Effect of IL-1β on pancreatic acinar cells mitochondrial TPP carrier-mediated uptake: inhibition mediated via the intracellular NF-κB signaling pathway.

We investigated the effects of proinflammatory cytokines on carrier-mediated thiamin pyrophosphate (TPP) uptake by pancreatic acinar cells (PACs) mitochondria using mouse-derived pancreatic acinar 266-6 cells (PAC 266-6) and human primary PACs as models. First, we assessed the level of expression of the mitochondrial TPP transporter (MTPPT) mRNA in the 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 proinflammatory cytokines. Focusing on IL-1β (since it showed a more severe effect), we found this proinflammatory cytokine to also cause a significant inhibition in MTPPT protein and mRNA expression, as well as in the activity of the SLC25A19 promoter. Effect on the latter, appeared to be mediated via a decrease in the binding affinity of NF-Y (a nuclear factor that drives Slc25a19 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 SLC25A19 transcription and is mediated via the NF-κB signaling pathway.NEW & NOTEWORTHY This study demonstrates that exposure of pancreatic acinar cells to IL-1β leads to inhibition in carrier-mediated thiamin pyrophosphate uptake by their mitochondria. This effect appears to be exerted at the level of SLC25A19 transcription and is mediated via the NF-κB signaling pathway.