1. Phenformin Down-Regulates c-Myc Expression to Suppress the Expression of Pro-Inflammatory Cytokines in Keratinocytes.
- Author
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Liu, Guanyi, Li, Dingyang, Zhang, Liwei, Xu, Qiuping, Zhuang, Dexuan, Liu, Panpan, Hu, Ling, Deng, Huiting, Sun, Jianfeng, Wang, Shuangshuang, Zheng, Bin, Guo, Jing, and Wu, Xunwei
- Subjects
KERATINOCYTE differentiation ,KERATINOCYTES ,SKIN inflammation ,CYTOKINES ,AMP-activated protein kinases ,ORGAN culture ,FILAGGRIN - Abstract
The treatment of many skin inflammation diseases, such as psoriasis and atopic dermatitis, is still a challenge and inflammation plays important roles in multiple stages of skin tumor development, including initiation, promotion and metastasis. Phenformin, a biguanide drug, has been shown to play a more efficient anti-tumor function than another well-known biguanide drug, metformin, which has been reported to control the expression of pro-inflammatory cytokines; however, little is known about the effects of phenformin on skin inflammation. This study used a mouse acute inflammation model, ex vivo skin organ cultures and in vitro human primary keratinocyte cultures to demonstrate that phenformin can suppress acute skin inflammatory responses induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in vivo and significantly suppresses the pro-inflammatory cytokines IL-1β, IL-6 and IL-8 in human primary keratinocytes in vitro. The suppression of pro-inflammatory cytokine expression by phenformin was not directly through regulation of the MAPK or NF-κB pathways, but by controlling the expression of c-Myc in human keratinocytes. We demonstrated that the overexpression of c-Myc can induce pro-inflammatory cytokine expression and counteract the suppressive effect of phenformin on cytokine expression in keratinocytes. In contrast, the down-regulation of c-Myc produces effects similar to phenformin, both in cytokine expression by keratinocytes in vitro and in skin inflammation in vivo. Finally, we showed that phenformin, as an AMPK activator, down-regulates the expression of c-Myc through regulation of the AMPK/mTOR pathways. In summary, phenformin inhibits the expression of pro-inflammatory cytokines in keratinocytes through the down-regulation of c-Myc expression to play an anti-inflammation function in the skin. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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