Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro.

Objectives: In the present study, we first confirmed the suppressive function of MSCs in allogeneic T cell proliferation and then examined the underlying mechanisms for MSCs' immunomodulation and the role of the pro-inflammatory cytokine interferon (IFN)-gamma. Methods: Human MSCs were cultured in the presence or absence of IFN-gamma. The expression level of prostaglandin E-2 (PGE(2)), hepatocyte growth factor (HGF), transforming growth factor (TGF)-beta(1) and indoleamine 2,3-dioxygenase (IDO) by MSCs were measured. T lymphocytes were isolated from peripheral blood of healthy donors and then induced to proliferate under the stimulation of anti-human CD3 mAb and anti-human CD28 mAb. In the presence of MSCs, T cell proliferation was examined by BrdU incorporation. In addition, PGE(2), HGF, TGF-beta(1), Kynurenine, recombinant human IFN-gamma and anti-IFN-gamma mAb were added and cell proliferation was examined. Results: Compared to the controls (MSCs alone), MSCs cocultured with IFN-gamma expressed significantly higher concentrations of PGE(2), HGF and TGF-beta(1). The mRNA level of IDO was remarkably increased. Human bone marrow-derived MSCs alone notably suppressed T lymphocytes proliferation in vitro. Addition of exogenous IFN-gamma did not ablate the immunosuppressive effects of MSCs. Addition of anti-IFN-gamma mAb partially restored suppression of T cell proliferation by MSCs. Conclusions: Human MSCs constitutively expressed immunosuppressive levels of PGE(2), HGF and TGF-beta(1). The proinflammatory cytokine IFN-gamma exhibited synergistic effects with MSCs on immunosuppression, possibly by up-regulating PGE(2), HGF and TGF-beta(1) in MSCs and inducting MSCs expression of IDO, involved in tryptophan catabolism.