Inflammatory cytokine oncostatin M induces endothelial activation in macro- and microvascular endothelial cells and in APOE*3Leiden.CETP mice

Abstract

AimsEndothelial 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 resultsHuman 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.ConclusionOSM 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.

Oncostatin M reduces atherosclerosis development in APOE*3Leiden.CETP mice and is associated with increased survival probability in humans

“…This cytokine is secreted by activated macrophages and neutrophils and signals through the Leukemia Inhibitory Factor Receptor (LIFR) and the OSM receptor (OSMR)[5–7]. OSM induces endothelial activation by increasing cytokine release, adhesion molecule expression, and leukocyte adhesion to the activated endothelium in cultured endothelial cells[8–10]. Moreover, OSM reduces vascular integrity of rat blood brain barrier endothelial cells and enhances angiogenesis[11,12].…”

“…Using a different approach, we recently demonstrated that short-term OSM administration (for 3 weeks) to APOE*3Leiden.CETP mice increased plasma E-selectin levels, Interleukin (IL)-6 mRNA expression in the aorta and Intercellular Adhesion Molecule 1 (ICAM-1) expression and monocyte adherence to the activated endothelium in the aortic root[10]. Collectively, these findings suggest that OSM may be involved in atherosclerosis development but so far this has never been studied.…”

Relationships among oncostatin M, insulin resistance, and chronic inflammation: a pilot study

“…By activating the JAK/STAT pathways, it affects cell growth, neuron development, the inflammatory response, and other physiological process (6,7). OSM signals via the LIF receptor-alfa (LIFR) and OSM receptor (OSMR) (8). OSM and the OSMR are potential therapeutic targets in chronic inflammatory diseases that cause endothelial dysfunction, such as rheumatoid arthritis, atherosclerosis, thrombosis, and abnormal angiogenesis (9)(10)(11)(12).…”

Oncostatin M in the Regulation of Connective Tissue Cells and Macrophages in Pulmonary Disease

“…OSM has been characterized as an angiogenic factor [58], and acts on vascular endothelial cells in a pro-inflammatory manner [59,60]. These studies were completed in aortic vascular endothelial cells, but whether pulmonary vasculature endothelial cells respond in the same manner is not clear at this time.…”