Topical Sunitinib ointment alleviates Psoriasis-like inflammation by inhibiting the proliferation and apoptosis of keratinocytes
Topical Sunitinib ointment alleviates Psoriasis-like inflammation by inhibiting the proliferation and apoptosis of keratinocytes
复制标题
外用舒尼替尼软膏通过抑制角质形成细胞的增殖和凋亡来减轻银屑病样炎症。
DOI：
10.1016/j.ejphar.2018.01.048
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发表时间：
2018-04-05
影响因子：
5
通讯作者：
Chen, Xiang
中科院分区：
文献类型：
--
作者：
Kuang, Ye-Hong;Lu, Yan;Chen, Xiang
银屑病是一种以皮肤损害和角质形成细胞异常增殖为特征的慢性自身免疫性炎症性疾病。舒尼替尼是一种多靶点酪氨酸激酶抑制剂，已知可选择性抑制多种生长因子受体，包括血管内皮生长因子受体、血小板衍生生长因子受体和干细胞因子。据报道，1例肾细胞癌（RCC）患者在舒尼替尼治疗期间银屑病病灶显著消退，但其机制尚不清楚。我们应用舒尼替尼软膏治疗咪喹莫特诱导的银屑病小鼠模型，发现舒尼替尼软膏可以减轻咪喹莫特诱导的银屑病样炎症，降低Ki 67表达，而舒尼替尼软膏不能减轻咪喹莫特诱导的小鼠模型脾肿大，于是我们集中研究舒尼替尼对角质形成细胞增殖和凋亡的影响，我们用表皮生长因子培养HaCaT细胞（HaCaT/E细胞）以呈现高度增殖的银屑病角质形成细胞的状态。舒尼替尼可通过影响细胞周期蛋白D1、E1的表达水平，抑制Hacat/E细胞增殖，并呈时间和浓度依赖性;舒尼替尼可诱导Hacat/E细胞凋亡，上调多聚腺苷二磷酸核糖聚合酶（PARP）的表达。舒尼替尼显著下调Hacat/E细胞磷酸化信号转导和转录激活因子3（p-Stat 3）的表达。我们得出结论，舒尼替尼通过抑制p-Stat 3的表达来调节HaCaT细胞的增殖和凋亡，从而抑制咪喹莫特诱导的银屑病样炎症。
Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. Sunitinib, a multi-targeted tyrosine kinase inhibitor, is known to selectively inhibit several growth factor receptors, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and stem cell factor. It was reported that a patient with renal cell carcinoma (RCC) whose psoriatic lesion was resolved dramatically during treatment with Sunitinib, however, the mechanism is still unclear. We applied Sunitinib ointment to treat imiquimod-induced mouse model of psoriasis and found that Sunitinib ointment could alleviate imiquimod-induced psoriasis-like inflammation and reduce the Ki67 expression, while Sunitinib ointment couldn't reduce imiquimod-induced splenomegaly of the mouse model, then we concentrated on studying the effect of Sunitinib on the proliferation and apoptosis of keratinocytes, we cultivated HaCaT cells with epidermal growth factor (HaCaT/E cells) to represent as a state of highly proliferative psoriatic keratinocytes. We found that Sunitinib could inhibit the proliferation of Hacat/E cell in a time and concentration dependent manner by influencing the expression level of cell cycle protein D1, cycle protein E1, in addition, Sunitinib could induce the apoptosis of Hacat/E cell and up-regulate the expression of poly ADP-ribose polymerase (PARP). Sunitinib down-regulated the expression of phosphorylated signal transduction and activator of transcription 3 (p-Stat3) of Hacat/E cells significantly. We conclude that Sunitinib alleviates imiquimod-induced psoriasis-like inflammation by regulating the proliferation and apoptosis of HaCaT cells through inhibiting the expression of p-Stat3.