巨噬细胞移动抑制因子（MIF）在周围神经再生中的作用：抗MIF抗体导致神经再生延迟及雪旺细胞凋亡。

Role of macrophage migration inhibitory factor (MIF) in peripheral nerve regeneration: anti-MIF antibody induces delay of nerve regeneration and the apoptosis of Schwann cells.

作者信息

Nishio Yasuhiko, Nishihira Jun, Ishibashi Teruo, Kato Hiroyuki, Minami Akio

机构信息

Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

出版信息

Mol Med. 2002 Sep;8(9):509-20.

PMID:12456989

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2040017/

Abstract

BACKGROUND

Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine involved in inflammation and immune responses as well as in cell growth. Although we previously demonstrated the presence of MIF in peripheral nerves, and MIF mRNA expression was up-regulated after axotomy, the role of MIF in nerve injury and regeneration has not been evaluated.

MATERIALS AND METHODS

To examine the potential role of MIF in nerve regeneration, we locally administered an anti-MIF polyclonal antibody into regenerating rat sciatic nerves using the silicone chamber model. The effect of the anti-MIF antibody on nerve regeneration was evaluated using an axonal reflex test. In addition, we carried out a terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assay and immunohistochemical analysis of the damaged nerve segments with regard to apoptosis-related proteins such as p53 to evaluate the effects of anti- MIF antibodies on apoptosis during the regeneration process.

RESULTS

The regeneration length of the nerve in the anti-MIF antibody-treated group was significantly shorter than that in the non-immune rabbit IgG-treated group at weeks 2, 4 and 6 after surgery. TUNEL assay showed that a large number of apoptotic cells, mostly Schwann cells, were observed in the intratubal and distal nerve segments at weeks 4 and 6 after surgery by the anti-MIF antibody treatment. Consistent with these results, Ki-67-positive cells were significantly decreased by the anti-MIF antibody treatment. Immunohistochemical analyses revealed that p53 and, to a lesser extent, Fas were more up-regulated in the anti-MIF antibody-treated nerves than in the controls.

CONCLUSION

Taken together, these results suggest that MIF plays an important role in acceleration of peripheral nerve regeneration and in prevention of Schwann cell apoptosis, mainly through overcoming the apoptotic effect of p53.

摘要

背景

巨噬细胞移动抑制因子（MIF）是一种多能细胞因子，参与炎症、免疫反应以及细胞生长过程。尽管我们之前已证实在周围神经中存在MIF，且轴突切断术后MIF mRNA表达上调，但MIF在神经损伤和再生中的作用尚未得到评估。

材料与方法

为研究MIF在神经再生中的潜在作用，我们使用硅胶室模型将抗MIF多克隆抗体局部注射到再生的大鼠坐骨神经中。通过轴突反射试验评估抗MIF抗体对神经再生的影响。此外，我们进行了末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记（TUNEL）检测，并对受损神经节段进行免疫组织化学分析，检测凋亡相关蛋白如p53，以评估抗MIF抗体对再生过程中细胞凋亡的影响。

结果

术后第2、4和6周，抗MIF抗体治疗组神经的再生长度显著短于非免疫兔IgG治疗组。TUNEL检测显示，抗MIF抗体治疗后，在术后第4和6周，在管内和远端神经节段观察到大量凋亡细胞，主要是雪旺细胞。与这些结果一致，抗MIF抗体治疗使Ki-67阳性细胞显著减少。免疫组织化学分析显示，抗MIF抗体治疗的神经中p53以及程度较轻的Fas的上调程度高于对照组。