Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation
Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation
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DOI：
10.1016/s0002-9440(10)63654-1
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发表时间：
2003-07-01
影响因子：
6
通讯作者：
Pastore, S
中科院分区：
文献类型：
--
作者：
Mascia, F;Mariani, V;Pastore, S
在银屑病、特应性皮炎和过敏性接触性皮炎等炎症性皮肤病中，表皮角质形成细胞过度表达大量的可溶性表皮生长因子受体配体，以响应肿瘤坏死因子a和干扰素γ。这些细胞因子还促进许多趋化因子的从头合成，包括CCL2/MCP-1、CCL5/RANTES、CXCL10/EP-10和CXCL8/IL-8，进而负责不同白细胞的招募。这项研究表明，EGFR的刺激下调了角质形成细胞中CCL2、CCL5和CXCL10的表达，而增加了CXCL8的表达。相反，阻断EGFR信号会产生相反的效果，增加CCL2、CCL5和CXCL10，减少CXCL8的表达。在接触性超敏反应的小鼠模型中，在抗原攻击前单一局部应用选择性EGFR激酶阻滞剂可显著增强免疫反应，并增加趋化因子的表达和更多的炎性细胞浸润。因此，将EGFR靶向于上皮细胞可能会对炎症和免疫反应产生深远影响。
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.