Ellermann, Sophie F. and Jongman, Rianne M. and Luxen, Matthijs and Kuiper, Timara and Plantinga, Josee and Moser, Jill and Scheeren, Thomas W. L. and Theilmeier, Gregor and Molema, Grietje and Van Meurs, Matijs (2022) Pharmacological inhibition of protein tyrosine kinases axl and fyn reduces TNF-α-induced endothelial inflammatory activation in vitro. Frontiers in pharmacology, 13. pp. 1-13. ISSN 1663-9812

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Abstract

Major surgery induces systemic inflammation leading to pro-inflammatory activation of endothelial cells. Endothelial inflammation is one of the drivers of postoperative organ damage, including acute kidney injury Tumour Necrosis Factor alpha (TNF-α) is an important component of surgery-induced pro-inflammatory activation of endothelial cells. Kinases, the backbone of signalling cascades, can be targeted by pharmacological inhibition. This is a promising treatment option to interfere with excessive endothelial inflammation. In this study, we identified activated kinases as potential therapeutic targets. These targets were pharmacologically inhibited to reduce TNF-α-induced pro-inflammatory signalling in endothelial cells. Kinome profiling using PamChip arrays identified 64 protein tyrosine kinases and 88 serine-threonine kinases, the activity of which was determined at various timepoints (5-240 min) following stimulation with 10 ng/ml TNF-α in Human umbilical vein endothelial cells in vitro . The PTKs Axl and Fyn were selected based on high kinase activity profiles. Co-localisation experiments with the endothelial-specific protein CD31 showed Axl expression in endothelial cells of glomeruli and Fyn in arterioles and glomeruli of both control and TNF-α-exposed mice. Pharmacological inhibition with Axl inhibitor BMS-777607 and Fyn inhibitor PP2 significantly reduced TNF-α-induced pro-inflammatory activation of E-selectin, VCAM-1, ICAM-1, IL-6 and IL-8 at mRNA and VCAM-1, ICAM-1, and IL-6 at protein level in HUVEC in vitro . Upon pharmacological inhibition with each inhibitor, leukocyte adhesion to HUVEC was also significantly reduced, however to a minor extent. In conclusion, pre-treatment of endothelial cells with kinase inhibitors BMS-777607 and PP2 reduces TNF-α-induced endothelial inflammation in vitro.

Item Type:	Article
Uncontrolled Keywords:	Endothelial inflammation, tumour necrosis factor alpha (TNF-α), postoperative organ damage, kinases, axl, fyn, BMS-777607, PP2
Subjects:	Science and mathematics > Life sciences, biology Technology, medicine, applied sciences > Medicine and health
Divisions:	Faculty of Medicine and Health Sciences > Department of Human Medicine
Date Deposited:	06 Dec 2022 09:50
Last Modified:	06 Dec 2022 09:50
URI:	https://oops.uni-oldenburg.de/id/eprint/5517
URN:	urn:nbn:de:gbv:715-oops-55980
DOI:	10.3389/fphar.2022.992262
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