Singh Bharat, Saini Sheetal, Kumari Smita, Shah Arunim, Singh Kulwant, Chaturvedi Chandra Prakash, Dube Anuradha, Sahatrabuddhe Amogh A, Thakur Chandreshwar P, Rai Ambak K
Department of Biotechnology, Motilal Nehru National Institute of Technology Allahabad, Allahabad 211004, UP, India.
Stem Cell Research Center, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, UP, India.
Cytokine. 2025 Sep;193:156981. doi: 10.1016/j.cyto.2025.156981. Epub 2025 Jun 17.
Visceral leishmaniasis, caused by Leishmania donovani is characterized by clinicopathological features like hepatomegaly with loss of liver function, etc. Albumin is an essential parameter of liver function, performing various tasks like maintaining osmotic balance in blood vessels, preventing tissue fluid leakage, carrier properties, etc. Human VL patients and Leishmania donovani-infected hamsters (ExVL) were tested for their albumin levels. IL-10 derived from Leishmania donovani-infected monocytes and recombinant IL-10 were tested on HepG2 cells for CEBP-β and albumin expression with IL-10 blocking and JAK1/STAT3 inhibition. CEBP-β binding onto the albumin promoter and its silencing were performed to confirm its role in albumin expression. Low albumin, i.e., hypoalbuminemia, was found in visceral leishmaniasis and ExVL. Its levels were inversely associated with parasitic load and hepatic IL-10 in both models. When treated with Leishmania donovani-driven IL-10 from the infected monocytes and recombinant IL-10, there was a significant decrease in albumin expression from HepG2 cells in a JAK1/STAT3-dependent manner. To further explore the molecular mechanism behind hypoalbuminemia in Visceral leishmaniasis, CEBP-β, a transcription factor having three isoforms (LAP1, LAP2, and LIP), was shown to increase upon recombinant IL-10 treatment and bind to the D site of the albumin promoter using Chromatin immunoprecipitation PCR. shRNA silencing results confirm CEBP-β-mediated decrease in albumin levels. Our findings showed that increased hepatic IL-10 upon Leishmania donovani infection reduces albumin levels in a JAK1/STAT3 and CEBP-β-dependent manner.
由杜氏利什曼原虫引起的内脏利什曼病，其临床病理特征包括肝肿大伴肝功能丧失等。白蛋白是肝功能的一个重要参数，具有多种功能，如维持血管内的渗透平衡、防止组织液渗漏、具有载体特性等。对人类内脏利什曼病患者和感染杜氏利什曼原虫的仓鼠（ExVL）进行了白蛋白水平检测。对源自感染杜氏利什曼原虫的单核细胞的白细胞介素-10（IL-10）和重组IL-10在HepG2细胞上进行检测，观察其对CEBP-β和白蛋白表达的影响，同时进行IL-10阻断和JAK1/STAT3抑制实验。进行CEBP-β与白蛋白启动子的结合及其沉默实验，以证实其在白蛋白表达中的作用。在内脏利什曼病和ExVL中发现白蛋白水平较低，即低白蛋白血症。在两种模型中，其水平均与寄生虫负荷和肝脏IL-10呈负相关。当用感染单核细胞产生的杜氏利什曼原虫驱动的IL-10和重组IL-10处理时，HepG2细胞中的白蛋白表达以JAK1/STAT3依赖的方式显著降低。为了进一步探究内脏利什曼病中低白蛋白血症背后的分子机制，研究发现一种具有三种异构体（LAP1、LAP-2和LIP）的转录因子CEBP-β在重组IL-10处理后增加，并通过染色质免疫沉淀PCR与白蛋白启动子D位点结合。短发夹RNA（shRNA）沉默结果证实了CEBP-β介导的白蛋白水平降低。我们的研究结果表明，杜氏利什曼原虫感染后肝脏IL-10增加，以JAK1/STAT3和CEBP-β依赖的方式降低白蛋白水平。
