Paeonol suppresses solar ultraviolet-induced skin inflammation by targeting T-LAK cell-originated protein kinase.
Paeonol suppresses solar ultraviolet-induced skin inflammation by targeting T-LAK cell-originated protein kinase.
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丹皮酚通过靶向 T-LAK 细胞来源的蛋白激酶来抑制太阳紫外线引起的皮肤炎症
DOI：
10.18632/oncotarget.15636
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发表时间：
2017-04-18
期刊：
影响因子：
--
通讯作者：
Duan Q
中科院分区：
文献类型：
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作者：
Xue P;Wang Y;Zeng F;Xiu R;Chen J;Guo J;Yuan P;Liu L;Xiao J;Lu H;Wu D;Pan H;Lu M;Zhu F;Shi F;Duan Q
过度暴露于太阳紫外线（sunny uv，SUV）与许多人类皮肤疾病有关，如皮肤炎症、光老化和癌变。T-LAK细胞源性蛋白激酶（TOPK）是p38丝裂原活化蛋白激酶（p38）和c-Jun N末端激酶（JNKs）的上游激酶，在SUV诱导的皮肤炎症中起重要作用，靶向TOPK已成为预防皮肤炎症的策略。在本研究中，我们发现TOPK、p38磷酸化或JNKs在人日光性皮炎组织中的表达增加。SUV处理后，HaCat细胞和JB 6 Cl 41细胞中p38或JNKs的磷酸化水平以剂量和时间依赖性方式增加。炔雌醇是从传统中草药中分离得到的活性成分，MTS（3-（4，5-二甲基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2H-四氮唑）试验表明其对细胞无毒性。微量热泳（MST）实验表明，丹皮酚可以结合TOPK离体。体外激酶活性测定表明丹皮酚对TOPK活性有抑制作用。体外研究进一步显示丹皮酚通过抑制TOPK活性以时间和剂量依赖性方式抑制SUV诱导的p38、JNKs、MSK 1和组蛋白H2 AX的磷酸化水平。体外培养HaCat和JB 6细胞，丹皮酚可抑制IL-6和TNF-α的分泌。体内实验表明，丹皮酚可抑制SUV诱导的TOPK、p38、JNKs和H2 AX的磷酸化以及IL-6和TNF-α的分泌。总之，我们的数据表明丹皮酚通过靶向TOPK对SUV诱导的炎症具有保护作用，丹皮酚可能是治疗SUV诱导的皮肤炎症的有前途的药物。
Excessive exposure to solar UV (SUV) is related with numerous human skin disorders, such as skin inflammation, photoaging and carcinogenesis. T-LAK cell- originated protein kinase (TOPK), an upstream of p38 mitogen-activated protein kinase (p38) and c-Jun N-terminal kinases (JNKs), plays an important role in SUV -induced skin inflammation, and targeting TOPK has already been a strategy to prevent skin inflammation. In this study, we found that the expression of TOPK, phosphorylation of p38 or JNKs was increased in human solar dermatitis tissues. The level of phosphorylation of p38 or JNKs increased in a dose and time dependent manner in HaCat cells or JB6 Cl41 cells after SUV treatment. Paeonol is an active component isolated from traditional Chinese herbal medicines, and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2H-tetrazdium) assay showed that it has no toxicity to cells. Microscale thermophoresis (MST) assay showed that paeonol can bind TOPK ex vivo. In vitro kinase assay showed paeonol can inhibit TOPK activity. Ex vivo studies further showed paeonol suppressed SUV-induced phosphorylation level of p38, JNKs, MSK1 and histone H2AX by inhibiting TOPK activity in a time and dose dependent manner. Paeonol inhibited the secretion of IL-6 and TNF-α in HaCat and JB6 cells ex vivo. In vivo studies demonstrated that paeonol inhibited SUV-induced increase of TOPK, the phosphorylation of p38, JNKs and H2AX, and the secretion of IL-6 and TNF-α in Babl/c mouse. In summary, our data indicated a protective role of paeonol against SUV-induced inflammation by targeting TOPK, and paeonol could be a promising agent for the treatment of SUV-induced skin inflammation.