A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis
A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis
复制标题
DOI：
10.1172/jci200112153
复制
发表时间：
2001-08-01
影响因子：
15.9
通讯作者：
Watt, FM
中科院分区：
文献类型：
--
作者：
Haase, I;Hobbs, RM;Watt, FM
在正常表皮中，β 1整联蛋白表达仅限于基底层，而在过度增殖表皮中，整联蛋白也在基底上层中表达。整合素通过外皮蛋白启动子在基底层上表达的转基因小鼠具有散发性银屑病表型;然而，整合素促进银屑病发病的机制尚不清楚。我们观察到人和转基因小鼠银屑病病变和愈合小鼠皮肤伤口的基底和基底上角质形成细胞中丝裂原活化蛋白激酶（MAPK）的活化，在每种情况下与基底上整合素表达相关。表型正常的人和转基因小鼠表皮不含活化的MAPK。转基因阳性的角质形成细胞产生更多的IL-1 α比对照组，角质形成细胞MAPK可以被激活的基底上的整合素连接或治疗与IL-1 α。MAPK的组成性激活增加了人角质形成细胞的生长速率，延迟了终末分化的发生，重现了银屑病表皮的许多组织学特征。我们认为，MAPK的激活整合素，无论是直接或通过增加IL-1 α的生产，是负责银屑病和伤口愈合的表皮过度增殖，和转基因小鼠的散发表型可能反映了复杂的机制，IL-1的释放和反应性控制在皮肤中。
In normal epidermis, beta1 integrin expression is confined to the basal layer, whereas in hyperproliferative epidermis, integrins are also expressed in the suprabasal layers. Transgenic mice in which integrins are expressed suprabasally via the involucrin promoter have a sporadic psoriatic phenotype; however, the mechanism by which integrins contribute to the pathogenesis of psoriasis is unknown. We observed activation of mitogen-activated protein kinase (MAPK) in basal and suprabasal keratinocytes of human and transgenic mouse psoriatic lesions and healing mouse skin wounds, correlating in each case with suprabasal integrin expression. Phenotypically normal human and transgenic mouse epidermis did not contain activated MAPK. Transgene-positive keratinocytes produced more IL-1 alpha than controls did, and keratinocyte MAPK could be activated by ligation of suprabasal integrins or treatment with IL-1 alpha. Constitutive activation of MAPK increased the growth rate of human keratinocytes and delayed the onset of terminal differentiation, recreating many of the histological features of psoriatic epidermis. We propose that activation of MAPK by integrins, either directly or through increased IL-1 alpha production, is responsible for epidermal hyperproliferation in psoriasis and wound healing, and that the sporadic phenotype of the transgenic mice may reflect the complex mechanisms by which IL-1 release and responsiveness are controlled in skin.