Involvement of TLR3-Dependent PGES Expression in Immunosuppression by Human Bone Marrow Mesenchymal Stem Cells

Human mesenchymal stem cells (MSCs) are known for their prostaglandin E₂ (PGE₂)-mediated immunosuppressive function but the precise molecular mechanisms underlying PGE₂ biosynthesis during inflammation have not been completely elucidated. In this study, we have investigated the involvement of PGE₂ pathway members in PGE₂ production by bone marrow (BM)-MSCs in response to inflammatory stimuli, and their role in immunosuppression mediated by BM-MSCs. We found that IFN-γ and TNF-α increased cyclooxygenase (COX)-2 expression but not that of prostaglandin E synthase (PGES), or PGE₂ production. On the other hand, the toll like receptor 3 (TLR3) stimulant poly(I:C) increased expression of both COX-2 and PGES, resulting in a significant increase in PGE₂ levels. This effect was reversed upon COX-2 inhibition with indomethacin or PGES downregulation by siRNA. Reduced PGE₂ levels decreased MSC's capacity to inhibit hPBMC proliferation. In addition, administration of MSCs with inhibited PGES expression into mice with graft-versus-host disease (GVHD) did not reduce mortality. In summary, the present study reveals that upregulation of PGES via TLR3 is critical for BM-MSCs-mediated immunosuppression by PGE₂ secretion via the COX-2/PGE₂ pathway. These results provide a basis for understanding the molecular mechanisms underlying the PGE₂-mediated immunosuppressive properties of MSCs.