Teoh Yong Bin, Jiang Jing-Jing, Yamasaki Takeshi, Nagata Noriyuki, Sugawara Toshiki, Hasebe Rie, Ohta Hiroshi, Sasaki Noboru, Yokoyama Nozomu, Nakamura Kensuke, Kagawa Yumiko, Takiguchi Mitsuyoshi, Murakami Masaaki
Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Laboratory of Veterinary Internal Medicine, Department of Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Front Vet Sci. 2023 Jul 14;10:1192888. doi: 10.3389/fvets.2023.1192888. eCollection 2023.
Inflammatory colorectal polyp (ICRP) in miniature dachshunds (MDs) is a chronic inflammatory bowel disease (IBD) characterized by granulomatous inflammation that consists of neutrophil infiltration and goblet cell hyperplasia in the colon. Recently, we identified five MD-associated single-nucleotide polymorphisms (SNPs), namely , and , by whole-exome sequencing. Here, we investigated whether c.4567C>T (p.R1523W) is associated with the ICRP pathology. We found that the frequency of the T/T SNP risk allele was significantly increased in MDs with ICRP. experiments showed that TG expression in non-immune cells was increased by inducing the IL-6 amplifier with IL-6 and TNF-α. On the other hand, a deficiency of suppressed the IL-6 amplifier. Moreover, recombinant TG treatment enhanced the activation of the IL-6 amplifier, suggesting that TG is both a positive regulator and a target of the IL-6 amplifier. We also found that expression together with two NF-κB targets, and , was increased in colon samples isolated from MDs with the T/T risk allele compared to those with the C/C non-risk allele, but serum TG was not increased. Cumulatively, these results suggest that the T/T SNP is an expression quantitative trait locus (eQTL) of mRNA in the colon, and local expression triggered by this SNP increases the risk of ICRP in MDs the IL-6 amplifier. Therefore, c.4567C>T is a diagnostic target for ICRP in MDs, and -mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP.
迷你腊肠犬（MD）中的炎性结肠息肉（ICRP）是一种慢性炎症性肠病（IBD），其特征为肉芽肿性炎症，包括结肠中的中性粒细胞浸润和杯状细胞增生。最近，我们通过全外显子测序鉴定出五个与MD相关的单核苷酸多态性（SNP），即 、 、 、 和 。在此，我们研究了c.4567C>T（p.R1523W）是否与ICRP病理学相关。我们发现，ICRP的MD中T/T SNP风险等位基因的频率显著增加。实验表明，通过用IL-6和TNF-α诱导IL-6放大器，非免疫细胞中的TG表达增加。另一方面， 的缺陷抑制了IL-6放大器。此外，重组TG处理增强了IL-6放大器的激活，表明TG既是IL-6放大器的正调节因子又是其靶标。我们还发现，与具有C/C非风险等位基因的MD相比，从具有T/T风险等位基因的MD分离的结肠样本中， 与两个NF-κB靶标 和 的表达一起增加，但血清TG没有增加。累积起来，这些结果表明T/T SNP是结肠中 mRNA的表达数量性状位点（eQTL），并且由该SNP触发的局部 表达增加了MD中ICRP的风险 IL-6放大器。因此，c.4567C>T是MD中ICRP的诊断靶标，并且结肠中 -介导的IL-6放大器激活是ICRP的可能治疗靶标。
