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An experimental study on the interaction between the neuro-endocrine and immune systems in the gastrointestinal tract
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The mucosa lining of the gastrointestinal (GI) tract is in immediate contact with food nutrients to allow a rapid and efficient digestion and absorption and at the same time protects against the incessant risk of attack from pathogenic microbes. Maintenance of normal physiological activities in the GI tract is dependent on a number of regulatory interactions between the nervous, endocrine, and immune systems, as well as environmental and genetic factors. Impaired nervous and/or endocrine systems may endanger mucosal immunity and thereby increase the susceptibility to infectious agents, elicit an uncontrolled inflammatory response and cause a failure of immune surveillance. Aberrant immune functions may also lead to an apparent neuro-endocrine disturbance. A better understanding of the neuro-endocrine immunomodulation in the GI tract and its influence on the inflammatory process, therefore, will hold the promise of novel strategy to the treatment of immunologically and/or neuro-endocrinologically mediated diseases with the use of appropriate regulatory substances.

In this thesis, the neuro-endocrine system and its interaction(s) with the immune system in the GI tract were studied using mouse models combined with immunological and molecular biological techniques (e.g. immunomorphometry, quantitative RT-PCR). The following could be concluded:

1) Vagus nerves are fundamental to the enteric neuro-endocrine system. Frequencies and morphology of several types of endocrine cells and tissue levels of neuropeptides along the GI tract were significantly changed by vagotomy.

2) The local enteric neuro-endocrine system may have important influences on bowel inflammation. Polypeptide YY (PYY) cells and tissue levels of PYY, substance P (SP) and vasoactive intestinal polypeptide (VIP) were dramatically decreased in the inflamed colon of IL-2-/- mice as compared to the health IL-2+/- and IL-2+/+ controls.

3) Notably, IL-2 deficiency per se caused marked neuro-endocrine alterations in the gut. The volume densities of enteroglucagon-, serotonin-cells and SP-, VIP- or total myenteric nerves were lower in IL-2+/- and IL-2-/- mice as compared to the wild type. The normally occurring age related neuro-endocrine changes were also absent in mice with no (IL-2-/- mice) or reduced levels of IL-2 (IL-2+/- mice).

4) VIP generally exerted immunosuppressive effects. The magnitude of the effect differed with T cells in different compartments. Proliferation in response to polyclonal T cell activators was significantly down-regulated by VIP in splenic but not intestinal T lymphocytes. Cytokine production was also affected. Expression of mRNAs for interleukin-2 (IL-2), the Th1 cytokine interferon-γ (IFN-γ), and the Th2 cytokine IL-4 in activated small intestinal lamina propria and splenic T cells was inhibited by VIP in a dose dependent manner. In contrast, the inhibitory action of VIP on cytokine production was much less pronounced in intestinal intraepithelial T lymphocytes in which only IFN-γ mRNA expression was reduced.

5) The effects of VIP on lymphocytes are most probably receptor mediated. Intestinal T cells were shown to bind VIP. T cells in both small and large intestine as well as spleen had the mRNA expression for VIP-receptor 1. It was expressed in all T cell subtypes tested i.e. CD4+ , CD8+, and CD4-CD8-CD3+ cells. Interestingly, VIP receptor 2 mRNA was only found in CD8+ lymphocytes of small intestine. This indicates a functional diversity and specificity of VIP in immune modulation.

6) SP may act as an autocrine as well as a paracrine immunoregulatory agent in intestinal mucosa. T cells from both the epithelium and lamina propria of small and large intestine were found to produce SP and at the same time express the SP receptor.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2001. , 62 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 719
Keyword [en]
gastrointestinal tract, neuro-endocrine system, substance P, vasoactive intestinal polypeptide, vagus nerves, mucosal immune system, T lymphocytes, cytokines, inflammation, mouse
National Category
Neurology Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:umu:diva-73364ISBN: 91-7191-994-5 (print)OAI: oai:DiVA.org:umu-73364DiVA: diva2:631158
Public defence
2001-03-15, Astrid Fagreussalen A103, Norrlands universitetssjukhus, Umeå, 09:00
Opponent
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved
List of papers
1. Effects of unilateral cervical vagotomy on antral endocrine cells in mouse
Open this publication in new window or tab >>Effects of unilateral cervical vagotomy on antral endocrine cells in mouse
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1999 (English)In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 14, no 3, 705-709 p.Article in journal (Refereed) Published
Abstract [en]

