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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-8999048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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