The Different Effects of IFN-β and IFN-γ on the Tumor-Suppressive Activity of Human Amniotic Fluid-Derived Mesenchymal Stem Cells.

Jingchun Du,Heng Su,Anqi Liu,Xia Xu,Chengbo Zhou,Guie Xie,Rui Zhu,Yingshan Deng

doi:10.1155/2019/4592701

Abstract

Current studies have shown that type I or II interferon-modified mesenchymal stem cells have great potential for the application of tumor-targeted therapy, but the underlying mechanism remains largely elusive. Here, we compared the different effects of IFN-β and IFN-γ on the antitumor activity of human amniotic fluid-derived mesenchymal stem cells (AFMSCs) and revealed the potential mechanism. In detail, AFMSCs primed with IFN-β or IFN-β plus IFN-γ, not IFN-γ, inhibited the proliferation of cancer cells in an immunocompetent mouse H460 subcutaneous model, although they all inhibited the proliferation of cancer cells in an immunocompromised mouse H460 subcutaneous model. TRAIL expressed by IFN-β- or IFN-γ-primed AFMSCs specifically exerted the antitumor effect of AFMSCs. AFMSCs primed with IFN-γ highly expressed immunosuppressive molecule IDO1, but IFN-β counteracted the IFN-γ-initiated IDO1 expression. 1-MT (IDO1 inhibitor) decreased TRAIL, but increased IDO1 expression in AFMSCs primed with interferon. As a result, AFMSCs primed with IFN-β or IFN-γ had the antitumor activity, and 1-MT failed to enhance the antitumor effect of IFN-γ-primed AFMSC in vitro and in the immunocompromised mouse H460 subcutaneous model. Furthermore, the expression of TRAIL in AFMSCs was upregulated by apoptotic cancer cells and this positive feedback intensified the antitumor effects of IFNs-primed AFMSCs. The different target gene expression profiles of AFMSCs regulated by IFN-β and IFN-γ determined the different antitumor effects of IFN-β- and IFN-γ-primed AFMSCs on tumor cells. Our finding may help to explore a clinical strategy for cancer intervention by understanding the antitumor mechanisms of MSCs and interferon.

Highlights

Interferons (IFNs) are a family of structurally related cytokines consisting mainly of type I IFN (α, β, ε, κ, ω, and δ) and type II IFN (IFN-γ only)
For culturing amniotic fluid-derived mesenchymal stem cells (AFMSCs), the nonadherent amniotic fluid cells were collected from primary culture and further expanded in a new 25 cm2 culture flask with low-glucose DMEM supplemented with 10% (v/v) fetal bovine serum (FBS), 100 U/ml penicillin, 100 μg/ml streptomycin (Gibco, Grand Island, NY), and 2 ng/ml bFGF (PeproTech, Rocky Hill, NJ) at 37°C in 5% CO2 and 8% O2
AFMSCs isolated from human amniotic fluid exhibited uniform spindle-like morphology, which was similar to that of bone marrowderived MSCs (Figure 1(a))

Summary

Introduction

Interferons (IFNs) are a family of structurally related cytokines consisting mainly of type I IFN (α, β, ε, κ, ω, and δ) and type II IFN (IFN-γ only). After interacting with the type-specific receptor complex, IFNs trigger the JAK-STAT pathway together with additional signaling cascades [1]. In addition to controlling viral infection, IFNs exhibit antitumor activity and immunoregulatory effects [2]. Besides immune cells (DCs, T, and NK cells), nonimmune cells might participate in IFN-mediated antitumor activity. IFN-β could exert antitumor activity via signals on nonhematopoietic Tie2+ cells, which is associated with extensive inhibition of angiogenesis [3, 4]. IFNrelated cell targets and antitumor mechanism are not fully recognized because of the almost ubiquitous expression of IFN receptors and the pleiotropic effects initiated by IFNs and their specific receptor interaction

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Results

Conclusion