RT Journal Article
SR Electronic
T1 Endothelial Resolution of Inflammation is Delayed Following JAK-driven but not NFκB-dependent Activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.18.449043
DO 10.1101/2021.06.18.449043
A1 Nicole M Valenzuela
YR 2021
UL http://biorxiv.org/content/early/2021/06/18/2021.06.18.449043.abstract
AB Blood endothelial cells actively regulate egress of leukocytes into peripheral tissues in response to inflammatory insult. The resolution of inflammation is critical for healing and return to homeostasis, but the timing and mechanisms involved in return to a non-inflamed state are not well-understood. We examined vascular endothelial activation comparing NFκB-driven TNFα and JAK/STAT-mediated IFNγ. Pro-adhesive gene expression, phenotype and secretome of human endothelial cells from 6 vascular beds were measured under chronic cytokine stimulation, and after short-term cytokine priming followed by withdrawal. The majority of inducible TNFα effectors require continuous exposure for reinforcement of the altered phenotype. NFκB and target genes are quickly down-regulated in the absence of cytokine. In contrast, the consequences of even short exposure to IFNγ are long-lasting and broad, with sustained elevation of adhesion molecules and chemokines up to 48hr later. JAK/STAT and interferon response factor expression are likewise durable, dependent on new transcription and autonomous of continuous IFNγ. Finally, intact persistent STAT expression and JAK signaling in the endothelium is required to maintain a pro-adhesive phenotype after IFNγ withdrawal, which could be prevented by the JAK1/2 inhibitor ruxolitinib. Our results reveal a sustained JAK-dependent perturbation of endothelial function after exposure to IFNγ, but not after NFκB-driven inflammation.Competing Interest StatementThe authors have declared no competing interest.