Regulation of interleukin-1α expression by integrins and epidermal growth factor receptor in keratinocytes from a mouse model of inflammatory skin disease
Regulation of interleukin-1α expression by integrins and epidermal growth factor receptor in keratinocytes from a mouse model of inflammatory skin disease
复制标题
DOI：
10.1074/jbc.m300513200
复制
发表时间：
2003-05-30
影响因子：
4.8
通讯作者：
Watt, FM
中科院分区：
文献类型：
--
作者：
Hobbs, RM;Watt, FM
在基底上表皮层表达β(1)整合素的转基因小鼠具有零星的皮肤过度增殖和炎症，这与细胞外信号调节激酶(Erk)丝裂原激活蛋白激酶的激活和白细胞介素(IL)-1α的产生增加相关。我们研究了异常整合素表达、Erk 激活和 IL-1α 表达之间的联系。转基因角质形成细胞比非转基因对照具有更高的基础 Erk 活性和 IL-1α 水平，并且对 IL-1α、12-O-十四烷酰佛波醇-13-乙酸酯 (TPA)、表皮生长因子 (EGF) 和血清刺激 Erk 活性和 IL-1α 产生更敏感。在转基因角质形成细胞中抑制 Erk 可降低基础 IL-1α 水平以及血清或佛波酯对 IL-1α 产生的刺激，表明 Erk 可以调节 IL-1α 表达。 TPA 或 IL-1α 处理导致转基因细胞中 EGF 受体快速下调，表明反式激活。抑制反式激活可阻断基础和 TPA 或 IL-1α 诱导的 Erk 激活，但不会阻断 IkappaBα 降解，并消除转基因细胞中 IL-1α 产生的增加。在转基因阴性细胞中，野生型或激酶死亡的 IRAK1 持续激活 IL-1 依赖性信号传导，刺激不依赖于 Erk 的 IL-1α 产生。我们得出结论，基底上整合素表达通过增强 EGF 受体的激活导致 Erk 激活并增加 IL-1α 表达。这些结果提供了异常整合素表达触发表皮过度增殖和炎症的机制。
Transgenic mice expressing beta(1) integrins in the suprabasal epidermal layers have sporadic skin hyperproliferation and inflammation correlated with activation of extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase and increased interleukin (IL)-1alpha production. We investigated the link between aberrant integrin expression, Erk activation, and expression of IL-1alpha. Transgenic keratinocytes had higher basal Erk activity and IL-1alpha levels than nontransgenic controls and were more sensitive to stimulation of Erk activity and IL-1alpha production by IL-1alpha, 12-O-tetradecanoylphorbol-13-acetate (TPA), epidermal growth factor (EGF), and serum. Inhibition of Erk in transgenic keratinocytes reduced basal IL-1alpha levels and the stimulation of IL-1alpha production by serum or phorbol ester, demonstrating that Erk could regulate IL-1alpha expression. TPA or IL-1alpha treatment resulted in rapid down-regulation of the EGF receptor in transgenic cells, indicative of transactivation. Inhibition of transactivation blocked basal and TPA or IL-1alpha induced Erk activation, but not IkappaBalpha degradation, and abolished increased IL-1alpha production in transgenic cells. In transgene-negative cells, constitutive activation of IL-1-dependent signaling by wild type or kinase-dead IRAK1 stimulated IL-1alpha production independent of Erk. We conclude that suprabasal integrin expression leads to Erk activation and increased IL-1alpha expression by potentiating activation of the EGF receptor. These results provide a mechanism by which aberrant integrin expression triggers epidermal hyperproliferation and inflammation.