Guangxi University Key Laboratory of Pathogenic Biology, Guilin Medical University, Guilin, Guangxi, People's Republic of China.
Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People's Republic of China.
Parasit Vectors. 2023 Jul 21;16(1):246. doi: 10.1186/s13071-023-05863-5.
Chronic infection with Clonorchis sinensis can cause hepatobiliary fibrosis and even lead to hepatobiliary carcinoma. Epstein-Barr virus-induced gene 3 protein (EBI3) is a subunit of interleukin 35, which can regulate inflammatory response and the occurrence of fibrotic diseases. Previous studies have reported that the expression of EBI3 in the serum of patients with liver cirrhosis is reduced. The present study aims to investigate the biological effects of EBI3 on liver fibrosis caused by C. sinensis and the underlying molecular mechanisms.
We first established a mouse model of liver fibrosis induced by C. sinensis infection and then measured the serum expression of EBI3 during the inflammatory and fibrotic phase. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses were performed to investigate the potential role of EBI3 in liver fibrosis by regulating the extracellular matrix structural constituent and collagen catabolic process. Recombinant protein EBI3 (rEBI3) was added to hepatic stellate cells (HSCs) in vitro with C. sinensis antigen to explore its function. Finally, the therapeutic effect of rEBI3 was verified by intravenous injection into C. sinensis-infected mice.
The results showed that the serum expression of EBI3 increased in the inflammatory response phase but decreased in the fibrotic phase. The excretory-secretory products of C. sinensis (Cs.ESP) were able to stimulate HSC activation, while rEBI3 reduced the activation of HSCs induced by Cs.ESP. Also, the protein expression of gp130 and downstream protein expressions of JAK1, p-JAK1, STAT3 and p-STAT3 in HSCs were increased after rEBI3 incubation. Finally, intravenously injected rEBI3 inhibited hepatic epithelial-mesenchymal transition in C. sinensis-infected mice by inhibiting HSC activation and reducing liver injury.
This study confirms that rEBI3 can attenuate C. sinensis-induced liver fibrosis by inhibiting HSC activation and may be one of the potential treatments for liver fibrosis.
华支睾吸虫慢性感染可导致肝胆纤维化，甚至导致肝胆癌。EB 病毒诱导基因 3 蛋白（EBI3）是白细胞介素 35 的一个亚单位，可调节炎症反应和纤维化疾病的发生。先前的研究报道，肝硬化患者血清中 EBI3 的表达降低。本研究旨在探讨 EBI3 对华支睾吸虫感染引起的肝纤维化的生物学作用及其潜在的分子机制。
我们首先建立了华支睾吸虫感染诱导的小鼠肝纤维化模型，然后在炎症和纤维化阶段测量了血清中 EBI3 的表达。通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路分析，研究了 EBI3 通过调节细胞外基质结构成分和胶原代谢过程在肝纤维化中的潜在作用。在体外用华支睾吸虫抗原刺激肝星状细胞（HSCs）时加入重组蛋白 EBI3（rEBI3），以探讨其功能。最后，通过静脉注射 rEBI3 验证其在华支睾吸虫感染小鼠中的治疗效果。
结果表明，EBI3 的血清表达在炎症反应阶段增加，但在纤维化阶段减少。华支睾吸虫的排泄分泌产物（Cs.ESP）能够刺激 HSC 活化，而 rEBI3 降低了 Cs.ESP 诱导的 HSC 活化。此外，rEBI3 孵育后 HSCs 中 gp130 及其下游蛋白 JAK1、p-JAK1、STAT3 和 p-STAT3 的蛋白表达增加。最后，静脉注射 rEBI3 通过抑制 HSC 活化和减少肝损伤，抑制华支睾吸虫感染小鼠的肝上皮-间充质转化。
本研究证实 rEBI3 可通过抑制 HSC 活化减轻华支睾吸虫诱导的肝纤维化，可能是肝纤维化的潜在治疗方法之一。
