Thiamin (vitamin B1) plays critical roles in normal metabolism and function of all mammalian cells. Pancreatic acinar cells (PACs) import thiamin from circulation via specific carrier-mediated uptake that involves thiamin transporters-1 & -2 (THTR-1 & -2; products of SLC19A2 and SLC19A3, respectively). Our aim in this study was to investigate the effect(s) of pro-inflammatory cytokines on thiamin uptake by PACs. We used human primary (h)PACs, PAC 266-6 cells, and mice in vivo as models in the investigations. First, we examined the level of expression of THTR-1 & -2 mRNA in pancreatic tissues of patients with chronic pancreatitis and observed severe reduction in their expression compared to normal control subjects. Exposing hPACs and PAC 266-6 to pro-inflammatory cytokines (hyper IL-6, TNF-α, and IL-1β) was found to lead to a significant inhibition in thiamin uptake. Focusing on hyper-IL-6 (which also inhibited thiamin uptake by primary mouse PACs), the inhibition in thiamin uptake was found to be associated with significant reduction in THTR-1 & -2 proteins and mRNAs expression as well as in activity of the SLC19A2 and SLC19A3 promoters; it was also associated with reduction in level of expression of the transcription factor Sp1 (which is required for activity of these promoters). Finally, blocking the intracellular Stat3 signaling pathway was found to lead to a significant reversal in the inhibitory effect of hyper IL-6 on thiamin uptake by PAC 266-6. These results show that exposure of PACs to pro-inflammatory cytokines negatively impacts thiamin uptake via (at least in part) transcriptional mechanism(s).

中文翻译：

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促炎细胞因子抑制人和小鼠胰腺腺泡细胞对硫胺素的摄取：参与转录机制

硫胺素（维生素 B1）在所有哺乳动物细胞的正常代谢和功能中起着关键作用。胰腺腺泡细胞 (PAC) 通过特定载体介导的摄取从循环中输入硫胺，该摄取涉及硫胺转运蛋白-1 和 -2（THTR-1 和 -2；分别是 SLC19A2 和 SLC19A3 的产物）。我们在本研究中的目的是研究促炎细胞因子对 PAC 摄取硫胺素的影响。我们使用人类原代 (h) PAC、PAC 266-6 细胞和体内小鼠作为研究模型。首先，我们检查了慢性胰腺炎患者胰腺组织中 THTR-1 和 -2 mRNA 的表达水平，并观察到与正常对照受试者相比，它们的表达严重降低。将 hPAC 和 PAC 266-6 暴露于促炎细胞因子（超 IL-6、TNF-α、和 IL-1β) 被发现导致硫胺素摄取的显着抑制。关注 hyper-IL-6（也抑制原代小鼠 PAC 对硫胺素的摄取），发现抑制硫胺素摄取与 THTR-1 和 -2 蛋白和 mRNA 表达的显着降低以及SLC19A2 和 SLC19A3 启动子；它还与转录因子 Sp1（这是这些启动子的活性所必需的）表达水平的降低有关。最后，发现阻断细胞内 Stat3 信号通路导致高 IL-6 对 PAC 266-6 摄取硫胺素的抑制作用显着逆转。这些结果表明，PACs 暴露于促炎细胞因子会对硫胺素的摄取产生负面影响，通过（至少部分）转录机制。