IL-37 过表达增强了子宫内膜再生细胞在刀豆蛋白 A 诱导的肝炎中的治疗效果。

IL-37 overexpression enhances the therapeutic effect of endometrial regenerative cells in concanavalin A-induced hepatitis.

机构信息

Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.

出版信息

Cytotherapy. 2021 Jul;23(7):617-626. doi: 10.1016/j.jcyt.2020.12.006. Epub 2021 Feb 13.

DOI:10.1016/j.jcyt.2020.12.006

PMID:33593687

Abstract

BACKGROUND AIMS

Mesenchymal stromal cells and immunosuppressive factor IL-37 can both suppress concanavalin A (Con A)-induced hepatitis in mice. Endometrial regenerative cells (ERCs), novel types of mesenchymal-like stromal cells, possess powerful immunomodulatory effects and are effective in treating various diseases. The aim of this study was to explore the effects of ERCs in suppressing Con A-induced hepatitis and determine whether IL-37 overexpression could enhance the therapeutic effect of ERCs in this process.

METHODS

ERCs were extracted from the menstrual blood of healthy female volunteer donors. The IL-37 gene was transferred into ERCs, and the expression of IL-37 in cells was detected by western blot and enzyme-linked immunosorbent assay. Hepatitis was induced by Con A in C57BL/6 mice that were randomly divided into groups treated with phosphate-buffered saline, ERCs, IL-37 or ERCs transfected with the IL-37 gene (IL-37-ERCs). Cell tracking, liver function, histopathological and immunohistological changes, immune cell proportions and levels of cytokines were measured 24 h after Con A administration.

RESULTS

Compared with ERC or IL-37 treatment, IL-37-ERCs further reduced levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase) and improved histopathological changes in the liver. In addition, IL-37-ERC treatment further reduced the proportions of M1 macrophages and CD4 T cells and increased the proportion of regulatory T cells. Moreover, IL-37-ERC treatment resulted in lower levels of IL-12 and interferon gamma, and higher level of transforming growth factor beta.

CONCLUSIONS

The results of this study suggest that ERCs can effectively alleviate Con A-induced hepatitis. Furthermore, IL-37 overexpression can significantly enhance the therapeutic efficacy of ERCs by augmenting the immunomodulatory and anti-inflammatory properties of ERCs. This study may provide a promising strategy for treatment of T-cell-dependent hepatitis.

摘要

背景目的

间充质基质细胞和免疫抑制因子 IL-37 均可抑制伴刀豆球蛋白 A（Con A）诱导的小鼠肝炎。子宫内膜再生细胞（ERCs），新型间充质样基质细胞，具有强大的免疫调节作用，在治疗各种疾病方面有效。本研究旨在探讨 ERCs 抑制 Con A 诱导的肝炎的作用，并确定 IL-37 过表达是否可以增强 ERCs 在该过程中的治疗效果。

方法

从健康女性志愿者的月经血中提取 ERCs。将 IL-37 基因转入 ERCs 中，通过 Western blot 和酶联免疫吸附试验检测细胞中 IL-37 的表达。用 Con A 诱导 C57BL/6 小鼠肝炎，将小鼠随机分为磷酸盐缓冲液组、ERCs 组、IL-37 组或转染 IL-37 基因的 ERCs 组（IL-37-ERCs 组）。在 Con A 给药后 24 h 测量细胞跟踪、肝功能、组织病理学和免疫组织化学变化、免疫细胞比例和细胞因子水平。

结果

与 ERC 或 IL-37 治疗相比，IL-37-ERCs 进一步降低了肝酶（丙氨酸氨基转移酶和天冬氨酸氨基转移酶）水平，并改善了肝组织病理学变化。此外，IL-37-ERC 治疗进一步降低了 M1 巨噬细胞和 CD4 T 细胞的比例，增加了调节性 T 细胞的比例。此外，IL-37-ERC 治疗导致 IL-12 和干扰素 γ水平降低，转化生长因子 β水平升高。