Elsevier

Biomedicine & Pharmacotherapy

Volume 105, September 2018, Pages 151-158
Biomedicine & Pharmacotherapy

Total glucosides of paeony improves the immunomodulatory capacity of MSCs partially via the miR-124/STAT3 pathway in oral lichen planus

https://doi.org/10.1016/j.biopha.2018.05.076Get rights and content

Highlights

  • The immunomodulatory function of OLP-MSCs is impaired compared with N-MSCs.

  • TGP partially improved OLP-MSCs immunomodulatory function via miR-124/STAT3 pathway.

  • TGP may be a new and safe drug for priming mesenchymal stem cells.

Abstract

Mesenchymal stem cells (MSCs) have been used clinically and experimentally to relieve severe immune-related diseases due to their immunomodulatory properties, but these are impaired by inflammation. Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease. In the present study, we found MSCs from OLP with higher expression of interleukin (IL)-6, tumour necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β) and IL-10 compared with control. Total glucosides of paeony (TGP) significantly improves the immunomodulatory function of MSCs by inhibiting IL-6 and TNF-α expression and increasing TGF-β and IL-10 expression. Moreover, TGP can downregulate p-STAT3 expression through upregulation of miR-124. The changes of IL-6, TGF-β and p-STAT3 were further confirmed by overexpression and knockdown of miR-124 in MSCs. Taken together, the immune-regulating function of MSCs can be improved by TGP via the miR-124/STAT3 pathway.

Introduction

Mesenchymal stem cells (MSCs) are adult stem cells, which were first isolated and identified in the bone marrow (BM). MSCs have now been found in many other tissues, such as adipose, umbilical cord blood, dental pulp and oral mucosa [[1], [2], [3], [4]].

MSCs have been reported to be fibroblast-like cells that positively express CD105, CD73 and CD90, while negatively expressing CD45, CD34, CD14 or CD11b, CD79a or CD19 and HLA-DR [5]. For their self-renewal, multipotency and immunomodulatory properties, MSCs are an attractive tool for regenerative medicine and immune-related diseases. To date, MSCs have been used to treat several immune-related diseases in clinical and experimental trials, such as graft-versus-host disease (GVHD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) [[6], [7], [8], [9]]. Most cases have obtained favourable outcomes. However, some studies have shown that the inflammatory microenvironment affects the immunomodulatory function of MSCs [[10], [11], [12], [13]]. This might be due to a poor survival rate of MSCs, leading to the weakened immunoregulatory properties and treatment efficacy.

Oral lichen planus (OLP) is recognised as a chronic inflammatory disease that involves oral mucosa and may be accompanied by skin lesions, which has no obvious cause [14]. The prevalence of OLP in the general adult population is 0.5–3% and often found in middle-aged female patients [15]. Moreover, it has a frequency of malignant transformation between 0.4% and 5% [[16], [17], [18]]. In terms of the pathogenesis of OLP, some studies have shown that uncertain stimulations can activate dendritic cells. They produced interleukin IL-12, IL-18 and tumour necrosis factor alpha (TNF-α) to home T cells to lesions and activate T cell differentiation into Th1 and Th17 cells. These cells secrete many inflammatory mediators, including IL-6, IL-8 and TNF-α, finally leading to OLP lesions [14]. MSCs in OLP tissues were first isolated in our previous study [1]. However, whether the functions of OLP-derived MSCs (OLP-MSCs) are impaired and the relationship between the function of OLP-MSCs and the progression of OLP remain largely unknown.

Total glucosides of paeony (TGP) is an effective constituent purified and extracted from the dried root of Paeonia. Paeonia lactiflora, which is called “Shao Yao” in Chinese, has been widely used in China as a therapeutic drug for pain, congestion and inflammation [19]. Studies show that TGP dramatically impacts immune-related diseases, such as RA, psoriasis and SLE [[20], [21], [22]]. TGP can increase synoviocyte proliferation and reduce IL-1β, TNF-α, IL-2 and IL-6 expression and increase IL-4, IL-10 and TGF-β expression through the cAMP [23,24] and NF-κB pathways [25]. In clinical therapy, TGP has been proven as a safe and effective drug for OLP with rare side effects [26]. However, the effect of TGP on OLP-MSCs has not yet been investigated.

Several studies have shown that microRNAs (miRs) play a very important role in regulating inflammation-related diseases [[27], [28], [29]]. miRs are non-coding transcripts of 18–25 nucleotides. miR-124 is a member of miRNAs. In traumatic brain injury (TBI), miR-124-3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via inhibiting mTOR signalling [28]. In addition, phosphorylated signal transducer and activator of transcription 3 (p-STAT3) would be decreased if increased miR-124-3p expression in IBD [30]. Similar reports show that overexpression of miR-124-3p downregulates inflammatory cytokine by blocking nuclear factor (NF)-κB signalling [31]. Moreover, miR124-3p expression the affects the self-renewal of mouse embryonic stem cells by inhibiting the MEK/ERK pathway [32].However, the effect of miR-124-3p on the immunomodulatory function of MSCs has not been reported so far.

