TY - JOUR
T1 - Notch down-regulation in regenerated epidermis contributes to enhanced expression of interleukin-36α and suppression of keratinocyte differentiation during wound healing
AU - Takazawa, Yuko
AU - Ogawa, Eisaku
AU - Saito, Rumiko
AU - Uchiyama, Ryuhei
AU - Ikawa, Shuntaro
AU - Uhara, Hisashi
AU - Okuyama, Ryuhei
N1 - Funding Information:
This study was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (to RO, grant number 26461686 ).
Publisher Copyright:
© 2015 Japanese Society for Investigative Dermatology.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
KW - Cytokine
KW - Keratin
KW - Keratinocyte
KW - Notch pathway
KW - Wound healing
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U2 - 10.1016/j.jdermsci.2015.04.003
DO - 10.1016/j.jdermsci.2015.04.003
M3 - Article
C2 - 25982147
AN - SCOPUS:84929945511
VL - 79
SP - 10
EP - 19
JO - Journal of Dermatological Science
JF - Journal of Dermatological Science
SN - 0923-1811
IS - 1
ER -