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Gastroenterology. 2009 Nov;137(5):1649-60. doi: 10.1053/j.gastro.2009.08.041. Epub 2009 Aug 23.

Serotonin has a key role in pathogenesis of experimental colitis.

Author information

1
Farncombe Family Digestive Health Research Institute, Department of Pathology & Molecular Medicine, McMaster University, Ontario, Canada.

Abstract

BACKGROUND & AIMS:

Mucosal changes in inflammatory bowel disease are characterized by ulcerative lesions accompanied by a prominent infiltrate of immune cells as well as alteration in serotonin (5-hydroxytryptamine [5-HT])-producing enterochromaffin cells. We investigated the role of 5-HT in colonic inflammation in mice.

METHODS:

Colitis was induced with dextran sulfate sodium or dinitrobenzene sulfonic acid in tryptophan hydroxylase 1-deficient (TPH1(-/-)) mice, which have markedly reduced 5-HT in the gastrointestinal tract, and in mice given the 5-HT synthesis inhibitor parachlorophenylalanine.

RESULTS:

Delayed onset, decreased severity of clinical disease, and significantly lower macroscopic and histologic damage scores were observed in TPH1(-/-) mice, compared with wild-type mice, and in mice given parachlorophenylalanine after induction of colitis by dextran sulfate sodium. This was associated with down-regulation of macrophage infiltration and production of proinflammatory cytokines. 5-HT stimulated production of proinflammatory cytokines from macrophages collected from the peritoneal cavity of wild-type mice; this process was inhibited by a nuclear factor kappaB inhibitor, indicating a critical role for nuclear factor kappaB signaling in 5-HT-mediated activation of immune cells. Restoration of 5-HT levels in TPH1(-/-) mice by the 5-HT precursor 5-hydroxytryptophan increased the severity of DSS-induced colitis. We also observed significant reduction in severity of colitis in TPH1(-/-) mice after induction of dinitrobenzene sulfonic acid-induced colitis.

CONCLUSIONS:

5-HT is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of gastrointestinal inflammation and could lead to new therapeutic strategies for inflammatory disorders.

PMID:
19706294
DOI:
10.1053/j.gastro.2009.08.041
[Indexed for MEDLINE]
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