In this study, the effect of TGP on OLP-MSCs will be investigated to further explore its possible mechanisms. We also investigated whether function of MSCs primed with TGP is enhanced via the miR-124-3p/STAT3 pathway and whether TGP may recover the damaged immunomodulatory function of OLP-MSCs.

Section snippets

OLP clinical specimen collection

OLP tissues biopsied from the buccal mucosa of OLP patients. OLP diagnoses agreed with the modified World Health Organisation diagnostic criteria for OLP [31]. Normal oral mucosal tissues were obtained from patients who underwent the crown lengthening surgery or mucous retention cyst resection. Samples were obtained between September 2016 and March 2017 and stored at a biobank at the Peking University School of Stomatology. The following inclusion criteria were used: OLP patients confirmed by

Expression of IL-6, TNF-α, TGF-β and IL-10 in OLP and normal sub-epithelial lamina tissues

To verify the expression of IL-6, TNF-α, TGF-β and IL-10 in OLP and normal sub-epithelial lamina tissues, immunohistochemical staining was performed. As shown in Fig. 1, compared with normal sub-epithelial lamina, four cytokines all expressed significantly higher in OLP tissues, which confirmed that the OLP microenvironment co-exists between pro-inflammatory and anti-inflammatory cytokines.

Production of IL-6, TNF-α, TGF-β and IL-10 in N-MSCs and OLP-MSCs

To explore the effect of the OLP microenvironment on MSCs, we performed reverse transcription (RT)-PCR and

Discussion

OLP is a chronic inflammatory disease characterised by dense sub-epithelial lymphocytic infiltration, increased number of intra-epithelial lymphocytes and degeneration of basal keratinocytes. Additionally, it prevails among 40-60-year-old female patients [16,33]. In this study, OLP tissues expressed more IL-6, TNF-α, and IL-10 than control. Given that OLP has a high morbidity in people more than 40 years old and has complex inflammation conditions. It is unknown whether anything of OLP-MSCs has

Conflict of interest

All authors have read the journal’s policy on the disclosure of potential conflicts of interest and have none to declare.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (nos. 81441034 and 81772873), Foundation of Capital Health Development (2014-2-4102 and 2011-4025-02), and Beijing Natural Science Foundation (nos. 7172240 and 7182181).

References (46)

  • L. Zhou et al.

    Clinical observation on the treatment of oral lichen planus with total glucosides of paeony capsule combined with corticosteroids

    Int. Immunopharmacol.

    (2016)
  • Z. Yang et al.

    MicroRNA-124 alleviates chronic skin inflammation in atopic eczema via suppressing innate immune responses in keratinocytes

    Cell. Immunol.

    (2017)
  • Y. Wang et al.

    Total glucosides of paeony (TGP) inhibits the production of inflammatory cytokines in oral lichen planus by suppressing the NF-kappaB signaling pathway

    Int Immunopharmacol.

    (2016)
  • D. Wang et al.

    Activation of PPARgamma inhibits pro-inflammatory cytokines production by upregulation of miR-124 in vitro and in vivo

    Biochem. Biophys. Res. Commun.

    (2017)
  • Z. Zhang et al.

    Interferon-gamma regulates the function of mesenchymal stem cells from oral lichen planus via indoleamine 2,3-dioxygenase activity

    J. Oral Pathol. Med.

    (2015)
  • Z. Zhang et al.

    Impairment of mesenchymal stem cells derived from oral leukoplakia

    Int. J. Clin. Exp. Pathol.

    (2015)
  • X. Ji et al.

    Mesenchymal stem cells derived from normal gingival tissue inhibit the proliferation of oral cancer cells in vitro and in vivo

    Int. J. Oncol.

    (2016)
  • C. Fernandez-Maqueda et al.

    Mesenchymal stromal cells for steroid-refractory acute GvHD

    Bone Marrow Transplant.

    (2017)
  • J. Chen et al.

    Umbilical cord-derived mesenchymal stem cells suppress autophagy of T cells in patients with systemic lupus erythematosus via transfer of mitochondria

    Stem Cells Int.

    (2016)
  • L. Zhang et al.

    Use of immune modulation by human adipose-derived mesenchymal stem cells to treat experimental arthritis in mice

    Am. J. Transl. Res.

    (2017)
  • C. Gregoire et al.

    Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases

    Aliment. Pharmacol. Ther.

    (2017)
  • L. Wang et al.

    IFN-gamma and TNF-alpha synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFkappaB signaling

    Stem Cells

    (2013)
  • M. Sudres et al.

    Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice

    J. Immunol.

    (2006)
  • Cited by (0)

    View full text