Crosstalk between mesenchymal stem cells and endothelial cells leads to downregulation of cytokine-induced leukocyte recruitment.
Mesenchymal stem cells (MSC) have immunomodulatory 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 downregulate adhesion of flowing neutrophils or lymphocytes and their subsequent transendothelial migration. This applied for EC treated with tumor 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 neutralizing 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 knockdown 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. Neutralization 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 upregulation of production of IL-6 by MSC which in turn downregulated 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.
Centre for Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom.
N Thin
NT
Luu
Helen M
HM
McGettrick
Christopher D
CD
Buckley
Phil N
PN
Newsome
G Ed
GE
Rainger
Jon
J
Frampton
Gerard B
GB
Nash
D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D015536:Down-Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*
D016207:Cytokines
Endothelial cells; Inflammation; Leukocytes; Mesenchymal stem cells