Inflammatory cytokine oncostatin M induces endothelial activation in macro- and microvascular endothelial cells and in APOE3Leiden.CETP mice

• Published in: PloS one Vol. 13; no. 10; p. e0204911
• Main Authors: van Keulen, Danielle, Pouwer, Marianne G, Pasterkamp, Gerard, van Gool, Alain J, Sollewijn Gelpke, Maarten D, Princen, Hans M G, Tempel, Dennie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2018; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Animals; Aorta; Apolipoprotein E; Apolipoproteins; Arteriosclerosis; Arthritis; Atherosclerosis; Biology and Life Sciences; Cancer; Cardiology; Cardiovascular disease; Cell activation; Cell Adhesion; Cells, Cultured; Cellular signal transduction; Chemokine CCL2 - genetics; Cholesterol Ester Transfer Proteins - genetics; Cytokines; Data collection; E-selectin; E-Selectin - blood; E-Selectin - genetics; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelium; Gene expression; Hematology; Human Umbilical Vein Endothelial Cells; Humans; Inflammatory diseases; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Interleukin 6; Interleukin-6 - genetics; Laboratories; Laboratory rats; Medical research; Medicine and Health Sciences; Metabolism; Mice; Microvasculature; Monocyte chemoattractant protein 1; Monocytes; Oncostatin M; Oncostatin M - metabolism; Phosphorylation; Proteins; Research and Analysis Methods; Signal Transduction; siRNA; STAT Transcription Factors - metabolism; Stat1 protein; Stat3 protein; Umbilical vein; Vascular cell adhesion molecule 1; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0204911

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. 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. 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.