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IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis

Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, wh...

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Autores principales: Ng, Benjamin, Viswanathan, Sivakumar, Widjaja, Anissa A., Lim, Wei-Wen, Shekeran, Shamini G., Goh, Joyce Wei Ting, Tan, Jessie, Kuthubudeen, Fathima, Lim, Sze Yun, Xie, Chen, Schafer, Sebastian, Adami, Eleonora, Cook, Stuart A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999048/
https://www.ncbi.nlm.nih.gov/pubmed/35408908
http://dx.doi.org/10.3390/ijms23073549
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author Ng, Benjamin
Viswanathan, Sivakumar
Widjaja, Anissa A.
Lim, Wei-Wen
Shekeran, Shamini G.
Goh, Joyce Wei Ting
Tan, Jessie
Kuthubudeen, Fathima
Lim, Sze Yun
Xie, Chen
Schafer, Sebastian
Adami, Eleonora
Cook, Stuart A.
author_facet Ng, Benjamin
Viswanathan, Sivakumar
Widjaja, Anissa A.
Lim, Wei-Wen
Shekeran, Shamini G.
Goh, Joyce Wei Ting
Tan, Jessie
Kuthubudeen, Fathima
Lim, Sze Yun
Xie, Chen
Schafer, Sebastian
Adami, Eleonora
Cook, Stuart A.
author_sort Ng, Benjamin
collection PubMed
description Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis.
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spelling pubmed-89990482022-04-12 IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis Ng, Benjamin Viswanathan, Sivakumar Widjaja, Anissa A. Lim, Wei-Wen Shekeran, Shamini G. Goh, Joyce Wei Ting Tan, Jessie Kuthubudeen, Fathima Lim, Sze Yun Xie, Chen Schafer, Sebastian Adami, Eleonora Cook, Stuart A. Int J Mol Sci Article Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis. MDPI 2022-03-24 /pmc/articles/PMC8999048/ /pubmed/35408908 http://dx.doi.org/10.3390/ijms23073549 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ng, Benjamin
Viswanathan, Sivakumar
Widjaja, Anissa A.
Lim, Wei-Wen
Shekeran, Shamini G.
Goh, Joyce Wei Ting
Tan, Jessie
Kuthubudeen, Fathima
Lim, Sze Yun
Xie, Chen
Schafer, Sebastian
Adami, Eleonora
Cook, Stuart A.
IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis
title IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis
title_full IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis
title_fullStr IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis
title_full_unstemmed IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis
title_short IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis
title_sort il11 activates pancreatic stellate cells and causes pancreatic inflammation, fibrosis and atrophy in a mouse model of pancreatitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999048/
https://www.ncbi.nlm.nih.gov/pubmed/35408908
http://dx.doi.org/10.3390/ijms23073549
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