Anthonymuthu Selvaraj, Sabui Subrata, Ramamoorthy Kalidas, Ahmed Yusuf Ali, Balamurugan Appakalai, Said Hamid M
Department of Physiology and Biophysics, UCI, Irvine, CA, United States.
Tibor Rubin Veterans Affairs Medical Center, Long Beach, California, United States.
Am J Physiol Cell Physiol. 2025 Jul 31. doi: 10.1152/ajpcell.00375.2025.
We investigated the effect(s) of pro-inflammatory cytokines on carrier-mediated thiamin pyrophosphate (TPP) uptake by pancreatic acinar cells (PACs) mitochondria using mouse-derived PAC 266-6 cells and human primary PACs as models. First, we assessed the level of expression of the mitochondrial TPP transporter (MTPPT) mRNA in pancreatic tissue of patients with chronic pancreatitis and found the level to be significantly lower than that in normal control subjects. We then examined the effects of exposing PACs to IL-1β, IL-6, and TNF-α on mitochondrial TPP uptake and observed significant inhibition by all these pro-inflammatory cytokines. Focusing on IL-1β (since it showed a more severe effect), we found this pro-inflammatory cytokine to also cause a significant inhibition in MTPPT protein and mRNA expression, as well as in activity of the promoter. Effect on the latter, appeared to be mediated via a decrease in the binding affinity of NF-Y (a nuclear factor that drives promoter activity) as well as via epigenetic mechanism/histone-modification were significant reduction in levels of enrichment of the activator markers H3K4-trimethylation and H3K9-acetylation, and an increase in level of enrichment of the repressor marker H3K27-trimethylation were observed. Finally, evidence was obtained suggesting a role for the intracellular NF-κB signaling pathway in mediating the effects of IL-1β on PAC mitochondrial TPP uptake process. These results show that exposure of PACs to IL-1β causes inhibition in mitochondrial TPP uptake, and that this effect is exerted at the level of transcription and is mediated via the NF-κB signaling pathway.
我们以小鼠来源的PAC 266-6细胞和人原代胰腺腺泡细胞（PACs）为模型，研究了促炎细胞因子对胰腺腺泡细胞（PACs）线粒体中载体介导的硫胺素焦磷酸（TPP）摄取的影响。首先，我们评估了慢性胰腺炎患者胰腺组织中线粒体TPP转运体（MTPPT）mRNA的表达水平，发现该水平显著低于正常对照受试者。然后，我们检测了将PACs暴露于白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）对线粒体TPP摄取的影响，观察到所有这些促炎细胞因子均有显著抑制作用。聚焦于IL-1β（因为它显示出更严重的作用），我们发现这种促炎细胞因子还会导致MTPPT蛋白和mRNA表达以及启动子活性的显著抑制。对后者的影响似乎是通过核因子Y（驱动启动子活性的核因子）结合亲和力的降低介导的，以及通过表观遗传机制/组蛋白修饰，观察到激活标记物H3K4三甲基化和H3K9乙酰化的富集水平显著降低，而抑制标记物H3K27三甲基化的富集水平增加。最后，获得的证据表明细胞内NF-κB信号通路在介导IL-1β对PAC线粒体TPP摄取过程的影响中起作用。这些结果表明，将PACs暴露于IL-1β会导致线粒体TPP摄取受到抑制，并且这种作用是在转录水平上发挥的，并通过NF-κB信号通路介导。
