TSH受体抑制型抗体(TBAb)激活PI3K-AKT促使胫前黏液性水肿皮损原代成纤维细胞产生透明质酸胞外累积  

TSH receptor inhibitory antibody(TBAb) promotes extracellular accumulation of hyaluronic acid in pretibial myxedema primary fibroblasts via PI3K-AKT pathway

作　　者：胡利萍 邱娇娇 任小林 杨菁 张涛 蒋胜 兰长贵 Hu Liping;Qiu Jiaojiao;Ren Xiaolin;Yang Jing;Zhang Tao;Jiang Sheng;Lan Changgui(Department of Dermatology and Venerealogy,The Second Affiliated Hospital of Chengdu Medical College,China National Nuclear Corporation 416 Hospital,Chengdu 610051,China;School of Bioscience and Technology,Chengdu Medical College,Chengdu 610500,China;Department of Scientific Research and Teaching Management,The Second Affiliated Hospital of Chengdu Medical College,China National Nuclear Corporation 416 Hospital,Chengdu 610051,China)

机构地区：[1]成都医学院第二附属医院·核工业四一六医院皮肤性病科,610051 [2]成都医学院生物科学与技术学院,610500 [3]成都医学院第二附属医院·核工业四一六医院科教科,610051

出　　处：《中华内分泌代谢杂志》2022年第8期658-664,共7页Chinese Journal of Endocrinology and Metabolism

基　　金：四川省科学技术厅面上项目(2018JY0372);四川省教育厅项目(18ZB0173)。

摘　　要：目的胫前黏液性水肿(pretibial myxedema,PTM)是以真皮大量透明质酸(hyaluronan,HA)沉积和血清促甲状腺激素受体的抗体(TSH receptor antibody,TRAb)升高为特征的一种局限性甲状腺相关皮肤病。本研究探讨TRAb及其两种亚型[刺激型抗体TSAb(M22)和抑制型抗体TBAb(K1-70)]对PTM原代真皮成纤维细胞合成透明质酸的影响。方法分离培养正常人及胫前黏液性水肿真皮成纤维细胞,用M22、K1-70及患者IgG分别刺激原代成纤维细胞,利用ELISA检测刺激原代成纤维细胞前后上清液中HA浓度,Western Blot检测细胞CEMIP、HAS2、PI3K-AKT通路蛋白及其磷酸化的变化。结果患者IgG(TRAb 8.4 IU/L)可显著刺激PTM患者原代成纤维细胞的透明质酸胞外累积。同样,M22、K1-70处理PTM患者原代成纤维细胞均可上调上清液透明质酸含量,还显示K1-70刺激作用显著高于M22。IgG、M22及K1-70处理后,原代成纤维细胞HAS2表达增加,CEMIP表达减少;同时,p-PI3K及p-AKT增加。其中,对K1-70进一步研究,通过调控PI3K-AKT信号通路促进HA产生可被PI3K抑制剂(LY294002)抑制。结论TRAb尤其是TBAb,通过活化成纤维细胞PI3K-AKT信号途径,促进HA的酶(HAS2)增加,HA分解酶(CEMIP)减少,造成HA在成纤维细胞外聚集,从而导致PTM皮损的发生。Objective Pretibial myxedema(PTM)is a localized myxedema characterized by excessive dermal hya-luronan(HA)deposition and elevated serum TSH receptor antibody(TRAb).In this study,we investigated the effects of TRAb and its subtypes,stimulating antibody[TSAb(M22)]and inhibitory antibody[TBAb(K1-70)],on the synthesis of hyaluronic acid produced by PTM primary dermal fibroblasts.Methods Normal and PTM dermal fibroblasts were isolated and stimulated with M22,K1-70,and IgG from patients respectively.HA concentration in the supernatant before and after stimulation was tested by ELISA.The protein level and phosphorylation variation of CEMIP,HAS2 and PI3K-AKT pathway were detected by Western blot.Results IgG from patients(TRAb 8.4 IU/L)significantly stimulated the extracellular accumulation of HA in PTM primary fibroblasts.Similarly,both M22 and K1-70 also upregulated HA level in the supernatant,though K1-70 seemed much more effecitve.After treatment with IgG,M22,and K1-70,the expression of HAS2 increased and the expression of CEMIP decreased;meanwhile,p-PI3K and p-AkT increased.Among them,further study on K1-70,promoting HA production by regulating PI3K-AkT signal pathway could be inhibited by PI3K inhibitor(LY294002).Conclusion TSAb(M22)and TBAb(K1-70),especially TBAb,increase HAS2 and inhibit CEMIP expression by activating PI3-AKT signaling pathway in PTM fibroblasts,leading to increased extracellular HA level.

关 键 词：胫前黏液性水肿 成纤维细胞 TSH受体抑制型抗体 TSH受体刺激型抗体 PI3K-AKT 

分 类 号：R751[医药卫生—皮肤病学与性病学]