Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium
Abstract Background Loss of CFTR-dependent anion and fluid secretion in the ducts of the exocrine pancreas is thought to contribute to the development of pancreatitis, but little is known about the impact of inflammation on ductal CFTR function. Here we used adult stem cell-derived cell cultures (or...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Cellular & Molecular Biology Letters |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s11658-024-00537-1 |
| _version_ | 1797276386652585984 |
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| author | Dora Angyal Tessa A. Groeneweg Anny Leung Max Desain Kalyan Dulla Hugo R. de Jonge Marcel J. C. Bijvelds |
| author_facet | Dora Angyal Tessa A. Groeneweg Anny Leung Max Desain Kalyan Dulla Hugo R. de Jonge Marcel J. C. Bijvelds |
| author_sort | Dora Angyal |
| collection | DOAJ |
| description | Abstract Background Loss of CFTR-dependent anion and fluid secretion in the ducts of the exocrine pancreas is thought to contribute to the development of pancreatitis, but little is known about the impact of inflammation on ductal CFTR function. Here we used adult stem cell-derived cell cultures (organoids) obtained from porcine pancreas to evaluate the effects of pro-inflammatory cytokines on CFTR function. Methods Organoids were cultured from porcine pancreas and used to prepare ductal epithelial monolayers. Monolayers were characterized by immunocytochemistry. Epithelial bicarbonate and chloride secretion, and the effect of IL-1β, IL-6, IFN-γ, and TNF-α on CFTR function was assessed by electrophysiology. Results Immunolocalization of ductal markers, including CFTR, keratin 7, and zonula occludens 1, demonstrated that organoid-derived cells formed a highly polarized epithelium. Stimulation by secretin or VIP triggered CFTR-dependent anion secretion across epithelial monolayers, whereas purinergic receptor stimulation by UTP, elicited CFTR-independent anion secretion. Most of the anion secretory response was attributable to bicarbonate transport. The combination of IL-1β, IL-6, IFN-γ, and TNF-α markedly enhanced CFTR expression and anion secretion across ductal epithelial monolayers, whereas these cytokines had little effect when tested separately. Although TNF-α triggered apoptotic signaling, epithelial barrier function was not significantly affected by cytokine exposure. Conclusions Pro-inflammatory cytokines enhance CFTR-dependent anion secretion across pancreatic ductal epithelium. We propose that up-regulation of CFTR in the early stages of the inflammatory response, may serve to promote the removal of pathogenic stimuli from the ductal tree, and limit tissue injury. |
| first_indexed | 2024-03-07T15:27:33Z |
| format | Article |
| id | doaj.art-2b6764ebb7ab4c6aaab158efdbccfd7c |
| institution | Directory Open Access Journal |
| issn | 1689-1392 |
| language | English |
| last_indexed | 2024-03-07T15:27:33Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj.art-2b6764ebb7ab4c6aaab158efdbccfd7c2024-03-05T16:36:09ZengBMCCellular & Molecular Biology Letters1689-13922024-01-0129112010.1186/s11658-024-00537-1Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epitheliumDora Angyal0Tessa A. Groeneweg1Anny Leung2Max Desain3Kalyan Dulla4Hugo R. de Jonge5Marcel J. C. Bijvelds6Department of Gastroenterology and Hepatology, Erasmus MC University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical CenterBoehringer Ingelheim Pharma GmbH & Co. KGDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical CenterDepartment of Gastroenterology and Hepatology, Erasmus MC University Medical CenterAbstract Background Loss of CFTR-dependent anion and fluid secretion in the ducts of the exocrine pancreas is thought to contribute to the development of pancreatitis, but little is known about the impact of inflammation on ductal CFTR function. Here we used adult stem cell-derived cell cultures (organoids) obtained from porcine pancreas to evaluate the effects of pro-inflammatory cytokines on CFTR function. Methods Organoids were cultured from porcine pancreas and used to prepare ductal epithelial monolayers. Monolayers were characterized by immunocytochemistry. Epithelial bicarbonate and chloride secretion, and the effect of IL-1β, IL-6, IFN-γ, and TNF-α on CFTR function was assessed by electrophysiology. Results Immunolocalization of ductal markers, including CFTR, keratin 7, and zonula occludens 1, demonstrated that organoid-derived cells formed a highly polarized epithelium. Stimulation by secretin or VIP triggered CFTR-dependent anion secretion across epithelial monolayers, whereas purinergic receptor stimulation by UTP, elicited CFTR-independent anion secretion. Most of the anion secretory response was attributable to bicarbonate transport. The combination of IL-1β, IL-6, IFN-γ, and TNF-α markedly enhanced CFTR expression and anion secretion across ductal epithelial monolayers, whereas these cytokines had little effect when tested separately. Although TNF-α triggered apoptotic signaling, epithelial barrier function was not significantly affected by cytokine exposure. Conclusions Pro-inflammatory cytokines enhance CFTR-dependent anion secretion across pancreatic ductal epithelium. We propose that up-regulation of CFTR in the early stages of the inflammatory response, may serve to promote the removal of pathogenic stimuli from the ductal tree, and limit tissue injury.https://doi.org/10.1186/s11658-024-00537-1CFTRCystic fibrosisCytokinesEpithelial ion transportOrganoidPancreatitis |
| spellingShingle | Dora Angyal Tessa A. Groeneweg Anny Leung Max Desain Kalyan Dulla Hugo R. de Jonge Marcel J. C. Bijvelds Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium Cellular & Molecular Biology Letters CFTR Cystic fibrosis Cytokines Epithelial ion transport Organoid Pancreatitis |
| title | Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium |
| title_full | Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium |
| title_fullStr | Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium |
| title_full_unstemmed | Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium |
| title_short | Pro-inflammatory cytokines stimulate CFTR-dependent anion secretion in pancreatic ductal epithelium |
| title_sort | pro inflammatory cytokines stimulate cftr dependent anion secretion in pancreatic ductal epithelium |
| topic | CFTR Cystic fibrosis Cytokines Epithelial ion transport Organoid Pancreatitis |
| url | https://doi.org/10.1186/s11658-024-00537-1 |
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