The present study was carried out to investigate the effect of unilateral cervical vagotomy on the antral endocrine cells in mouse. Fifty-four mice were randomly divided into three groups, 18 in each, for left or right cervical vagotomy, or sham operation as controls. The animals were sacrificed 2, 4, and 8 weeks after the operation, respectively. Chromogranin-, gastrin/CCK-, serotonin-, and somatostatin-cells were detected by immunohistochemistry and quantitated by computerised image analysis. The results showed that the number of chromogranin-cells was decreased in both left and right vagotomized mice after 4 weeks and remained at the same level after 8 weeks. The numbers of gastrin-, serotonin- and somatostatin-cells did not change after right vagotomy. However, the numbers of gastrin- and somatostatin-cells were decreased after left vagotomy, whereas no change was found in serotonin-cells. Endocrine cells with vacuolated cytoplasm and pyknotic nuclei were also observed during the course of time. The alteration in the antral endocrine cells observed in this study seemed to be dynamic and depended on the observation time after the operation as well as the denervated branches of the vagus nerve. This may explain, at least partially the contradictory results obtained earlier by different investigators.

Keyword
Computerised image analysis, Endocrine cells, Antrum, Mouse, Unilateral vagotomy
National Category
Neurology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-73344 (URN)10425538 (PubMedID)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2017-12-06Bibliographically approved
2. Changes in intestinal endocrine cells in the mouse after unilateral cervical vagotomy
Open this publication in new window or tab >>Changes in intestinal endocrine cells in the mouse after unilateral cervical vagotomy
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1999 (English)In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 14, no 2, 453-460 p.Article in journal (Refereed) Published
Abstract [en]

The effect of right or left unilateral cervical vagotomy on the intestinal endocrine cells was studied in 23 mice at 2 and 8 weeks after operation, respectively. The results were compared with that from 10 sham operated mice. Various types of endocrine cells in duodenum and proximal colon were detected by immunohistochemistry and quantified by computerized image analysis. In mouse duodenum, chromogranin-, CCK/gastrin-, GIP- and somatostatin-cells were significantly decreased at 2 weeks after right vagotomy, but returned to the control levels at 8 weeks. Serotonin-cells were reduced at both 2 and 8 weeks after right vagotomy. The amount of the duodenal endocrine cells did not change after left vagotomy with the exception of secretin-cells, which were diminished at 8 weeks after both right and left vagotomy. In the proximal colon, chromogranin-cells were also decreased at 2 weeks after right vagotomy. Serotonin-cells were reduced at 8 weeks after left vagotomy but not right vagotomy. There was no significant difference between the unilaterally vagotomized and the sham operated mice with regard to PYY- and glucagon-cells. It was concluded that vagotomy affected the intestinal endocrine cells in mouse. The influence was more pronounced in the small intestine than the proximal colon. The right vagus nerves seemed to exert more effect on the intestinal endocrine cells than the left ones.

Keyword
Computerised image analysis, Endocrine cells, Intestine, Mouse, Unilateral vagotomy
National Category
Neurology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-73345 (URN)10212806 (PubMedID)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2017-12-06Bibliographically approved
3. Neuroendocrine peptide levels in the gastrointestinal tract of mice after unilateral cervical vagotomy
Open this publication in new window or tab >>Neuroendocrine peptide levels in the gastrointestinal tract of mice after unilateral cervical vagotomy
2000 (English)In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 88, no 1-3, 15-20 p.Article in journal (Refereed) Published
Abstract [en]

The effects of left and right unilateral cervical vagotomy on the content of several neuroendocrine peptides were studied in different parts of the murine gastrointestinal tract, known to receive vagal innervation. The neuroendocrine peptides investigated were secretin, gastric inhibitory peptide (GIP), gastrin, motilin, peptide YY (PYY), somatostatin, substance P, VIP, neurotensin, neuropeptide Y (NPY), and galanin. The neuroendocrine peptide concentration was affected after both left and right vagotomy, and that the changes in the concentrations of the neuroendocrine peptide levels occurred in all the gastrointestinal segments investigated, namely antrum, small and large intestine. However, these changes varied, depending on which side was vagotomized and the interval after vagotomy. It is concluded that the vagus nerve had an important impact on the neuroendocrine system in the murine gut. It is suggested, furthermore that the contradictory results obtained earlier on the effect of vagotomy on the gastrointestinal peptides may depend on differences in the vagotomy methods used and on differences in observation time after vagotomy.

