Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation

作     者：Mascia, F Mariani, V Girolomoni, G Pastore, S 

作者机构：Ist Dermopat Immacolata Ist Ricovero & Cura Carottere Sci Immunol Lab I-00167 Rome Italy 

出 版 物：《AMERICAN JOURNAL OF PATHOLOGY》 (美国病理学杂志)

年 卷 期：2003年第163卷第1期

页      面：303-312页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：Ministero della Salute 

主　　题：细胞 培养的 炎症趋化因子类/遗传学 炎症趋化因子类/免疫学 炎症趋化因子类/代谢 培养技术 皮炎 接触性/免疫学 皮炎 接触性/代谢 疾病模型 动物 炎症/免疫学 炎症/代谢 干扰素γ/代谢 角蛋白细胞/细胞学 角蛋白细胞/免疫学 角蛋白细胞/代谢 小鼠 近交BALBC 信号传导/生理学 皮肤/细胞学 皮肤/免疫学 皮肤/代谢 皮肤/病理生理学 转录激活 转化生长因子α/遗传学 转化生长因子α/代谢 肿瘤坏死因子α/代谢 成年人 动物 女(雌)性 人类 男(雄)性 小鼠 

摘      要：During inflammatory skin disorders such as psoriasis, atopic dermatitis, and allergic contact dermatitis, epidermal keratinocytes overexpress large amounts of soluble epidermal growth factor receptor ligands in response to tumor necrosis factor a and interferon gamma. These cytokines also promote de novo synthesis of numerous chemokines, including CCL2/MCP-1, CCL5/RANTES, CXCL10/EP-10, and CXCL8/IL-8, in turn responsible for the recruitment of different leukocyte populations. This study demonstrates that stimulation of EGFR down-regulates CCL2, CCL5, and CXCL10, while it increases CXCL8 expression in keratinocytes. Conversely, EGFR signaling blockade produces opposite effects, with increased CCL2, CCL5, and CXCL10, and reduced CXCL8 expression. In a mouse model of contact hypersensitivity, a single topical administration of a selective EGFR kinase blocker before antigen challenge results in a markedly enhanced immune response with increased chemokine expression and heavier inflammatory cell infiltrate. Targeting EGFR on epithelial cells may thus have profound impact on inflammatory and immune responses.