Regulation of nitric oxide production in mesenchymal stem cells via aryl hydrocarbon receptor

초록

The Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which is induced by dioxins. It is also implicated in the regulation of anti-inflammatory and pro-inflammatory immune responses. Mesenchymal stem cells (MSCs) have a powerful immune regulatory capability. These cells can inhibit T and B cell proliferation. MSC-mediated immunosuppression occurs via nitric oxide (NO) in mice. Here, we isolated AhR (-/-) MSCs from bone marrow in C57BL/6 mice, then compared the immunosuppressive functions with wild type (WT) MSCs. We found AhR-/- MSCs less inhibited T cell proliferation, particularly CD25 and CD122 expression, IL-17 and IFN-γ expression and Th17 differentiation. In addition, we found AhR-/- MSCs produced a lesser amount of NO and expressed lower inducible nitric oxide synthase (iNOS) protein than the WT MSCs, when MSCs stimulated by IFN-γ, TNF-α, and IL-1β. Since MSCs have been reported to be effective for graft-vs-host disease (GvHD) treatment, we injected the WT and AhR-/- MSCs into the GvHD mice model. The AhR-/- MSCs exhibited less therapeutic efficacy than the WT MSCs. Thus, our result indicate that AhR in MSCs is involved in the production of NO via regulating iNOS expression which might be required for the increasing therapeutic efficacy of immune diseases.