ERK1/2 regulates epidermal chemokine expression and skin inflammation
ERK1/2 regulates epidermal chemokine expression and skin inflammation
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DOI：
10.4049/jimmunol.174.8.5047
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发表时间：
2005-04-15
影响因子：
4.4
通讯作者：
Girolomoni, G
中科院分区：
文献类型：
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作者：
Pastore, S;Mascia, F;Girolomoni, G
皮肤的常驻细胞群通过产生一系列趋化因子来促进炎症反应，这些趋化因子从循环中吸引白细胞。tnf - α是角化细胞中促炎介质的主要诱导剂。我们最近观察到表皮生长因子受体（EGFR）信号传导影响表皮角质形成细胞中tnf - α驱动的趋化因子的表达，其功能损伤会增加关键趋化因子如CCL2/MCP-1、CCL5/RANTES和CXCL10/ ifn - γ诱导蛋白-10的水平。在本研究中，我们报告了egfr依赖性ERK1/2活性参与该机制的证据。用特异性抑制剂抑制ERK1/2活性可通过增强mRNA稳定性来增加趋化因子在角质形成细胞中的表达。在小鼠模型中，当先前用EGFR或MAPK激酶1/2抑制剂治疗过的皮肤区域引发炎症反应时，对刺激物的炎症反应和T细胞介导的接触过敏症都会加重。相反，p38 α β MAPK磷酸化的损伤明显减弱了这些反应。我们的数据表明，角质形成细胞中egfr依赖的ERK1/2活性参与了调节炎症反应的稳态机制，并强调了MAPKs作为操纵皮肤炎症的潜在靶点的独特作用。
Resident cell populations of the skin contribute to the inflammatory response by producing an array of chemokines, which attract leukocytes from the circulation. TNF-alpha is a major inducer of proinflammatory mediators in keratinocytes. We have recently observed that epidermal growth factor receptor (EGFR) signaling affects TNF-alpha-driven chemokine expression in epidermal keratinocytes, and its functional impairment increases the levels of crucial chemoattractants such as CCL2/MCP-1, CCL5/RANTES, and CXCL10/IFN-gamma-inducible protein-10. In this study, we report evidence that EGFR-dependent ERK1/2 activity is implicated in this mechanism. Abrogation of ERK1/2 activity with specific inhibitors increased chemokine expression in keratinocytes by enhancing mRNA stabilization. In mouse models, inflammatory response to irritants and T cell-mediated contact hypersensitivity were both aggravated when elicited in a skin area previously treated with an EGFR or a MAPK kinase 1/2 inhibitor. In contrast, impairment of p38 alpha beta MAPK phosphorylation markedly attenuated these responses. Our data indicate that EGFR-dependent ERK1/2 activity in keratinocytes takes part to a homeostatic mechanism regulating inflammatory responses, and emphasize the distinct role of MAPKs as potential targets for manipulating inflammation in the skin.