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Neuroendocrine changes in colon of mice with a disrupted IL-2 gene
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
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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.

Place, publisher, year, edition, pages
2000. Vol. 120, no 3, 424-433 p.
Keyword [en]
IL-2; gene knock-out; colonic inflammation; neuroendocrine system; mice
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:umu:diva-68022DOI: 10.1046/j.1365-2249.2000.01255.xPubMedID: 10844519OAI: oai:DiVA.org:umu-68022DiVA: diva2:615465
Available from: 2013-04-10 Created: 2013-04-10 Last updated: 2017-12-06Bibliographically approved
In thesis
1. An experimental study on the interaction between the neuro-endocrine and immune systems in the gastrointestinal tract
Open this publication in new window or tab >>An experimental study on the interaction between the neuro-endocrine and immune systems in the gastrointestinal tract
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
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:nbn:se:umu:diva-73364 (URN)91-7191-994-5 (ISBN)
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

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