Bakiallah Ayoub El, Damayanti Desy Simamora, Nogueira Rosana, Choi Hack Sun, Chun Kyung-Hee
Department of Biochemistry & Molecular Biology, School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea.
Department of Biochemistry & Molecular Biology, School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722; Affiliate faculty, Pohang University of Science and Technology, Pohang 37673, Korea.
BMB Rep. 2025 Jun;58(6):250-256.
Leukocyte cell-derived chemotaxin 2 (LECT2), a secreted protein, is implicated in various physiological and pathological processes. As a hepatokine, LECT2 is predominantly synthesized and secreted by hepatocytes, with elevated levels being associated with multiple human inflammatory diseases. Although LECT2 plays a critical role in liver and systemic inflammation, the intracellular signaling mechanisms governing its expression under inflammatory conditions remain unclear. This study demonstrates that lipopolysaccharide (LPS) directly induces LECT2 expression in AML12 mouse hepatocytes. Use of a TLR4-specific inhibitor confirmed that LPS-induced LECT2 expression is mediated via its canonical receptor, TLR4. Furthermore, the p38 MAPK pathway was identified as a key mediator of this response, as evidenced by pharmacological modulation with a p38-specific inhibitor and agonist. Promoter analysis of the Lect2 gene revealed the presence of a putative AP-1-like binding site, suggesting transcriptional regulation by AP-1. Overexpression of c-Fos and c-Jun, along with ChIP-qPCR analysis, confirmed that AP-1 directly binds to Lect2 promoter, and regulates its transcription in response to LPS. Together, these findings reveal a novel TLR4/p38 MAPK/AP-1 signaling axis that, during inflammation, regulates LECT2 expression in hepatocytes, providing new insights into the molecular mechanisms underlying liver inflammation and LECT2-mediated pathophysiology. [BMB Reports 2025; 58(6): 250-256].
白细胞衍生趋化因子2（LECT2）是一种分泌蛋白，参与多种生理和病理过程。作为一种肝源细胞因子，LECT2主要由肝细胞合成和分泌，其水平升高与多种人类炎症性疾病相关。尽管LECT2在肝脏和全身炎症中起关键作用，但炎症条件下调控其表达的细胞内信号机制仍不清楚。本研究表明，脂多糖（LPS）可直接诱导AML12小鼠肝细胞中LECT2的表达。使用TLR4特异性抑制剂证实，LPS诱导的LECT2表达是通过其经典受体TLR4介导的。此外，p38丝裂原活化蛋白激酶（MAPK）途径被确定为这一反应的关键介质，p38特异性抑制剂和激动剂的药理学调节证明了这一点。对Lect2基因的启动子分析揭示了一个假定的AP-1样结合位点的存在，提示由AP-1进行转录调控。c-Fos和c-Jun的过表达以及染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）分析证实，AP-1直接结合到Lect2启动子，并在LPS刺激下调节其转录。总之，这些发现揭示了一种新的TLR4/p38 MAPK/AP-1信号轴，在炎症过程中，该信号轴调节肝细胞中LECT2的表达，为肝脏炎症和LECT2介导的病理生理学的分子机制提供了新的见解。[《BMB报告》2025年；58(6): 250-256]
