Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma‐derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)‐induced hepatitis model. In cultured hepatocytes, ConA treatment‐elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA‐evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA‐induced neutrophils recruitment in livers. Above all, the ConA‐mediated activation of tumor necrosis factor‐α (TNF‐α)/interleukin‐1β (IL‐1β)/interleukin‐6 (IL‐6)/cyclooxygenase‐2 (COX‐2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose‐dependently stimulated the expression of TNF‐α/IL‐1β/IL‐6/COX‐2 in hepatocytes, further supporting the pro‐inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA‐mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA‐induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA‐induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis.

中文翻译：

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肝癌源性生长因子参与伴刀豆球蛋白 A 诱发的肝炎

肝炎是世界范围内一个重要的健康问题。肝炎的检测和管理需要新的分子靶标。肝癌衍生生长因子 (HDGF) 已被描述参与肝纤维化和肝癌发生。然而，肝炎与 HDGF 之间的关系仍不清楚。本研究旨在使用刀豆球蛋白 A (ConA) 诱导的肝炎模型阐明 HDGF 在肝炎过程中的作用。在培养的肝细胞中，ConA 处理在转录水平引发 HDGF 上调并促进 HDGF 分泌，同时降低细胞内 HDGF 蛋白水平和细胞活力。类似地，接受 ConA 给药的小鼠表现出肝脏 HDGF 表达降低和循环 HDGF 水平升高，这与血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平呈正相关。通过使用 HDGF 敲除 (KO) 小鼠，发现与对照相比，在 KO 中 ConA 诱发的细胞死亡显着减轻。此外，还描述了 HDGF 消融通过抑制肝脏中 ConA 诱导的中性粒细胞募集来提供保护。最重要的是，ConA 介导的肿瘤坏死因子-α（TNF-α）/白介素-1β（IL-1β）/白介素-6（IL-6）/环氧合酶-2（COX-2）炎症信号的激活显着在 KO 小鼠中被废除。重组 HDGF (rHDGF) 剂量依赖性地刺激肝细胞中 TNF-α/IL-1β/IL-6/COX-2 的表达，进一步支持 HDGF 的促炎功能。最后，HDGF抗体的应用不仅减弱了ConA介导的肝细胞炎症级联反应，而且改善了ConA诱导的小鼠肝坏死和AST升高。总之，HDGF 通过中性粒细胞募集参与 ConA 诱导的肝炎，并可能构成急性肝炎的治疗靶点。