Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea; Cancer and Metabolism Institute, Konkuk University, Seoul, Republic of Korea.
Biochem Biophys Res Commun. 2021 Jan 1;534:303-309. doi: 10.1016/j.bbrc.2020.11.089. Epub 2020 Dec 1.
Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine peptidase that plays a crucial role in regulating skin desquamation. KLK7 expression is highly upregulated in atopic dermatitis (AD) skin lesions in both humans and mice. Th2-lymphocyte-derived cytokines, including interleukin (IL)-4 and IL-13, have been shown to promote KLK7 expression in keratinocytes in patients with AD. However, the molecular mechanism underlying KLK7 expression remains poorly understood. Here, we demonstrated that the EGR-1-binding sequence (EBS) in the promoter region of KLK7 played a crucial role in IL-13-induced KLK7 transcription. Disruption of the EBS induced by a point mutation inhibited IL-13-induced KLK7 promoter activity. EGR-1 was shown to directly bind to the EBS, and EGR1 knockdown with shRNA abrogated IL-13-induced KLK7 expression. Using Egr1 knockout mice, we showed that Egr-1 was necessary for KLK7 expression in AD-like lesions induced by the repeated topical application of 2,4-dinitrobenzene on the dorsal skin of mice. We also demonstrated that the ERK1/2 mitogen-activated protein kinase (MAPK) pathway was responsible for EGR-1-dependent KLK7 transcription in response to IL-13 stimulation. Our findings delineate a signaling pathway that contributes to the regulation of KLK7 expression through the IL13-ERK MAPK-EGR1 signaling axis.
激肽释放酶相关肽酶 7（KLK7）是一种糜蛋白酶样丝氨酸肽酶，在调节皮肤脱屑中起着关键作用。在人类和小鼠的特应性皮炎（AD）皮肤损伤中，KLK7 的表达均被高度上调。Th2 淋巴细胞衍生的细胞因子，包括白细胞介素（IL）-4 和 IL-13，已被证明可促进 AD 患者角质形成细胞中 KLK7 的表达。然而，KLK7 表达的分子机制仍知之甚少。在这里，我们证明了 KLK7 启动子区域中的 EGR-1 结合序列（EBS）在 IL-13 诱导的 KLK7 转录中起着关键作用。点突变引起的 EBS 破坏抑制了 IL-13 诱导的 KLK7 启动子活性。结果表明 EGR-1 可直接与 EBS 结合，并且使用 shRNA 敲低 EGR1 可消除 IL-13 诱导的 KLK7 表达。使用 Egr1 基因敲除小鼠，我们表明 Egr-1 对于 2,4-二硝基苯在小鼠背部皮肤重复局部应用诱导的 AD 样病变中 KLK7 的表达是必需的。我们还证明了 ERK1/2 丝裂原活化蛋白激酶（MAPK）途径负责 IL-13 刺激下 EGR-1 依赖性 KLK7 转录。我们的研究结果描绘了一条信号通路，该通路通过 IL13-ERK MAPK-EGR1 信号轴来调节 KLK7 的表达。
