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

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.