Finasteride Enhances the Generation of Human Myeloid-Derived Suppressor Cells by Up-Regulating the COX2/PGE2 Pathway.

Shaoying Zhang,Hui Zhang,Yongshui Fu,Ting Pan,Xu Zhang,Yufeng Liu,Kang Wu,Yingtong Lin,Jie Zhou

doi:10.1371/journal.pone.0156549

Abstract

Myeloid-derived suppressor cells (MDSCs) have been known to be a key factor in the regulation of the immune system under numerous conditions such as tumors, infections, autoimmune diseases, and transplantations. In contrast to the proposed deleterious role of MDSCs in tumors and infections, MDSCs with their suppressive function are now proved to have the beneficial potential of suppressing the autoimmune response and promoting tolerance to transplantation. Therefore, the expansion of MDSCs could be a promising therapeutic strategy for many diseases. In this study, we aimed to identify FDA-approved drugs that could aid in the expansion of functional MDSCs. We performed a high-throughput screening (HTS) of FDA-approved drugs based on the in vitro human MDSC-differentiation system and identified finasteride (FIN) to have the best potency to aid the generation of human MDSCs. The FIN-induced MDSCs were quite similar to monocytic MDSCs with regard to their surface phenotype, morphology, immunosuppressive function, and related gene expression. Next, we aimed to determine the mechanism of action of FIN and found that FIN induced the expansion of MDSCs through up-regulation of the COX2/PGE2 pathway by enhancing the activity of COX2 promoter. In addition, the administration of indomethacin (IND), a COX2 inhibitor, abrogated the effect of FIN. Based on these results, we suggested that FIN could find applications in the future in the expansion of MDSCs. Further development of FIN-like compounds could be a novel strategy for generating functional MDSCs for immunosuppressive therapies in various immune disorder conditions.

Highlights

Myeloid-derived suppressor cells (MDSCs) are identified as a heterogeneous population of multipotent progenitor cells that include granulocytes, monocytes, macrophages, and dendritic cells (DCs) precursors
Finasteride (FIN), has widely been used in the clinic to treat benign prostatic hyperplasia (BPH) and has relatively less side effects; it was chosen for further analysis (Fig 1B)
In recent years, emerging reports have shown that functional MDSCs could be generated using many factors in vitro

Summary

Introduction

Myeloid-derived suppressor cells (MDSCs) are identified as a heterogeneous population of multipotent progenitor cells that include granulocytes, monocytes, macrophages, and dendritic cells (DCs) precursors. Over the last few years, increasing numbers of investigations have demonstrated the accumulation of MDSCs under pathological conditions such as autoimmune diseases [2,3,4] and transplant rejection [5, 6]. The adoptive transfer of induced-MDSCs showed the capacity of prolonging the survival of allogeneic allograft in many cases of solid organ transplantation [10,11,12,13]. Given the vital regulatory capacity of MDSCs in the immune system [14, 15], these cells are expected to be a potential candidate for the treatment of immune disorders. The efficient in vitro generation and the subsequent adoptive transfer of MDSCs in some hyper-responsive conditions is of great significance [16]

Objectives

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Conclusion