Serotonin regulates amylase secretion and acinar cell damage during murine pancreatitis
- Sabrina Sonda1,
- Alberto B Silva1,
- Kamile Grabliauskaite1,
- Enrica Saponara1,
- Achim Weber2,
- Jae-Hwi Jang1,
- Richard A Züllig3,
- Martha Bain1,
- Theresia Reding Graf1,
- Adrian B Hehl4,
- Rolf Graf1
- 1Department of Visceral and Transplantation Surgery, Swiss Hepato-Pancreato-Biliary Center, University Hospital, Zurich, Switzerland
- 2Institute of Surgical Pathology, University Hospital, Zurich, Switzerland
- 3Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Zurich, Switzerland
- 4Institute of Parasitology, University of Zurich, Zurich, Switzerland
- Correspondence to Dr Sabrina Sonda, Visceral Surgery, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland; Dr Rolf Graf, Visceral Surgery, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland;
Contributors All the authors of this manuscript contributed in the study design, acquisition, analysis, interpretation of data, drafting and critical revision of the manuscript.
- Revised 19 March 2012
- Accepted 20 March 2012
- Published Online First 16 May 2012
Objective Serotonin (5-hydroxytryptamine, 5-HT) is a potent bioactive molecule involved in a variety of physiological processes. In this study, the authors analysed whether 5-HT regulates zymogen secretion in pancreatic acinar cells and the development of pancreatic inflammation, a potentially lethal disease whose pathophysiology is not completely understood.
Methods 5-HT regulation of zymogen secretion was analysed in pancreatic acini isolated from wild-type or tryptophan hydoxylase-1 knock-out (TPH1−/−) mice, which lack peripheral 5-HT, and in amylase-secreting pancreatic cell lines. Pancreatitis was induced by cerulein stimulation and biochemical and immunohistochemical methods were used to evaluate disease progression over 2 weeks.
Results Absence and reduced intracellular levels of 5-HT inhibited the secretion of zymogen granules both ex vivo and in vitro and altered cytoskeleton dynamics. In addition, absence of 5-HT resulted in attenuated pro-inflammatory response after induction of pancreatitis. TPH1−/− mice showed limited zymogen release, reduced expression of the pro-inflammatory chemokine MCP-1 and minimal leucocyte infiltration compared with wild-type animals. Restoration of 5-HT levels in TPH1−/− mice recovered the blunted inflammatory processes observed during acute pancreatitis. However, cellular damage, inflammatory and fibrotic processes accelerated in TPH1−/− mice during disease progression.
Conclusions These results identify a 5-HT-mediated regulation of zymogen secretion in pancreatic acinar cells. In addition, they demonstrate that 5-HT is required for the onset but not for the progression of pancreatic inflammation. These findings provide novel insights into the normal physiology of pancreatic acinar cells and into the pathophysiology of pancreatitis, with potential therapeutic implications.
- zymogen secretion
- acute pancreatitis
- immune response
- actin cytoskeleton
- gastric cancer
- hepatocellular carcinoma
- liver metastases
- pancreatic pathology
- pancreatic tumours
- molecular pathology
- gastrointestinal lymphoma
- liver biopsy
- chronic pancreatitis
- experimental pancreatitis
- exocrine pancreatic secretion
ABS, KG and ES contributed equally to this work.
Funding This research received grants from the Swiss National Science Foundation (3200-129969), the Amélie Waring Foundation and the Gottfried und Julia Bangerter-Rhyner-Stiftung.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
This paper is dedicated to Professor Rudolf Ammann in honour of his interest and achievements in pancreatology.