Keyword
Neuroendocrine peptides; Mouse; Gastrointestinal tract; Radioimmunoassay; Vagotomy
National Category
Neurology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-73346 (URN)10.1016/S0167-0115(99)00107-X (DOI)10706947 (PubMedID)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2017-12-06Bibliographically approved
4. Neuroendocrine changes in colon of mice with a disrupted IL-2 gene
Open this publication in new window or tab >>Neuroendocrine changes in colon of mice with a disrupted IL-2 gene
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2000 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 120, no 3, 424-433 p.Article in journal (Refereed) Published
Abstract [en]

Neuroendocrine peptides have a variety of physiological functions in the gastrointestinal tract. This study was carried out to investigate the impact of IL-2 deficiency on the neuroendocrine system in normal colon, and the neuroendocrine changes during colonic inflammation. Mice with homozygous disrupted IL-2 gene (IL-2-/-) spontaneously developed a bowel disease with similarities to human ulcerative colitis. Different types of colonic endocrine cells and myenteric nerves were analysed in the IL-2-/- mice using immunomorphometry. The neuropeptide contents in the colonic tissues were determined by radioimmunoassay. Age-matched healthy IL-2+/- and IL-2+/+ mice served as controls and the colonic IL-2 levels were compared between these two groups of mice by ELISA. Our data showed that less than half the amount of IL-2 was synthesized in the colon of IL-2+/- mice compared with the IL-2+/+ wild-type mice. Two major differences in the neuroendocrine colon were found between the mice with an intact and disrupted IL-2 gene. One was age-related. The frequencies of various endocrine cells and myenteric nerves increased with age in the IL-2+/+ mice. However, no such increases were seen in the mice with a disrupted IL-2 gene. Instead, the volume densities of enteroglucagon, serotonin cells and substance P (SP), vasoactive intestinal polypeptide (VIP) and total myenteric nerves were lower in the older IL-2+/- and IL-2-/- mice compared with the wild type. The other was disease-related. Polypeptide YY (PYY) cells and tissue levels of PYY, SP and VIP were significantly decreased in the IL-2-/- mice during the course of bowel inflammation compared with the healthy IL-2+/- and IL-2+/+ controls. These findings indicate that colonic neuroendocrine alterations did occur in the mice with a disrupted IL-2 gene and diminished local IL-2 level, suggesting a role of IL-2 in the regulation of the neuroendocrine system and a prevalent interaction between the immune and neuroendocrine systems in normal colon. On the other hand, there were some changes that seemed to correlate with the bowel inflammatory process. They might be associated with the impaired function in inflamed gut and contribute to the development and/or prolongation of disease.

Keyword
IL-2; gene knock-out; colonic inflammation; neuroendocrine system; mice
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-68022 (URN)10.1046/j.1365-2249.2000.01255.x (DOI)10844519 (PubMedID)
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2017-12-06Bibliographically approved
5. Both substance P and its receptor are expressed in mouse intestinal T lymphocytes
Open this publication in new window or tab >>Both substance P and its receptor are expressed in mouse intestinal T lymphocytes
2001 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 73, no 5, 358-368 p.Article in journal (Refereed) Published
Abstract [en]

