccharide-Induced VCAM-1 Expression Independent of NFκB
Author(s) -
Rui Yan,
Matijs van Meurs,
Eliane R. Popa,
Rianne M. Jongman,
Peter J. Zwiers,
Anita E. Niemarkt,
Timara Kuiper,
Jan A. A. M. Kamps,
Peter Heeringa,
Jan G. Zijlstra,
Grietje Molema,
Jill Moser
Publication year - 2017
Publication title -
journal of innate immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.078
H-Index - 64
eISSN - 1662-8128
pISSN - 1662-811X
DOI - 10.1159/000477211
Subject(s) - proinflammatory cytokine , signal transduction , microbiology and biotechnology , biology , endothelial activation , vcam 1 , lipopolysaccharide , regulator , nf κb , irf1 , gene knockdown , immunology , cancer research , inflammation , transcription factor , icam 1 , cell adhesion molecule , apoptosis , biochemistry , gene
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.