NF-κB 和 AP-1对 A 型流感病毒性心肌炎组织中异位胰蛋白酶及促炎细胞因子表达的调控

摘要

目的：探讨核因子κB（NF-κB）及激活蛋白1（AP-1）对A型流感病毒（IAV）性心肌炎心肌组织中异位胰蛋白酶及促炎细胞因子表达的调控作用。方法：40只8周龄雄性BALB／c小鼠随机分为4组：正常对照组经鼻假感染15μL生理盐水；感染对照组经鼻感染40空斑形成单位（ PFU） IAV；NF-κB抑制剂组经鼻感染40 PFU的IAV，腹腔注射吡咯烷二硫代氨基甲酸（PDTC）10 mg／kg，每天1次；AP-1抑制剂组经鼻感染40 PFU的IAV，腹腔注射去甲二氢愈创木酸（NDGA）2.5 mg／kg，每天1次。感染后第9天处死小鼠，切取心脏组织分别进行病理及生化检查。结果：IAV感染可诱导心肌组织中异位胰蛋白酶及促炎细胞因子白细胞介素（ IL）-6、IL-1β及肿瘤坏死因子（ TNF）-α表达显著上调，引发心肌急性炎症反应。 PDTC能显著抑制心肌中NF-κB激活以及异位胰蛋白酶和促炎细胞因子表达上调，有效抑制IAV复制，减轻心肌炎症反应（ P＜0.01）。 NDGA能有效抑制AP-1活性（ P＜0.01），轻度抑制促炎细胞因子表达上调（P＜0.05），但对异位胰蛋白酶表达、IAV复制及心肌炎症程度无显著影响（P＞0.05）。结论：IAV感染心肌组织后主要通过激活NF-κB诱导心肌中异位胰蛋白酶及促炎细胞因子表达上调，AP-1通路可能仅部分参与了促炎细胞因子的表达调控。%AIM: To investigate the regulatory effects of nuclear factor-κB ( NF-κB) and activator protein-1 (AP-1) on the expression of ectopic trypsin and proinflammatory cytokines in influenza A virus (IAV)-induced myocardi-tis.METHODS:Male BALB/c mice of 8 weeks old ( n=40) were randomly divided into 4 groups:normal control group ( NC) , infection control group ( IC) , NF-κB inhibitor group ( NI) and AP-1 inhibitor group ( AI) .The mice in NC group and IC group were instilled intranasally with 15μL saline and 40 plaque forming units ( PFU) IAV, respectively.The mice in NI group and AI group were infected intranasally with 40 PFU IAV and injected intraperitoneally with 10 mg/kg NF-κB inhibitor pyrrolidine dithiocarbamate ( PDTC) or 2.5 mg/kg AP-1 inhibitor nordihydroguaiaretic acid ( NDGA) once daily. The mice were euthanized at day 9 after instillation, and the hearts were removed for pathological and biochemical analysis. RESULTS:IAV infection induced significant up-regulation of ectopic trypsin, and proinflammatory cytokines interleukin 6 (IL-6), IL-1βand tumor necrosis factor-α(TNF-α) in the myocardium, and triggered acute myocarditis.PDTC signifi-cantly inhibited NF-κB activation and up-regulation of ectopic trypsin and proinflammatory cytokines, and effectively sup-pressed IAV replication and myocardial inflammatory response (P<0.01).NDGA effectively inhibited AP-1 activity (P<0.01) and mildly suppressed up-regulation of proinflammatory cytokines ( P<0.05) , but had no effects on the expression of ectopic trypsin, IAV replication and the extent of myocarditis ( P>0.05) .CONCLUSION:IAV infection induces up-regulation of ectopic trypsin and proinflammatory cytokines in myocardium predominantly by the activation of NF-κB.AP-1 signaling pathway might be only partially involved in the regulation of proinflammatory cytokines.