STING-mediated IL-6 inhibits OATP1B1 expression via the TCF4 signaling pathway in cholestasis
image: (A) Schematic illustration of the generation of C57/6J mice model of cholestasis. The experimental procedure for investigating the protective role of C170 in mice administered a 0.1% DDC diet at week 8 for 14 days. Intraperitoneal injections of corn oil or 10M C170 were administered daily to the treatment group mice (Chow Oil n = 4; Chow C170 n = 5; DDC Oil n = 7; DDC C170 n = 6). (B, C) Representative images (original magnification: 20×) and quantitative analysis of immunofluorescence staining for STING (yellow) and F4/80 (red). (scale bar: 50 µm). (D) Western blot of IFN-β in mouse livers. Expression levels were normalized to those of GAPDH. (E) Quantitative analysis of qPCR (top panel) and ELISA (lower panel) data for TNF-α, IL-6, and IL-1β. Data presented as mean ± standard deviation (SD). *p < 0.05, **p < 0.01. STING, stimulator of interferon genes; DAPI, 4′,6-Diamidino-2′-phenylindole; IFN-β, interferon-beta; GAPDH, glyceraldehyde -3-phosphate dehydrogenase; DDC, 3,5-diethoxycarbonyl-1,4-dihydroxychollidine; C170, a STING inhibitor; IFN-β, interferon-beta; IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta.
Credit: Jin Chai, Can-E Tang, Yan Guo
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.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2024-00017
The study was recently published in the Journal of Clinical and Translational Hepatology.
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