Substance P (SP), one of the most prevalent neuropeptides in gut, has been reported to have potent immune modulatory effects as a proinflammatory agent. The synthesis of SP and SP receptor expression in intraepithelial and lamina propria T lymphocytes of mouse intestine was investigated. Using RT-PCR analysis, it was demonstrated that SP receptor mRNA was exclusively expressed in intraepithelial and lamina propria T lymphocytes as well as their purified CD4+, CD8+ and CD4-CD8-CD3+ subsets. Messenger RNAs (mRNAs) for the two precursors of SP, beta and gamma-preprotachykinin-A, were also detected. These results were consistent in lymphocytes from both epithelium and lamina propria of small and large intestines, although the frequencies and/or intensities of mRNA expression varied. However, none of the findings could be repeated in splenic T lymphocytes. Activation of splenocytes with anti-CD3epsilon-chain mAb and PMA did not induce expression of SP or its receptor mRNAs. Furthermore, both cytoplasmic and surface-bound SP was demonstrated in intestinal T lymphocytes using dual color immunocytochemistry and immunoflow cytometry. In vitro treatment with SP did not significantly change the size of the SP-immunoreactive T cell population, indicating the presence of SP receptor on intestinal T lymphocytes as well as in vivo binding of endogenously released SP. Our data suggest that SP production and SP receptor expression are distinctive for mouse intestinal mucosal immunity and that SP may act as a modulator of an ongoing controlled inflammation in normal gut, by acting through its specific receptor on T lymphocytes in an autocrine and/or paracrine pattern.

Keyword
Substance P, Substance P receptor, Intestine, Lymphocytes
National Category
Neurosciences Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-68057 (URN)10.1159/000054653 (DOI)11399909 (PubMedID)
Available from: 2013-04-11 Created: 2013-04-11 Last updated: 2017-12-06Bibliographically approved
6. Differential expression of vasoactive intestinal polypeptide receptor 1 and 2 mRNA in murine intestinal T lymphocyte subtypes
Open this publication in new window or tab >>Differential expression of vasoactive intestinal polypeptide receptor 1 and 2 mRNA in murine intestinal T lymphocyte subtypes
2001 (English)In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 13, no 9, 818-825 p.Article in journal (Refereed) Published
Abstract [en]

Neuropeptides may exert a variety of effects on the immune cells at both systemic and mucosal immune sites. The immunoregulatory properties refer to the ability of physiological signals and pathways to influence various immune functions. Vasoactive intestinal polypeptide (VIP), a neuropeptide present in high concentration in gut, was studied for its production and receptor expression in intraepithelial and lamina propria T lymphocytes of mouse intestine. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, it was demonstrated that VIP receptor 1 (VIPR1) was constantly expressed in intraepithelial and lamina propria T lymphocytes from both small and large intestine. In contrast, VIPR2 was identified only in T cells from small intestine. Further studies on purified subpopulations of T lymphocytes indicated the existence of VIPR2 in CD8(+) T cells, but not CD4(+) and CD4CD8 double negative T cells, although all these three subpopulations displayed VIPR1. In addition, VIPR1 mRNA was detected in splenic T lymphocytes, but no signal was obtained for VIPR2 mRNA, even after stimulation of the cells with anti-CD3(epsilon)-chain mAb, phorbol 12-myristate 13-acetate (PMA) and/or VIP. The presence of VIP receptor(s) on intestinal T lymphocytes was supported by the detection of VIP on the cell surface using dual colour immunoflowcytometry. In-vitro treatment with VIP resulted in a tendency towards an increased size of the VIP immunoreactive T cell population and significantly enhanced the average immunofluorescence intensity of the surface labelling. This indicates that the receptors are partially occupied by locally produced VIP in vivo and that more peptide molecules can be bound on the lymphocytes when needed, released and accumulated in higher concentration at the action sites. We failed to detect the expression of VIP mRNA in T lymphocytes, from either intestine or spleen. These observations support that VIP may be an important immune modulator in gut acting through specific receptors on T lymphocytes. The differential mRNA expression of VIP receptor subtypes in cells with different phenotypes and in different immune compartments may suggest diverse regulatory roles of the neuropeptide in immune responses.

Keyword
vasoactive intestinal polypeptide; receptor; intestinal lymphocyte(s); mouse
National Category
Neurosciences Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-68059 (URN)10.1046/j.1365-2826.2001.00703.x (DOI)11578532 (PubMedID)
Available from: 2013-04-11 Created: 2013-04-11 Last updated: 2017-12-06Bibliographically approved
7. Inhibitory effects of vasoactive intestinal polypeptide on the proliferation and cytokine mRNA expression by mouse intestinal and splenic T lymphocytes
Open this publication in new window or tab >>Inhibitory effects of vasoactive intestinal polypeptide on the proliferation and cytokine mRNA expression by mouse intestinal and splenic T lymphocytes
(English)Manuscript (preprint) (Other academic)
National Category
Neurology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-73363 (URN)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved

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