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ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a

Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 (ANGPTL4) as one of the most significantl...

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Autores principales: Jung, Kyung Hee, Son, Mi Kwon, Yan, Hong Hua, Fang, Zhenghuan, Kim, Juyoung, Kim, Soo Jung, Park, Jung Hee, Lee, Ji Eun, Yoon, Young‐Chan, Seo, Myeong Seong, Han, Beom Seok, Ko, Soyeon, Suh, Young Ju, Lim, Joo Han, Lee, Don‐Haeng, Teo, Ziqiang, Wee, Jonathan Wei Kiat, Tan, Nguan Soon, Hong, Soon‐Sun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411571/
https://www.ncbi.nlm.nih.gov/pubmed/32638512
http://dx.doi.org/10.15252/emmm.201911222
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author Jung, Kyung Hee
Son, Mi Kwon
Yan, Hong Hua
Fang, Zhenghuan
Kim, Juyoung
Kim, Soo Jung
Park, Jung Hee
Lee, Ji Eun
Yoon, Young‐Chan
Seo, Myeong Seong
Han, Beom Seok
Ko, Soyeon
Suh, Young Ju
Lim, Joo Han
Lee, Don‐Haeng
Teo, Ziqiang
Wee, Jonathan Wei Kiat
Tan, Nguan Soon
Hong, Soon‐Sun
author_facet Jung, Kyung Hee
Son, Mi Kwon
Yan, Hong Hua
Fang, Zhenghuan
Kim, Juyoung
Kim, Soo Jung
Park, Jung Hee
Lee, Ji Eun
Yoon, Young‐Chan
Seo, Myeong Seong
Han, Beom Seok
Ko, Soyeon
Suh, Young Ju
Lim, Joo Han
Lee, Don‐Haeng
Teo, Ziqiang
Wee, Jonathan Wei Kiat
Tan, Nguan Soon
Hong, Soon‐Sun
author_sort Jung, Kyung Hee
collection PubMed
description Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis‐associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS‐activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis.
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spelling pubmed-74115712020-08-10 ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a Jung, Kyung Hee Son, Mi Kwon Yan, Hong Hua Fang, Zhenghuan Kim, Juyoung Kim, Soo Jung Park, Jung Hee Lee, Ji Eun Yoon, Young‐Chan Seo, Myeong Seong Han, Beom Seok Ko, Soyeon Suh, Young Ju Lim, Joo Han Lee, Don‐Haeng Teo, Ziqiang Wee, Jonathan Wei Kiat Tan, Nguan Soon Hong, Soon‐Sun EMBO Mol Med Articles Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 (ANGPTL4) as one of the most significantly upregulated genes. Clinically, ANGPTL4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis‐associated pathological outcomes. Conversely, exogenous ANGPTL4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI3K/AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS‐activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL4 is a potential strategy for the treatment of pancreatitis. John Wiley and Sons Inc. 2020-07-07 2020-08-07 /pmc/articles/PMC7411571/ /pubmed/32638512 http://dx.doi.org/10.15252/emmm.201911222 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Jung, Kyung Hee
Son, Mi Kwon
Yan, Hong Hua
Fang, Zhenghuan
Kim, Juyoung
Kim, Soo Jung
Park, Jung Hee
Lee, Ji Eun
Yoon, Young‐Chan
Seo, Myeong Seong
Han, Beom Seok
Ko, Soyeon
Suh, Young Ju
Lim, Joo Han
Lee, Don‐Haeng
Teo, Ziqiang
Wee, Jonathan Wei Kiat
Tan, Nguan Soon
Hong, Soon‐Sun
ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
title ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
title_full ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
title_fullStr ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
title_full_unstemmed ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
title_short ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a
title_sort angptl4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of c5a
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411571/
https://www.ncbi.nlm.nih.gov/pubmed/32638512
http://dx.doi.org/10.15252/emmm.201911222
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