再生表皮中Notch的下调有助于在伤口愈合过程中增强白细胞介素-36α的表达并抑制角质形成细胞分化。

Notch down-regulation in regenerated epidermis contributes to enhanced expression of interleukin-36α and suppression of keratinocyte differentiation during wound healing.

作者信息

Takazawa Yuko, Ogawa Eisaku, Saito Rumiko, Uchiyama Ryuhei, Ikawa Shuntaro, Uhara Hisashi, Okuyama Ryuhei

机构信息

Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.

出版信息

J Dermatol Sci. 2015 Jul;79(1):10-9. doi: 10.1016/j.jdermsci.2015.04.003. Epub 2015 Apr 25.

DOI:10.1016/j.jdermsci.2015.04.003

PMID:25982147

Abstract

BACKGROUND

Notch signaling controls a number of cellular processes, including cell fate decisions, proliferation, differentiation, and survival/apoptosis, in multiple tissues. In the epidermis, Notch1 functions as a molecular switch that controls the transition of cells from an undifferentiated state into a differentiated state.

OBJECTIVE

To clarify the functions of Notch in the regenerated epidermis during wound healing.

METHODS

Wounds on mouse skin were immunostained. To investigate the functions of Notch, Notch was inhibited in primary keratinocytes by treatment with a γ-secretase inhibitor and by small interfering RNA-mediated knockdown, and was activated by a recombinant adenovirus approach.

RESULTS

Notch1 and Notch2 were down-regulated in the regenerated epidermis during wound healing. To clarify the significance of this down-regulation, we examined its effect on expression of the interleukin (IL)-1 family of proinflammatory cytokines because wounds are exposed to pathogens from the outside world. Among the IL-1 family, IL-36α expression was induced by Notch inhibition. This was consistent with the decreased IL-36α expression in Notch-overexpressing keratinocytes. Notch down-regulation in the regenerated epidermis may reinforce defense against stress from the outside world by inducing IL-36α expression. Next, we examined the effects of Notch down-regulation on keratinocyte growth and differentiation. Notch down-regulation did not alter keratinocyte proliferation. On the other hand, Notch1 down-regulation suppressed induction of spinous layer-specific keratins (keratin1 and keratin10) in keratinocytes, which was consistent with the decreased expression of these keratins in the regenerated epidermis. The reduced levels of these keratins would increase cellular flexibility.

CONCLUSION

Notch down-regulation in the epidermis appears to contribute to tissue regeneration during wound healing.

摘要

背景

Notch信号通路调控多种组织中的一系列细胞过程，包括细胞命运决定、增殖、分化以及存活/凋亡。在表皮中，Notch1作为一个分子开关，控制细胞从未分化状态向分化状态的转变。

目的

阐明Notch在伤口愈合过程中再生表皮中的功能。

方法

对小鼠皮肤伤口进行免疫染色。为研究Notch的功能，通过用γ-分泌酶抑制剂处理和小干扰RNA介导的敲低在原代角质形成细胞中抑制Notch，并通过重组腺病毒方法激活Notch。

结果

在伤口愈合过程中，再生表皮中的Notch1和Notch2表达下调。为阐明这种下调的意义，我们检测了其对促炎细胞因子白细胞介素（IL）-1家族表达的影响，因为伤口会接触外界病原体。在IL-1家族中，Notch抑制可诱导IL-36α表达。这与Notch过表达的角质形成细胞中IL-36α表达降低一致。再生表皮中Notch下调可能通过诱导IL-36α表达增强对外界应激的防御。接下来，我们检测了Notch下调对角质形成细胞生长和分化的影响。Notch下调未改变角质形成细胞的增殖。另一方面，Notch1下调抑制了角质形成细胞中棘层特异性角蛋白（角蛋白1和角蛋白10）的诱导，这与再生表皮中这些角蛋白表达降低一致。这些角蛋白水平的降低会增加细胞的柔韧性。