杨洪　李慧　马红艳

[摘要]目的：探討阿维A联合阿达木单抗调控丝裂原活化蛋白激酶（Mitogen-activated protein kinases，MAPK）/核转录因子κB（NF-κB）通路对银屑病小鼠模型的疗效及辅助性T细胞17（T helper cell 17，Th17）/Th22、树突状细胞（Dendriticcells，DC）水平的影响研究。方法：将BALB/c雌性小鼠作为研究对象，背部涂抹咪喹莫特乳膏构建银屑病小鼠模型，并随机分为模型组、干预组即阿维A组、阿达木单抗组以及阿维A联合阿达木单抗组，模型组注射生理盐水，干预三组分别给予阿维A灌胃、阿达木单抗静脉注射以及阿维A灌胃联合阿达木单抗静脉注射，干预治疗7d后动态观察各组小鼠皮损变化情况并进行皮损面积和严重程度指数（Psoriasis area and severity index，PASI）评分，比较各组小鼠外周血炎症因子表达水平以及Th17/Th22细胞以及DC水平，采用Western-blot法测定各组小鼠皮损组织中NF-κB蛋白水平。结果：与模型组相比，阿达木单抗组、阿维A组和阿达木单抗联合阿维A组三组小鼠鳞屑程度和鳞屑厚度明显减轻，红斑面积缩小，皮损症状明显缓解，其中阿达木单抗联合阿维A组皮损改善程度最显著，PASI评分上升趋势最缓慢。干预后7d，阿达木单抗组、阿维A组和阿达木单抗联合阿维A组三组小鼠血清IL-17、IL-21、IL-23、IFN-γ、TNF-α等炎症因子水平、外周血Th17/Th22细胞及DC水平相比模型组明显下降，差异有统计学意义（P<0.05）;且联合用药组各炎症因子表达水平明显低于阿达木单抗组和阿维A组，差异有统计学意义（P<0.05）。阿达木单抗组、阿维A组和阿达木单抗联合阿维A组三组皮损组织NF-κB蛋白相对表达水平明显下降，差异有统计学意义（P<0.05）;且联合用药组NF-κB蛋白水平相对表达水平明显低于阿达木单抗组、阿维A组，差异有统计学意义（P<0.05）。结论：阿维A联合阿达木单抗可能通过调控MAPK/NF-κB通路影响银屑病小鼠Th17/Th22、DC水平，从而抑制炎症反应和改善银屑病症状。

[关键词]银屑病;阿维A;阿达木单抗;MAPK/NF-κB通路;Th17/Th22;树突状细胞

[中图分类号]R758.63    [文献标志码]A    [文章编号]1008-6455（2021）09-0007-05

Effect of Acitretin Combined with Adalimumab on the Efficacy of MAPK/NF-κB Pathway in Psoriasis Mouse Model and the Effect of Th17/Th22 and DC Levels

YANG Hong，LI Hui，MA Hong-yan

（Department of Dermatology，Children's Hospital of Xinjiang Uygur Autonomous Region，Urumqi 830000，Xinjiang，China）

Abstract： Objective  To investigate the effect of acitretin combined with adalimumab on the regulation of MAPK/NF-κB pathway in psoriasis mouse model and the effects of Th17/Th22 and dendritic cells （DC）. Methods  BALB/c female mice were used as subjects， and a psoriasis mouse model was constructed by applying imiquimod cream on the back and randomly divided into the model group， the acitretin group， the adalimumab group and the adalimumab combined with acitretin group. The model group was injected with normal saline， and the three groups were given intravenous administration of acitretin， intravenous adalimumab， and intravenous injection of acitretin combined with adalimumab. After 7 days of intervention treatment， the changes of skin lesions in each group were observed dynamically and the Psoriasis area and severity index （PASI） score was obtained. The expression levels of peripheral blood inflammatory factors and Th17/ Th22 cells and DC levels in each group were compared， and the NF-κB protein levels in the skin lesions of each group were determined by Western-blot method. Results  Compared with the model group， the degree of scaly and scaly thickness of the adalimumab group， the acitretin group and the adalimumab combined with acitretin group were significantly reduced， the area of erythema was reduced， and the symptoms of skin lesions were significantly relieved. Among them， the adalimumab combined with acitretin group had the most significant improvement in skin lesions， and the PASI score increased the slowest. On the 7th day after the intervention， the serum levels ofvIL-17， IL-21， IL-23， TNF-α and IFN-γ were significantly decreased in the adalimumab group， the acitretin group， and the adalimumab combined with acitretin group compared with the model group， the differences were statistically significant （P<0.05）. And the expression levels of inflammatory factors in the combination group were significantly lower than those in the adalimumab group and the acitretin group （P<0.05）. In addition， the relative expression levels of NF-κB protein in the adalimumab group， the acitretin group and the adalimumab combined with acitretin group were significantly decreased （P<0.05）. And the level of NF-κB protein in the combination group was significantly lower （P<0.05）. And the combination group was significantly lower than the adalimumab group and the acitretin group （P<0.05）. Conclusion  Acitretin combined with adalimumab may inhibit the levels of Th17/Th22 and DC in psoriasis mice by regulating MAPK/NF-κB pathway， thereby inhibiting inflammatory response and improving symptoms of psoriasis.

Key words： psoriasis; acitretin; adalimumab; MAPK/NF-κB pathway; Th17/Th22; dendritic cells

银屑病（Psoriasis）是一种由多重因素诱导的免疫异常性和慢性炎症皮肤病，患处皮肤常呈现为红色丘疹且表面覆盖有数层银白色的鳞屑[1]。银屑病发病累及范围大且病情反复迁延不愈，目前临床上尚无良好的根治方案，只能通过药物对疾病进程进行控制和减轻患者痛苦[2]。……