Mao Qiang, Xie Zhizhi, Wang Xiaoyun, Chen Wenjun, Ren Mengyu, Shang Mei, Lei Huali, Tian Yanli, Li Shan, Liang Pei, Chen Tingjin, Liang Chi, Xu Jin, Li Xuerong, Huang Yan, Yu Xinbing
Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Parasitol Res. 2015 Feb;114(2):659-70. doi: 10.1007/s00436-014-4230-0. Epub 2014 Nov 22.
Clonorchiasis, caused by direct and continuous contact with Clonorchis sinensis, is associated with hepatobiliary damage, inflammation, periductal fibrosis, and the development of cholangiocarcinoma. Hepatic stellate cells respond to liver injury through production of proinflammatory mediators which drive fibrogenesis; however, their endogenous sources and pathophysiological roles in host cells were not determined. C. sinensis ferritin heavy chain (CsFHC) was previously confirmed as a component of excretory/secretory products and exhibited a number of extrahepatic immunomodulatory properties in various diseases. In this study, we investigated the expression pattern and biological role of CsFHC in C. sinensis. CsFHC was expressed throughout life stages of C. sinensis. More importantly, we found that treatment of human hepatic stellate cell line LX-2 with CsFHC triggered the production of free radicals via time-dependent activation of NADPH oxidase, xanthine oxidase, and inducible nitric oxide synthase. The increase in free radicals substantially promoted the degradation of cytosolic IκBα and nuclear translocation of NF-κB subunits (p65 and p50). CsFHC-induced NF-κB activation was markedly attenuated by preincubation with specific inhibitors of corresponding free radical-producing enzyme or the antioxidant. In addition, CsFHC induced an increased expression level of proinflammatory cytokines, IL-1β and IL-6, in NF-κB-dependent manner. Our results indicate that CsFHC-triggered free radical-mediated NF-κB signaling is an important factor in the chronic inflammation caused by C. sinensis infection.
华支睾吸虫病是由于直接和持续接触华支睾吸虫而引起的，与肝胆损伤、炎症、胆管周围纤维化以及胆管癌的发生有关。肝星状细胞通过产生驱动纤维化形成的促炎介质来应对肝损伤；然而，它们在宿主细胞中的内源性来源和病理生理作用尚未确定。华支睾吸虫铁蛋白重链（CsFHC）先前被确认为排泄/分泌产物的一个组成部分，并在各种疾病中表现出许多肝外免疫调节特性。在本研究中，我们调查了CsFHC在华支睾吸虫中的表达模式和生物学作用。CsFHC在华支睾吸虫的整个生命阶段均有表达。更重要的是，我们发现用CsFHC处理人肝星状细胞系LX-2会通过NADPH氧化酶、黄嘌呤氧化酶和诱导型一氧化氮合酶的时间依赖性激活触发自由基的产生。自由基的增加显著促进了细胞质IκBα的降解和NF-κB亚基（p65和p50）的核转位。用相应自由基产生酶的特异性抑制剂或抗氧化剂预孵育可显著减弱CsFHC诱导的NF-κB激活。此外，CsFHC以NF-κB依赖的方式诱导促炎细胞因子IL-1β和IL-6的表达水平升高。我们的结果表明，CsFHC触发的自由基介导的NF-κB信号传导是华支睾吸虫感染引起的慢性炎症中的一个重要因素。
