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Human Gastroenteropancreatic Expression of Melatonin and Its Receptors MT1 and MT2
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, e0120195Article in journal (Refereed) Published
Abstract [en]

Background and Aim The largest source of melatonin, according to animal studies, is the gastrointestinal (GI) tract but this is not yet thoroughly characterized in humans. This study aims to map the expression of melatonin and its two receptors in human GI tract and pancreas using microarray analysis and immunohistochemistry. Method Gene expression data from normal intestine and pancreas and inflamed colon tissue due to ulcerative colitis were analyzed for expression of enzymes relevant for serotonin and melatonin production and their receptors. Sections from paraffin-embedded normal tissue from 42 individuals, representing the different parts of the GI tract (n= 39) and pancreas (n= 3) were studied with immunohistochemistry using antibodies with specificity for melatonin, MT1 and MT2 receptors and serotonin. Results Enzymes needed for production of melatonin are expressed in both GI tract and pancreas tissue. Strong melatonin immunoreactivity (IR) was seen in enterochromaffin (EC) cells partially co-localized with serotonin IR. Melatonin IR was also seen in pancreas islets. MT1 and MT2 IR were both found in the intestinal epithelium, in the submucosal and myenteric plexus, and in vessels in the GI tract as well as in pancreatic islets. MT1 and MT2 IR was strongest in the epithelium of the large intestine. In the other cell types, both MT2 gene expression and IR were generally elevated compared to MT1. Strong MT2, IR was noted in EC cells but not MT1 IR. Changes in gene expression that may result in reduced levels of melatonin were seen in relation to inflammation. Conclusion Widespread gastroenteropancreatic expression of melatonin and its receptors in the GI tract and pancreas is in agreement with the multiple roles ascribed to melatonin, which include regulation of gastrointestinal motility, epithelial permeability as well as enteropancreatic cross-talk with plausible impact on metabolic control.

Place, publisher, year, edition, pages
2015. Vol. 10, no 3, e0120195
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-252709DOI: 10.1371/journal.pone.0120195ISI: 000352134700057PubMedID: 25822611OAI: oai:DiVA.org:uu-252709DiVA: diva2:811536
Available from: 2015-05-12 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Melatonin and its receptors in the normal human gastrointestinal tract, pancreas and in small intestinal neuroendocrine tumours
Open this publication in new window or tab >>Melatonin and its receptors in the normal human gastrointestinal tract, pancreas and in small intestinal neuroendocrine tumours
2017 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Melatonin, “the hormone of darkness” is well known to regulate sleep and circadian rhythm. However, melatonin is also present in numerous peripheral tissues and the number of actions assigned to this neurohormone is growing steadily. Based on animal studies, it has been proposed that gastrointestinal melatonin is produced in enterochromaffin cells.

The aims were to characterise the expression of melatonin and its receptors MT1 and MT2 in normal human gastrointestinal tract and pancreas as well as in tumours derived from enterochromaffin cells, small intestinal neuroendocrine tumours (SI-NET), using immunohistochemistry. Melatonin and receptor expression was furthermore compared to clinical symptoms, tumour prognostic factors and treatment response.

In enterochromaffin cells from normal gastrointestinal tissue and in SI-NETs a strong immunoreactivity (IR) for melatonin and MT2 was found, while MT1 IR was low or absent. Melatonin, MT1 and MT2 IR was also seen in the large intestinal epithelium of normal gastrointestinal tract and in pancreatic islets, although the expression of MT1 in pancreatic tissue varied. Analyses of mRNA data confirmed the expression of the enzymes needed for melatonin synthesis as well as MT1 and MT2 in small intestine and pancreas.

The intensity of melatonin IR in SI-NETs correlated to lower proliferation index and less symptoms of diarrhoea, which is well in line with the proposed actions of melatonin described in nimal studies. The intensity of MT2 IR was generally lower in metastases than in primary tumours. Plasma levels of melatonin in patients with SI-NETs and disease stabilisation/remission were reduced after treatment and higher levels were associated with nausea.

In conclusion, melatonin and its receptors are present in the normal human gastrointestinal tract, pancreas and in SI-NETs. Melatonin IR intensity in tumours correlated significantly to less diarrhoea and to lower proliferation index. Plasma levels of melatonin in patients with SI-NETs were reduced with treatment response, indicating a possible tumour-derived origin of circulating melatonin levels.

These results are in agreement with the suggested actions of melatonin on gastrointestinal motility and tumour growth.

Place, publisher, year, edition, pages
Uppsala: Uppsala University, 2017. 31 p.
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-319920 (URN)
Presentation
2017-04-25, Lilla konferensrummet, Blå korset, Akademiska sjukhuset, 75185, Uppsala, 09:15 (Swedish)
Supervisors
Available from: 2017-04-11 Created: 2017-04-11 Last updated: 2017-04-27Bibliographically approved

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Söderquist, FannyHellström, Per M.Cunningham, Janet L.

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