Amphiregulin causes functional downregulation of adherens junctions in psoriasis
Amphiregulin causes functional downregulation of adherens junctions in psoriasis
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DOI：
10.1111/j.0022-202x.2005.23762.x
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发表时间：
2005-06-01
影响因子：
6.5
通讯作者：
Coffey, RJ
中科院分区：
文献类型：
--
作者：
Chung, E;Cook, PW;Coffey, RJ
在小鼠和人类中，双调节蛋白(AR)的过度表达与银屑病有关。由于银屑病的特点是角质形成细胞过度增殖，表皮屏障功能丧失，炎症细胞渗入表皮和真皮，我们推测AR可能通过影响细胞-细胞连接的完整性而参与银屑病的发病。我们发现，在INV-AR小鼠和牛皮癣患者的银屑病皮损中，功能性E-钙粘素显著减少。INV-AR小鼠的银屑病皮损中总E-钙粘附素水平显著降低。与正常皮肤相比，银屑病患者的皮损表现出细胞骨架相关的Triton不溶性E-钙粘素池的下调，并在细胞质Triton可溶池中出现一个80 kDa的胞外结构域片段。银屑病皮损基底表皮E-钙粘附素免疫组织化学染色减弱。此外，应用AR后，人中性粒细胞通过MDCK细胞的极化上皮细胞单层迁移增强，而不是转化生长因子-α，进一步支持了AR在银屑病发病机制中的特殊作用。
Overexpression of amphiregulin (AR) has been linked to psoriasis in mouse and man. Since psoriasis is marked by hyperproliferation of keratinocytes and loss of epidermal barrier function with infiltration of inflammatory cells into the epidermis and dermis, we hypothesized that AR might contribute to the pathogenesis of psoriasis by affecting the integrity of cell-cell junctions. We find that there is a marked reduction of functional E-cadherin in psoriatic lesions from both INV-AR mice and individuals with psoriasis. Total E-cadherin levels are dramatically reduced in psoriatic lesions from INV-AR mice. Compared with normal skin, psoriatic lesions from individuals with psoriasis exhibit downregulation of the cytoskeletal-associated triton-insoluble pool of E-cadherin and the appearance of an 80 kDa ectodomain fragment in the cytoplasmic triton-soluble pool. There is reduced immunohistochemical staining for E-cadherin in the basal epidermis of human psoriatic lesions. Moreover, there is enhanced transmigration of human neutrophils through polarized epithelial cell monolayers of MDCK cells after administration of AR, but not transforming growth factor-alpha, further supporting a specific role for AR in the pathogenesis of psoriasis.