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Mesenchymal stem cells (MSC) have immunomodulatory capacity, but their effects on endothelial cells (EC) and recruitment of leukocytes are unknown. We cocultured human bone marrow-derived MSC and EC, and found that MSC could down-regulate adhesion of flowing human neutrophils or lymphocytes, and their subsequent transendothelial migration. This applied for EC treated with tumour necrosis factor-alpha (TNF), interleukin-1beta (IL-1) or TNF and interferon-gamma combined. Supernatant from cocultures added to EC also had an inhibitory effect on recruitment. This supernatant had much higher levels of IL-6 than supernatant from cultures of the individual cells, and the individual supernatants had no inhibitory functions. Addition of neutralising antibody against IL-6 removed the bioactivity of the coculture supernatant and also the immunomodulatory effects of coculture. Studies using siRNA to reduce IL-6 production in each cell type showed that it came mainly from the MSC in coculture, and reduction in production in these cells alone was sufficient to lose the inhibitory effects of coculture. Interestingly, studies using siRNA to reduce IL-6-receptor expression also showed that expression in MSC contributed to the effects of coculture. This was explained when we detected soluble IL-6R in supernatants and showed that receptor removal greatly reduced the potency of supernatant. 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 release of soluble IL-6R. These studies establish a novel mechanism by which MSC delivered from the blood might have protective effects against inflammatory pathology and cardiovascular disease. [ABSTRACT FROM AUTHOR]