EGFR Regulates the Expression of Keratinocyte-Derived Granulocyte/Macrophage Colony-Stimulating Factor In Vitro and In Vivo
EGFR Regulates the Expression of Keratinocyte-Derived Granulocyte/Macrophage Colony-Stimulating Factor In Vitro and In Vivo
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DOI：
10.1038/jid.2009.336
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发表时间：
2010-03-01
影响因子：
6.5
通讯作者：
Pastore, Saveria
中科院分区：
文献类型：
--
作者：
Mascia, Francesca;Cataisson, Christophe;Pastore, Saveria
EGFR通路知识的最新进展揭示了其对表皮不同免疫/炎症功能的贡献。本研究的目的是评估表皮生长因子受体在调节角质形成细胞GM-CSF表达中的作用。在培养的人角质形成细胞中，促炎细胞因子与TGF-α协同诱导GM-CSF表达。因此，高表皮水平的EGFR活化与银屑病或变应性接触性皮炎患者皮损皮肤中GM-CSF表达增强相关。在培养的角质形成细胞中，EGFR活性的药理学抑制降低了GM-CSF启动子的反式激活，而AP-1的遗传抑制降低了GM-CSF的表达。此外，EGFR激活增强TNF-α诱导的c-Jun磷酸化和DNA结合，而c-Jun沉默降低GM-CSF表达。使用两种不同的小鼠模型，我们表明，缺乏功能性EGFR通路与降低的精氨酸诱导的ERK 1/2，JNK 1/2，c-Jun磷酸化和降低的角质形成细胞衍生的GM-CSF表达在体外和体内。最后，抗EGFR药物治疗的癌症患者皮肤中CM-CSF表达的分析显示ERK活性、c-Jun磷酸化和表皮GM-CSF表达之间存在关联。这些数据表明，EGFR途径对于在细胞因子刺激条件下角质形成细胞GM-CSF表达的上调至关重要。
Recent advances in the knowledge of the EGFR pathway have revealed its contribution to distinct immune/inflammatory functions of the epidermis. The purpose of our study was to evaluate the role of EGFR in the regulation of keratinocyte GM-CSF expression. In cultured human keratinocytes, proinflammatory cytokines synergized with TGF-alpha to induce GM-CSF expression. Accordingly, high epidermal levels of EGFR activation are associated with enhanced expression of GM-CSF in lesional skin of patients with psoriasis or allergic contact dermatitis. In cultured keratinocytes, pharmacological inhibition of EGFR activity reduced GM-CSF promoter transactivation, whereas genetic inhibition of AP-1 reduced expression of GM-CSF. Furthermore, EGFR activation enhanced TNF-alpha-induced c-Jun phosphorylation and DNA binding, whereas c-Jun silencing reduced GM-CSF expression. Using two different mouse models, we showed that the lack of a functional EGFR pathway was associated with reduced cytokine-induced phosphorylation of ERK1/2, JNK1/2, c-Jun and reduced keratinocyte-derived GM-CSF expression both in vitro and in vivo. Finally, the analysis of CM-CSF expression in the skin of cancer patients treated with anti EGFR drugs showed an association between ERK activity, c-Jun phosphorylation, and epidermal GM-CSF expression. These data demonstrate that the EGFR pathway is critical for the upregulation of keratinocyte GM-CSF expression under conditions of cytokine stimulation.