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An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375717/
https://www.ncbi.nlm.nih.gov/pubmed/37519997
http://dx.doi.org/10.3389/fvets.2023.1192888
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author 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
author_facet 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
author_sort Teoh, Yong Bin
collection PubMed
description 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 PLG, TCOF1, TG, COL9A2, and COL4A4, by whole-exome sequencing. Here, we investigated whether TG 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. In vitro 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 TG 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 TG expression together with two NF-κB targets, IL6 and CCL2, 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 TG mRNA in the colon, and local TG expression triggered by this SNP increases the risk of ICRP in MDs via the IL-6 amplifier. Therefore, TG c.4567C>T is a diagnostic target for ICRP in MDs, and TG-mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP.
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spelling pubmed-103757172023-07-29 An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds 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 Front Vet Sci Veterinary Science 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 PLG, TCOF1, TG, COL9A2, and COL4A4, by whole-exome sequencing. Here, we investigated whether TG 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. In vitro 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 TG 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 TG expression together with two NF-κB targets, IL6 and CCL2, 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 TG mRNA in the colon, and local TG expression triggered by this SNP increases the risk of ICRP in MDs via the IL-6 amplifier. Therefore, TG c.4567C>T is a diagnostic target for ICRP in MDs, and TG-mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP. Frontiers Media S.A. 2023-07-14 /pmc/articles/PMC10375717/ /pubmed/37519997 http://dx.doi.org/10.3389/fvets.2023.1192888 Text en Copyright © 2023 Teoh, Jiang, Yamasaki, Nagata, Sugawara, Hasebe, Ohta, Sasaki, Yokoyama, Nakamura, Kagawa, Takiguchi and Murakami. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Veterinary Science
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
An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds
title An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds
title_full An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds
title_fullStr An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds
title_full_unstemmed An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds
title_short An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds
title_sort inflammatory bowel disease-associated snp increases local thyroglobulin expression to develop inflammation in miniature dachshunds
topic Veterinary Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375717/
https://www.ncbi.nlm.nih.gov/pubmed/37519997
http://dx.doi.org/10.3389/fvets.2023.1192888
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