生长停滞特异性蛋白 6（Gas6）可减轻碘诱导的 NOD.H-2 小鼠的炎症损伤和细胞凋亡。
Growth arrest-specific protein 6 (Gas6) attenuates inflammatory injury and apoptosis in iodine-induced NOD.H-2 mice.
机构信息
Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
出版信息
Int Immunopharmacol. 2019 Aug;73:333-342. doi: 10.1016/j.intimp.2019.04.038. Epub 2019 May 23.
PURPOSE
Growth arrest-specific protein 6 (Gas6) is a vitamin K-dependent protein that plays an important role in the pathogenesis of autoimmune diseases. The purpose of this study was to explore the expression of Gas6 and its effects on autoimmune thyroiditis (AIT).
METHOD
A total of 24 male NOD.H-2 mice were randomly assigned to three groups: (1) a control group supplied with regular water; (2) a sodium iodide (NaI) group supplied with 0.005% sodium iodide water; and (3) a group treated with recombinant mouse Gas6 (rmGas6) after iodine supplementation (NaI + Gas6 group). The severity of lymphocytic infiltration in the thyroid was measured through histopathology. Serum levels of tumor necrosis factor α (TNF-α), interleukin (IL) 6 and IL-1β, as well as anti-thyroglobulin antibody (TgAb) titers were measured using an enzyme-linked immunosorbent assay. In addition, the expression of Gas6, Caspase 3, TAM receptors (Axl and MerTK), nuclear factor κB (NF-κB) and I-kappa-B α (IκB-α) were measured by Western blotting. Finally, the proportions of T cells were determined in the splenocytes of NOD.H-2 mice by flow cytometry.
RESULTS
The mRNA and protein expression of Gas6 was significantly lower in the NaI group compared to the control group. Serum levels of TgAb, TNF-α, IL-6 and IL-1β were also significantly higher in the NaI group but were dramatically reduced after rmGas6 injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly lower in the NaI + Gas6 group compared to the NaI group. The protein expression of cleaved-Caspase 3, phosphorylation of MerTK, and NF-κB and IκB-α in the thyroid gland were significantly reduced after rmGas6 administration. The proportion of Th1, Th2 and Th17 cells in splenocytes were also significantly reduced after rmGas6 treatment, whereas there was a dramatic increase in the proportion of Treg cells.
CONCLUSION
Gas6 exerts an anti-inflammatory effect in a mouse model of AIT and may therefore be a potential therapeutic target.
目的
生长停滞特异性蛋白 6（Gas6）是一种维生素 K 依赖性蛋白，在自身免疫性疾病的发病机制中发挥重要作用。本研究旨在探讨 Gas6 的表达及其对自身免疫性甲状腺炎（AIT）的影响。
方法
将 24 只雄性 NOD.H-2 小鼠随机分为三组：（1）对照组，给予常规水；（2）碘酸钠（NaI）组，给予 0.005% 碘酸钠水；（3）碘补充后给予重组鼠 Gas6（rmGas6）治疗组（NaI+Gas6 组）。通过组织病理学测量甲状腺淋巴细胞浸润的严重程度。采用酶联免疫吸附试验测定肿瘤坏死因子 α（TNF-α）、白细胞介素（IL）6 和 IL-1β 以及抗甲状腺球蛋白抗体（TgAb）滴度。此外，通过 Western 印迹法测定 Gas6、半胱氨酸天冬氨酸蛋白酶 3（Caspase 3）、TAM 受体（Axl 和 MerTK）、核因子 κB（NF-κB）和 IκB-α的表达。最后，通过流式细胞术测定 NOD.H-2 小鼠脾细胞中 T 细胞的比例。
结果
与对照组相比，NaI 组 Gas6 的 mRNA 和蛋白表达明显降低。NaI 组血清 TgAb、TNF-α、IL-6 和 IL-1β 水平也明显升高，但 rmGas6 注射后显著降低。与 NaI 组相比，NaI+Gas6 组甲状腺炎的发生率和淋巴细胞浸润明显降低。rmGas6 给药后，甲状腺组织中 cleaved-Caspase 3、MerTK 磷酸化以及 NF-κB 和 IκB-α的蛋白表达明显降低。rmGas6 治疗后，脾细胞中 Th1、Th2 和 Th17 细胞的比例也明显降低，而 Treg 细胞的比例则明显升高。
结论
Gas6 在 AIT 小鼠模型中发挥抗炎作用，因此可能是一种潜在的治疗靶点。
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