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. 2010 Jul;22(7):826-34, e229.
doi: 10.1111/j.1365-2982.2010.01479.x. Epub 2010 Mar 8.

Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter

S Haub  1 , Y Ritze, I Bergheim, O Pabst, M D Gershon, S C Bischoff
Affiliations

Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter

S Haub et al. Neurogastroenterol Motil. 2010 Jul.

Abstract

Background: Enterochromaffin cells and enteric neurons synthesize and release serotonin (5-HT). Reuptake, mediated by a plasmalemmal transporter (SERT) terminates the action of released 5-HT. Serotonin secretion and serotonin reuptake transporter (SERT) expression have been reported to be decreased in TNBS-induced experimental colitis and in patients with ulcerative colitis. The present study was designed to utilize the transgenic deletion of SERT as a gain-of-function model to test the hypothesis that 5-HT is a pro-inflammatory mediator in experimental colitis.

Methods: Colitis was compared in animals with IL10(+/+)SERT(+/+) (wild-type), IL10(-/-)SERT(+/+), IL10(-/-)SERT(+/-), and IL10(-/-)/SERT(-/-) (double knockout) genotypes. Macroscopic and histological damage scores were evaluated after a time period of up to 15 weeks.

Key results: Serotonin reuptake transporter expression was significantly increased in the inflamed colons of IL-10(-/-) mice, which displayed intestinal damage and a minor decrement in general health. General health was significantly worse and intestinal inflammation was more severe in IL-10(-/-)SERT(+/-), and IL-10(-/-)SERT(-/-) mice than in IL-10(-/-)SERT(+/+) or wild-type animals. Regardless of the associated SERT genotype, the number of 5-HT-immunoreactive cells was decreased by approximately 55-65% in all mice lacking IL-10.

Conclusions & inferences: Our observations indicate that colitis associated with IL-10 deficient mice is enhanced when the IL-10 deficiency is combined with a SERT deficiency. The data support the concept that 5-HT is a pro-inflammatory mediator in the gut.

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Conflict of interest statement

Competing interests: the authors have no competing interests.

Figures

Figure 1
Figure 1
Expression of the serotonin reuptake transporter (SERT) in the colon of IL-10−/− mice and controls. Real-time RT-PCR was used to quantify transcripts encoding SERT. Data are mean ± SEM (n = 3–4). aP < 0.05 compared with wild-type mice.
Figure 2
Figure 2
Global assessment of health and macroscopic inflammation of colon in wild-type, IL-10−/−SERT+/+, IL-10−/−SERT+/−, and IL-10−/−SERT−/− mice. (A) The global assessment score is increased in IL-10−/−SERT+/− and IL-10−/−SERT−/− mice when compared to wild-type mice (aP < 0.05), but not when compared to IL-10−/−SERT+/+ mice. (B) Representative photomicrographs of abdomen of wild-type mice, IL-10−/−SERT+/+, IL-10−/−SERT+/−, and IL-10−/−SERT−/− mice are shown. Global assessment scores were obtained as described in Material and Methods. Data are mean ± SEM (n = 4).
Figure 3
Figure 3
Colonic inflammation in wild-type, IL-10−/−SERT+/+, IL-10−/−SERT+/−, and IL-10−/−SERT−/− mice. (A) Representative photomicrographs showing the histological appearance of the colon (H&E staining, 100× original magnification) in wild-type mice, IL-10−/−SERT+/+, IL-10−/−SERT+/−, and IL-10−/−SERT−/− mice. (B) Representative photomicrographs at higher magnification (400×) show infiltrating neutrophils and mononuclear cells in the submucosae of IL-10−/−SERT+/+, IL-10−/−SERT+/−, and IL-10−/−SERT−/− mice. (C) Inflammation scores obtained from the distal, middle, proximal colon. Data represent mean ± SEM (n = 4–6). aP < 0.05 compared to wild-type mice, bP < 0.05 compared to IL-10−/−SERT+/+ mice, cP < 0.05 compared to IL-10−/−SERT+/− mice. (D) Representative photomicrographs showing the simultaneous immunohistological identification of T and B lymphocytes infiltrating the mucosa. T lymphocytes were labeled with primary antibodies against CD3 (red) and B lymphocytes were labeled with antibodies against B220 (green). DNA was stained with DAPI to locate nuclei. Although lymphocytic infiltration of the mucosa was greater than normal (wild-type) in each of the strains of mice that lacked IL-10, lymphocytic infiltration of the mucosa was further potentiated when the IL-10 deficiency was combined with a partial (IL-10−/−SERT+/−) or complete knockout of serotonin reuptake transporter (SERT) (IL-10−/−SERT−/−).
Figure 4
Figure 4
Expression of transcripts encoding IL-6 and TNFα in the colons of wild-type, IL-10−/−SERT+/+, IL-10−/−SERT+/−, and IL-10−/−SERT−/− mice. (A) Abundance of transcripts encoding IL-6 is significantly greater in IL-10−/−SERT−/− than in wild-type mice (aP < 0.01, bP < 0.01 compared to IL-10−/−SERT+/+ mice, cP < 0.01 compared to IL-10−/−SERT+/− mice). Data represent mean ± SEM (n = 4–6). (B) Abundance of transcripts encoding TNFα is significantly greater in IL-10−/−SERT−/− than in wild-type animals (aP < 0.01). Data represent mean ± SEM (n = 4–6).
Figure 5
Figure 5
Serotonin immunoreactive cells in colon of wild-type, IL-10−/−SERT+/+, IL-10−/−SERT+/−, and IL-10−/−SERT−/− mice. Quantitative analysis of 5-HT immunoreactive cells in the proximal colon (400×). Data are shown as absolute numbers per field (mean ± SEM, n = 4–6). aP < 0.05 compared to wild-type mice.
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