Crosstalk between mesenchymal stem cells and endothelial cells leads to down-regulation of cytokine-induced leukocyte recruitment

Research output: Contribution to journalArticlepeer-review

Standard

Harvard

APA

Vancouver

Author

Bibtex

@article{731f620abca84e3da9142329f19695d0,
title = "Crosstalk between mesenchymal stem cells and endothelial cells leads to down-regulation of cytokine-induced leukocyte recruitment",
abstract = "Mesenchymal stem cells (MSC) have immuno-modulatory properties, but their effects on endothelial cells (EC) and recruitment of leukocytes are unknown. We cocultured human bone marrow-derived MSC with EC, and found that MSC could down-regulate adhesion of flowing neutrophils or lymphocytes, and their subsequent transendothelial migration. This applied for EC treated with tumour necrosis factor-α (TNF), interleukin-1β (IL-1) or TNF and interferon-γ combined. Supernatant from cocultures also inhibited endothelial responses. This supernatant had much higher levels of IL-6 than supernatant from cultures of the individual cells, which also lacked inhibitory functions. Addition of neutralising antibody against IL-6 removed the bioactivity of the supernatant and also the immunomodulatory effects of coculture. Studies using siRNA showed that IL-6 came mainly from the MSC in coculture, and reduction in production in MSC alone was sufficient to impair the protective effects of coculture. Interestingly, siRNA knock-down of IL-6-receptor expression in MSC as well as EC inhibited anti-inflammatory effects. This was explained when we detected soluble IL-6R-receptor in supernatants and showed that receptor removal reduced the potency of supernatant. Neutralisation of transforming growth factor-β indicated that activation of this factor in coculture contributed to Il-6 production. Thus, crosstalk between MSC and EC caused up regulation of production of IL-6 by MSC which in turn down regulated the response of EC to inflammatory cytokines, an effect potentiated by MSC release of soluble IL-6R. These studies establish a novel mechanism by which MSC might have protective effects against inflammatory pathology and cardiovascular disease. Stem Cells 2013.",
author = "Nguyet-Thin Luu and McGettrick, {Helen M} and Buckley, {Christopher D} and Philip Newsome and Ed Rainger and Jonathan Frampton and Nash, {Gerard B}",
year = "2013",
month = dec,
doi = "10.1002/stem.1511",
language = "English",
volume = "31",
pages = "2690--2702",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "12",

}

RIS

TY - JOUR

T1 - Crosstalk between mesenchymal stem cells and endothelial cells leads to down-regulation of cytokine-induced leukocyte recruitment

AU - Luu, Nguyet-Thin

AU - McGettrick, Helen M

AU - Buckley, Christopher D

AU - Newsome, Philip

AU - Rainger, Ed

AU - Frampton, Jonathan

AU - Nash, Gerard B

PY - 2013/12

Y1 - 2013/12

N2 - Mesenchymal stem cells (MSC) have immuno-modulatory properties, but their effects on endothelial cells (EC) and recruitment of leukocytes are unknown. We cocultured human bone marrow-derived MSC with EC, and found that MSC could down-regulate adhesion of flowing neutrophils or lymphocytes, and their subsequent transendothelial migration. This applied for EC treated with tumour necrosis factor-α (TNF), interleukin-1β (IL-1) or TNF and interferon-γ combined. Supernatant from cocultures also inhibited endothelial responses. This supernatant had much higher levels of IL-6 than supernatant from cultures of the individual cells, which also lacked inhibitory functions. Addition of neutralising antibody against IL-6 removed the bioactivity of the supernatant and also the immunomodulatory effects of coculture. Studies using siRNA showed that IL-6 came mainly from the MSC in coculture, and reduction in production in MSC alone was sufficient to impair the protective effects of coculture. Interestingly, siRNA knock-down of IL-6-receptor expression in MSC as well as EC inhibited anti-inflammatory effects. This was explained when we detected soluble IL-6R-receptor in supernatants and showed that receptor removal reduced the potency of supernatant. Neutralisation of transforming growth factor-β indicated that activation of this factor in coculture contributed to Il-6 production. Thus, crosstalk between MSC and EC caused up regulation of production of IL-6 by MSC which in turn down regulated the response of EC to inflammatory cytokines, an effect potentiated by MSC release of soluble IL-6R. These studies establish a novel mechanism by which MSC might have protective effects against inflammatory pathology and cardiovascular disease. Stem Cells 2013.

AB - Mesenchymal stem cells (MSC) have immuno-modulatory properties, but their effects on endothelial cells (EC) and recruitment of leukocytes are unknown. We cocultured human bone marrow-derived MSC with EC, and found that MSC could down-regulate adhesion of flowing neutrophils or lymphocytes, and their subsequent transendothelial migration. This applied for EC treated with tumour necrosis factor-α (TNF), interleukin-1β (IL-1) or TNF and interferon-γ combined. Supernatant from cocultures also inhibited endothelial responses. This supernatant had much higher levels of IL-6 than supernatant from cultures of the individual cells, which also lacked inhibitory functions. Addition of neutralising antibody against IL-6 removed the bioactivity of the supernatant and also the immunomodulatory effects of coculture. Studies using siRNA showed that IL-6 came mainly from the MSC in coculture, and reduction in production in MSC alone was sufficient to impair the protective effects of coculture. Interestingly, siRNA knock-down of IL-6-receptor expression in MSC as well as EC inhibited anti-inflammatory effects. This was explained when we detected soluble IL-6R-receptor in supernatants and showed that receptor removal reduced the potency of supernatant. Neutralisation of transforming growth factor-β indicated that activation of this factor in coculture contributed to Il-6 production. Thus, crosstalk between MSC and EC caused up regulation of production of IL-6 by MSC which in turn down regulated the response of EC to inflammatory cytokines, an effect potentiated by MSC release of soluble IL-6R. These studies establish a novel mechanism by which MSC might have protective effects against inflammatory pathology and cardiovascular disease. Stem Cells 2013.

U2 - 10.1002/stem.1511

DO - 10.1002/stem.1511

M3 - Article

C2 - 23939932

VL - 31

SP - 2690

EP - 2702

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 12

ER -