title: Serotonin has a key role in pathogenesis of experimental colitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Farncombe Family Digestive Health Research Institute, Department of Pathology & Molecular Medicine, McMaster University, Ontario, Canada.
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Ghia
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.forename: Matthew
authors.initials: M
authors.lastname: Collins
authors.forename: Yikang
authors.initials: Y
authors.lastname: Deng
authors.forename: Rami T
authors.initials: RT
authors.lastname: El-Sharkawy
authors.forename: Francine
authors.initials: F
authors.lastname: Côté
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
mesh_terms: D000818:Animals; D001557:Benzenesulfonates; D002097:C-Reactive Protein / Q000378:metabolism; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate; D010134:Fenclonine; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists; D014365:Tryptophan Hydroxylase / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001557:Benzenesulfonates; D053583:Interleukin-1beta; D015850:Interleukin-6; D012702:Serotonin Antagonists; D014409:Tumor Necrosis Factor-alpha; C007488:dinitrobenzenesulfonic acid; D012701:Serotonin; D002097:C-Reactive Protein; D016264:Dextran Sulfate; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D010134:Fenclonine