IL-6, along with IL-8, has been shown to promote Treg migration to certain tumours [45] and may therefore play a crucial role in Treg signalling. A recent study in type II diabetes has also shown that the percentage of CD4(+)CD25(hi)CD127(–) Tregs are correlated positively SP600125 research buy with plasma IL-6 [46]. Mesenchymal stem cells from mice were shown to promote the differentiation

of uncommitted naive T cells to FoxP3+ regulatory T cells [47]. This study has shown that the major cytokines involved in these processes were transforming growth factor (TGF)-β and IL-6 and that immunomodulation could be blocked by administration of anti-TGF-β or anti-IL-6, suggesting paracrine mechanisms. In another study in mice, excessive Selleckchem Fludarabine IL-6 production caused an increase in natural Tregs, which maintained their immunosuppressive capacities both in vitro and in vivo [48]. This suggests that IL-6 may be a key mediator in effector/regulatory T cell balance. However, there are also data that are in contrast to our findings. In another study, using Tregs derived from the rheumatic synovium, blocking IL-6

or TNF increased the suppressive immunomodulatory capacities of these cells [49]. This study suggests that Treg function varies importantly with the inflammatory milieu in the joint. These findings are not in accordance with our experiments, in which IL-6 maintained the percentage of Tregs. This discrepancy may be due to differences in the underlying pathologies, but also reflect the dual role of IL-6. However, the functional consequences remain to be identified in upcoming experiments. We have chosen to carry out our study on Tregs taken from healthy donors in order to provide information TGF-beta inhibitor on the immunomodulatory

capacities of MSCs and ruling out possible influences of OA on Tregs and thus on Treg–MSC interaction. An important question is whether or not Tregs taken from OA patients differ in their interaction with MSCs. Our findings therefore raise several questions that need to be verified by future research. Understanding the effects of MSCs in local joint inflammation in OA may pave the way for future cell-based approaches, as MSCs can be supposed to not only exert their regenerative potential when administered, but also intervene in local immunity. This study has several limitations. First, a comparison to MSCs taken from healthy donors would be useful to detect whether the inability to recruit Tregs from a CD4+ population, as has been shown by other groups, should be interpreted as a reduced capacity of immunomodulation in OA. This question has not yet been addressed due to ethical questions, as synovium from healthy individuals is not easily available. Taking synovium from a young population undergoing hip or knee arthroscopy might falsify the results, as it is known that cartilage injuries are found in up to 65% of the patients during arthroscopy, irrespective of the underlying pathology [50].