Suppression of IL 10 production by activated B cells via a cell contact dependent cyclooxygenase 2 pathway upregulated in IFN g treated mesenchymal stem cells.
The immunoregulatory properties of mesenchymal stem cells (MSCs) have been well documented in various models in vitro and in vivo. Furthermore, a population of regulatory B cells (Bregs) that produce relatively high concentrations of IL 10 has been recently described. To study the relationship between MSCs and Bregs, we analyzed the effects of MSCs on IL 10 production by lipopolysaccharide (LPS) activated mouse B cells. The production of IL 10 by B cells remained preserved in the presence of MSCs and was even significantly enhanced by IFN g. However, the production of IL 10 was strongly suppressed in cultures containing MSCs and IFN g. Preincubation of MSCs, but not of B cells, with IFN g induced the suppression of IL 10 secretion in cultures containing MSCs and B cells. The supernatants from IFN g treated MSCs had no inhibitory effect, and the suppression of IL 10 production was abrogated if the MSCs and B cells were separated in a transwell system. Analysis of the gene expression of IFN g or IFN g and LPS treated MSCs revealed a strong upregulation of genes for indoleamine 2,3 dioxygenase (IDO) cyclooxygenase 2 (Cox 2) and programmed cell death ligand 1 (PD L1) While the inhibition of IDO activity or the inclusion of the neutralization monoclonal antibody anti PD L1 did not abrogate the suppression, indomethacin, an inhibitor of Cox 2, completely inhibited the MSC mediated suppression of IL 10 production. Accordingly, the production of IL 10 by B cells was inhibited by exogenous prostaglandin E2. The results thus suggest that IFN g treated MSCs strongly inhibit IL 10 production by activated B cells by a mechanism requiring cell contact and involving the Cox 2 pathway.
Immunobiology