Stress Signals, Mediated by Membranous Glucocorticoid Receptor, Activate PLC/PKC/GSK-3β/β-catenin Pathway to Inhibit Wound Closure.
Stress Signals, Mediated by Membranous Glucocorticoid Receptor, Activate PLC/PKC/GSK-3β/β-catenin Pathway to Inhibit Wound Closure.
复制标题
DOI：
10.1016/j.jid.2016.11.036
复制
发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Tomic Canic M
中科院分区：
文献类型：
--
作者：
Jozic I;Vukelic S;Stojadinovic O;Liang L;Ramirez HA;Pastar I;Tomic Canic M
糖皮质激素（GC），应激信号的关键介质，也是有效的伤口愈合抑制剂。为了了解应激信号如何抑制伤口愈合，我们通过使用细胞不可渗透的BSA结合的地塞米松来研究膜糖皮质激素受体（mbGR）的作用。我们发现mbGR通过激活Wnt样磷脂酶（PLC）/蛋白激酶C（PKC）信号级联反应抑制角质形成细胞迁移和伤口闭合。mbGR/PLC/PKC的快速激活进一步导致患者中发现的已知的不愈合生物标志物β-连环蛋白和c-myc的激活。相反，PKC的选择性抑制剂calphostin C阻断mbGR/PKC途径，并在体外挽救GC介导的角质形成细胞迁移抑制，并在体外加速人伤口的伤口上皮形成。这种新的信号传导机制可能对理解通过GC信号传导的应激反应如何调节稳态及其在皮肤疾病（包括伤口愈合）的发展和治疗中的作用产生重大影响。为了测试这种非基因组信号传导机制的组织特异性，我们测试了视网膜和支气管人类上皮细胞和成纤维细胞。我们发现mbGR/PLC/PKC信号级联反应存在于所有测试的细胞类型中，表明更普遍的作用。糖皮质激素通过mbGR激活Wnt通路的非基因组信号通路的发现，为应激介导的信号如何激活各种上皮和间充质组织中的生长信号提供了新的见解。
Glucocorticoids (GCs), key mediators of stress signals, are also potent wound healing inhibitors. To understand how stress signals inhibit wound healing, we investigated the role of membranous glucocorticoid receptor (mbGR) by using cell-impermeable BSA-conjugated dexamethasone. We found that mbGR inhibits keratinocyte migration and wound closure by activating a Wnt-like phospholipase (PLC)/ protein kinase C (PKC) signaling cascade. Rapid activation of mbGR/PLC/PKC further leads to activation of known biomarkers of nonhealing found in patients, β-catenin and c-myc. Conversely, a selective inhibitor of PKC, calphostin C, blocks mbGR/PKC pathway, and rescues GC-mediated inhibition of keratinocyte migration in vitro and accelerates wound epithelialization of human wounds ex vivo. This novel signaling mechanism may have a major impact on understanding how stress response via GC signaling regulates homeostasis and its role in development and treatments of skin diseases, including wound healing. To test tissue specificity of this nongenomic signaling mechanism, we tested retinal and bronchial human epithelial cells and fibroblasts. We found that mbGR/PLC/PKC signaling cascade exists in all cell types tested, suggesting a more general role. The discovery of this nongenomic signaling pathway, in which glucocorticoids activate Wnt pathway via mbGR, provides new insights into how stress-mediated signals may activate growth signals in various epithelial and mesenchymal tissues.
登录
查看更多内容
影响因子：
17.1
作者：
Eming SA;Martin P;Tomic-Canic M
通讯作者：
Tomic-Canic M
糖皮质激素对非血液学恶性肿瘤的临床作用的系统评价。
影响因子：
3.8
作者：
Keith, Bruce D.
通讯作者：
Keith, Bruce D.
影响因子：
4.8
作者：
Hinoi, T;Yamamoto, H;Kikuchi, A
通讯作者：
Kikuchi, A
影响因子：
9.2
作者：
Hart, MJ;de los Santos, R;Polakis, P
通讯作者：
Polakis, P
影响因子：
5.7
作者：
Brem, Harold;Stojadinovic, Olivera;Tomic-Canic, Marjana
通讯作者：
Tomic-Canic, Marjana