| TPL2在小鼠自身免疫性肝炎中的作用 |
| 投稿时间：2025-04-25 修订日期：2025-09-23 点此下载全文 |
| 引用本文：武文博,马腾琪,李妍华,赵翠娟.TPL2在小鼠自身免疫性肝炎中的作用[J].医学研究杂志,2026,55(1):88-94 |
| DOI：
10.11969/j.issn.1673-548X.2026.01.016 |
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| 基金项目:内蒙古自治区科技计划项目(2022YFSH0042)；内蒙古医学科学院公立医院科研联合基金科技项目(2023GLLH0242)；中国金属学会冶金安全与健康分会健康卫生科研项目(jkws202409) |
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| 中文摘要:目的 明确肿瘤进展位点2(tumor progression locus 2,TPL2)在自身免疫性肝炎小鼠肝脏损伤及炎性反应中的作用和分子机制。方法 将40只健康C57BL/6雄性小鼠,随机分为正常对照组、模型对照组、低TPL2抑制剂组、高TPL2抑制剂组,每组10只。4组小鼠均采用正常饲料喂养4天后处死。模型对照组、低TPL2抑制剂组、高TPL2抑制剂组小鼠在处死前24h尾静脉注射ConA(18mg/kg),低TPL2抑制剂组、高TPL2抑制剂组小鼠在处死前3天给予TPL2抑制剂(2.5、4.5mg/kg)腹腔注射,每隔24h给药一次,其余小鼠同时间点给予同等容量0.9%氯化钠溶液。实验终点测量小鼠体质量,取小鼠眼眶血,脱臼处死小鼠取肝脏、脾脏,测量肝脏及脾脏重量,计算肝指数(肝指数=肝脏质量/体质量×100%)和脾指数(脾指数=脾脏重量/体质量×100％),检测血清谷丙转氨酶(alanine aminotransferase,ALT)及谷草转氨酶(aspartate aminotransferase,AST)水平,苏木精-伊红(hematoxylin and eosin,HE)染色法染色评估肝脏病理学改变,蛋白质印迹法检测肝脏组织中TPL2、c-Jun N-末端激酶(c-Jun N-terminal kinase,JNK)、磷酸化JNK(p-JNK)蛋白表达水平,反转录聚合酶链式反应(reverse transcription polymerase chain reaction,RT-PCR)检测肝脏中白细胞介素(interleukin,IL)-6、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)mRNA的表达水平。结果 与正常对照组比较,模型对照组小鼠体质量降低(P<0.001)；肝、脾指数升高(P<0.001)；血清ALT、AST水平升高(P<0.001)；HE染色显示肝小叶内大面积组织坏死,坏死灶周围可见大量炎性细胞浸润；肝脏中IL-6、TNF-α mRNA表达增高(P<0.001),模型对照组小鼠肝脏中TPL2、p-JNK蛋白表达均上调(P<0.001)。与模型对照组比较,高TPL2抑制剂组小鼠体质量上升(P<0.01),肝指数、脾指数下降(P<0.01、P<0.001),血清ALT、AST水平降低(P<0.01、P<0.001)。HE染色显示肝脏炎症明显改善,肝脏中IL-6、TNF-α mRNA表达下降(P<0.01、P<0.001)；肝脏中TPL2、p-JNK蛋白表达均显著降低(P<0.001、P<0.05),p-JNK/JNK比值显著下调(P<0.001)。结论 TPL2参与ConA诱导的小鼠免疫性肝损伤,TPL2抑制剂通过抑制TPL2活性进而抑制JNK信号通路可以改善免疫性肝损伤小鼠的肝脏损伤与炎症。 |
| 中文关键词:自身免疫性肝炎 肿瘤进展位点 2 c-Jun氨基末端激酶 刀豆蛋白A |
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| Role of TPL2 in Autoimmune Hepatitis in Mice. |
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| Abstract:Objective To clarify the role and molecular mechanism of tumor progression locus 2 (TPL2) in liver injury and inflammatory response in mice with immune liver injury. Methods Forty healthy C57BL/6male mice were randomly divided into normal control group, model control group, low-dose TPL2 inhibitor group, and high-dose TPL2 inhibitor group, with 10mice in each group. All mice of four groups were fed with normal diet for four days and then killed. ConA (18mg/kg, respectively) was injected into the tail vein 24hours before execution in the model control group, and TPL2 inhibitors (2.5mg/kg and 4.5mg/kg) were injected intraperitoneally in the the low-dose and high-dose TPL2 inhibitor groups three days before execution, once every 24hours. Mice in the other groups were given the same volume of normal saline at the same time points. At the end of the experiment, the weight of mice was measured, the orbital blood of mice was taken, and mice were killed by cervical dislocation to obtain the liver and spleen. The weights of the liver and spleen were measured to calculate the liver index (liver index = liver mass/weight ×100%) and spleen index (spleen index = spleen weight/weight × 100%). The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected, and hematoxylin-eosin (HE) staining was used to evaluate the pathological changes of liver. The expression levels of TPL2, c-Jun N-terminal kinase (JNK), and phosphorylated JNK (p-JNK) in liver tissues were detected by Western-blot. The expression levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) mRNA in liver were detected by reverse transcription polymerase chain reaction (RT-PCR). Results Compared with the normal control group, the weight of mice in the model control group was decreased (P<0.001). Liver and spleen indexes were increased (P<0.001). Serum ALT and AST levels were increased (P<0.001). HE staining showed a large area of tissue necrosis in hepatic lobules, and a large number of inflammatory cell infiltrated around the necrotic focus. The expressions of IL-6 and TNF-α mRNA in liver were increased (P<0.001), and the expressions of TPL2 and p-JNK protein in liver of mice in the model control group were up-regulated (P<0.001). Compared with the model control group, the weight of mice in the high-dose TPL2 inhibitor group increased (P<0.01), the liver and spleen indexes decreased (P<0.01, P<0.001), and the serum ALT and AST levels were decreased (P<0.01, P<0.001). HE staining showed that the liver inflammation was obviously improved, and the expressions of IL-6 and TNF-α mRNA in live were significantly decreased (P<0.01, P<0.001). The expressions of TPL2 and p-JNK protein in liver were decreased significantly (P<0.001, P<0.05), and the ratio of p-JNK/JNK was decreased significantly (P<0.001). Conclusion TPL2 participates in ConA-induced immune liver injury in mice, and inhibiting TPL2 activity can improve liver injury and inflammation in mice with immune liver injury by inhibiting the activation of JNK signal pathway. |
| keywords:Autoimmune hepatitis Tumor progression locus 2 c-Jun amino terminal kinase Concanavalin A |
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