Title
Inflammatory cytokine oncostatin M induces endothelial activation in macro- and microvascular endothelial cells and in APOE*3Leiden.CETP mice
Author
van Keulen, D.
Pouwer, M.G.
Pasterkamp, G.
van Gool, A.J.
Sollewijn Gelpke, M.D.
Princen, H.M.G.
Tempel, D.
Publication year
2018
Abstract
Aims Endothelial activation is involved in many chronic inflammatory diseases, such as atherosclerosis, and is often initiated by cytokines. Oncostatin M (OSM) is a relatively unknown cytokine that has been suggested to play a role in both endothelial activation and atherosclerosis. We comprehensively investigated the effect of OSM on endothelial cell activation from different vascular beds and in APOE*3Leiden.CETP mice. Methods and results Human umbilical vein endothelial cells, human aortic endothelial cells and human microvascular endothelial cells cultured in the presence of OSM express elevated MCP-1, IL-6 and ICAM-1 mRNA levels. Human umbilical vein endothelial cells and human aortic endothelial cells additionally expressed increased VCAM-1 and E-selectin mRNA levels. Moreover, ICAM-1 membrane expression is increased as well as MCP-1, IL-6 and E-selectin protein release. A marked increase was observed in STAT1 and STAT3 phosphorylation indicating that the JAK/STAT pathway is involved in OSM signaling. OSM signals through the LIF receptor alfa (LIFR) and the OSM receptor (OSMR). siRNA knockdown of the LIFR and the OSMR revealed that simultaneous knockdown is necessary to significantly reduce MCP-1 and IL-6 secretion, VCAM-1 and E-selectin shedding and STAT1 and STAT3 phosphorylation after OSM stimulation. Moreover, OSM administration to APOE*3Leiden.CETP mice enhances plasma E-selectin levels and increases ICAM-1 expression and monocyte adhesion in the aortic root area. Furthermore, Il-6 mRNA expression was elevated in the aorta of OSM treated mice. Conclusion OSM induces endothelial activation in vitro in endothelial cells from different vascular beds through activation of the JAK/STAT cascade and in vivo in APOE*3Leiden.CETP mice. Since endothelial activation is an initial step in atherosclerosis development, OSM may play a role in the initiation of atherosclerotic lesion formation. Chemicals / CAS cholesterol, 57-88-5; endothelial leukocyte adhesion molecule 1, 128875-25-2; intercellular adhesion molecule 1, 126547-89-5; Janus kinase, 161384-16-3; oncostatin M, 106956-32-5; Chemokine CCL2; Cholesterol Ester Transfer Proteins; E-Selectin; Intercellular Adhesion Molecule-1; Interleukin-6; Oncostatin M; STAT Transcription Factors.
Subject
ELSS - Earth, Life and Social Sciences
Life Life
Healthy Living
Biomedical Innovation
Inflammatory diseases
Animals
Cell Adhesion
Cells, Cultured
Chemokine CCL2
Cholesterol Ester Transfer Proteins
E-Selectin
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Humans
Intercellular Adhesion Molecule-1
Interleukin-6
Mice
Oncostatin M
Signal Transduction
STAT Transcription Factors
MHR - Metabolic Health Research
To reference this document use:
http://resolver.tudelft.nl/uuid:80ac3541-47b7-4fc6-8c1e-0705fe244367
DOI
https://doi.org/10.1371/journal.pone.0204911
TNO identifier
842388
Source
Plos One, 13 (13), e0204911
Document type
article