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STING介导的白细胞介素-6通过TCF4信号通路抑制胆汁淤积症中OATP1B1的表达。

STING-mediated IL-6 Inhibits OATP1B1 Expression via the TCF4 Signaling Pathway in Cholestasis.

作者信息

Guo Yan, Zhang Hongjia, Zhao Nan, Peng Ying, Shen Dongya, Chen Yubin, Zhang Xiaoxun, Tang Can-E, Chai Jin

机构信息

Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing, China.

出版信息

J Clin Transl Hepatol. 2024 Aug 28;12(8):701-712. doi: 10.14218/JCTH.2024.00017. Epub 2024 Jul 15.

DOI:10.14218/JCTH.2024.00017
PMID:39130625
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11310758/
Abstract

BACKGROUND AND AIMS

Organic anion-transporting polypeptides (OATPs) play a crucial role in the transport of bile acids and bilirubin. In our previous study, interleukin 6 (IL-6) reduced OATP1B3 levels in cholestatic disease. However, it remains unclear whether IL-6 inhibits OATP1B1 expression in cholestatic diseases. This study aimed to investigate whether IL-6 can inhibit OATP1B1 expression and explore the underlying mechanisms.

METHODS

The effect of stimulator of interferon genes (STING) signaling on inflammatory factors was investigated in a cholestatic mouse model using RT-qPCR and enzyme-linked immunosorbent assay. To assess the impact of inflammatory factors on OATP1B1 expression in hepatocellular carcinoma, we analyzed OATP1B1 expression by RT-qPCR and Western Blot after treating PLC/PRF/5 cells with TNF-α, IL-1β, and IL-6. To elucidate the mechanism by which IL-6 inhibits OATP1B1 expression, we examined the expression of the OATP1B1 regulator TCF4 in PLC/PRF/5 and HepG2 cells using RT-qPCR and Western Blot. The interaction mechanism between β-catenin/TCF4 and OATP1B1 was investigated by knocking down β-catenin/TCF4 through siRNA transfection.

RESULTS

The STING inhibitor decreased inflammatory factor levels in the cholestatic mouse model, with IL-6 exhibiting the most potent inhibitory effect on OATP1B1. IL-6 downregulated β-catenin/TCF4, leading to decreased OATP1B1 expression. Knocking-down β-catenin/TCF4 counteracted the β-catenin/TCF4-mediated repression of OATP1B1.

CONCLUSIONS

STING-mediated IL-6 up-regulation may inhibit OATP1B1, leading to reduced transport of bile acids and bilirubin by OATP1B1. This may contribute to altered pharmacokinetics in patients with diseases associated with increased IL-6 production.

摘要

背景与目的

有机阴离子转运多肽（OATPs）在胆汁酸和胆红素的转运中起关键作用。在我们之前的研究中，白细胞介素6（IL-6）降低了胆汁淤积性疾病中OATP1B3的水平。然而，IL-6是否抑制胆汁淤积性疾病中OATP1B1的表达仍不清楚。本研究旨在探讨IL-6是否能抑制OATP1B1的表达并探索其潜在机制。

方法

在胆汁淤积小鼠模型中，使用逆转录定量聚合酶链反应（RT-qPCR）和酶联免疫吸附测定法研究干扰素基因刺激物（STING）信号对炎症因子的影响。为了评估炎症因子对肝癌细胞中OATP1B1表达的影响，我们在用肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）处理PLC/PRF/5细胞后，通过RT-qPCR和蛋白质免疫印迹法分析OATP1B1的表达。为了阐明IL-6抑制OATP1B1表达的机制，我们使用RT-qPCR和蛋白质免疫印迹法检测PLC/PRF/5和HepG2细胞中OATP1B1调节因子TCF4的表达。通过小干扰RNA（siRNA）转染敲低β-连环蛋白/TCF4，研究β-连环蛋白/TCF4与OATP1B1之间的相互作用机制。

结果

STING抑制剂降低了胆汁淤积小鼠模型中的炎症因子水平，其中IL-6对OATP1B1的抑制作用最强。IL-6下调β-连环蛋白/TCF4，导致OATP1B1表达降低。敲低β-连环蛋白/TCF4可抵消β-连环蛋白/TCF4介导的对OATP1B1的抑制作用。

结论

STING介导的IL-6上调可能抑制OATP1B1，导致OATP1B1对胆汁酸和胆红素的转运减少。这可能导致IL-6产生增加相关疾病患者的药代动力学改变。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2093/11310758/1f380bf16969/JCTH-12-701-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2093/11310758/1f380bf16969/JCTH-12-701-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2093/11310758/7a32728909f0/JCTH-12-701-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2093/11310758/1f380bf16969/JCTH-12-701-g007.jpg

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