2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced aryl hydrocarbon receptor activation enhanced the suppressive function of mesenchymal stem cells against splenocyte proliferation

Guorui Zhang,Yi Cheng,Wen Gu,Xiaoming Li,Xuejun Guo,Haiyang Yu,Zhilei Cui

doi:10.1007/s11626-019-00383-y

Abstract

The immunosuppressive function of mesenchymal stem cells (MSCs) is well known. Aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, is widely expressed in several cells and is involved in various physiological and pathological processes. Previously, we found that the expression of AhR was downregulated in MSCs isolated from mice with neutrophilic asthma and that the activation of AhR enhanced the function of MSCs to alleviate neutrophilic asthma. We hypothesized that AhR activation enhanced MSCs for their immunosuppressive function. We aimed to investigate whether AhR activation can augment the suppressive function of MSCs against splenocyte proliferation. We co-cultured MSCs or AhR-activated MSCs with splenocytes at different ratios. The results showed that AhR activation in MSCs upregulated the expression of inducible nitric oxide (iNOS), which promoted the production of nitric oxide (NO), thus enhancing the inhibitory effect on splenocyte proliferation. The NO donor S-nitroso-N-acetylpenicillamine also inhibited the proliferation of splenocytes, and the iNOS inhibitor N(G)-nitro L-arginine methyl ester and NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide partially reversed the immunosuppressive function. Our study indicates that the AhR activation of MSCs might have an important role in the regulation of splenocyte proliferation and might serve as a potential strategy for treating immune-related diseases.

Highlights

Bone marrow-derived mesenchymal stem cells (MSCs) are pluripotent stem cells that play an important role in regenerative therapy (Uder et al 2018)
We aimed to investigate whether Aryl hydrocarbon receptor (AhR) activation can improve the inhibitory function of MSCs against splenocyte proliferation
AhR activation enhanced the inhibitory effect of MSCs on splenocyte proliferation in the cell–cell contact and transwell cultures We induced splenocyte proliferation using concanavalin A (ConA), which has the ability to induce the mitogenic activity of splenocytes and synthesis of cellular products

Summary

Introduction

Bone marrow-derived mesenchymal stem cells (MSCs) are pluripotent stem cells that play an important role in regenerative therapy (Uder et al 2018). The molecular mechanism by which MSCs exert their immunosuppressive function has been illustrated. 2012), and tumor necrosis factor-stimulated gene 6 (TSG-6) (Wang et al 2018) have been reported to mediate the suppressive function of MSCs. Different results may be associated with the isolation and culture condition of MSCs and different circumstances of the diseases. While many studies have showed that the mechanism of immunosuppressive function of MSCs varied among different species (Ren et al 2009; Su et al 2014). Human-, pig-, and monkey-derived MSCs utilize IDO for immunosuppression, while rat-, rabbit-, hamster-, and mousederived MSCs utilize NO. Aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor of the bHLH/PAS family, mediates several important physiological processes in response to exogenous substances and natural compounds such as tryptophan metabolites, dietary components, and microbial community–derived factors (Quintana and Sherr 2013; Cella and Colonna 2015). We found that the expression of AhR was downregulated in MSCs isolated from mice with neutrophilic asthma and that the activation of AhR in MSCs alleviated the neutrophilic airway

Objectives

Methods

Results

Conclusion