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


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
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.
Haub
S
S
Department of Nutritional Medicine and Immunology, University of Hohenheim, Stuttgart, Germany.
Ritze
Y
Y
Bergheim
I
I
Pabst
O
O
Gershon
M D
MD
Bischoff
S C
SC
D000818:Animals; D003092:Colitis / Q000235:genetics / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D016753:Interleukin-10 / Q000235:genetics* / Q000502:physiology; D007410:Intestinal Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology
D050486:Serotonin Plasma Membrane Transport Proteins; D016753:Interleukin-10