title: Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling.
abstract: OBJECTIVE
  The roles of intestinal Toll-like receptors (TLR) in the pathogenesis of colitis are not known. TLR2 and TLR4 appear to protect against dextran sodium sulfate-induced colitis by promoting mucosal integrity, but it is not clear whether this method of protection occurs in other models of colitis. We investigated the roles of TLR2 and TLR4 and the cell types that express these receptors during infectious colitis.
  
  
  METHODS
  We generated chimeric mice with TLR2(-/-) or TLR4(-/-) bone marrow and infected them with the bacterial pathogen Citrobacter rodentium. We assessed their susceptibility to colitis and the mechanisms of TLR-mediated mucosal integrity.
  
  
  RESULTS
  TLR2-expressing tissue resident cells prevented lethal colitis, whereas TLR4-dependent inflammatory responses of hematopoietic cells mediated intestinal damage. TLR2 expression protected against intestinal damage by maintaining epithelial barrier function and inducing expression of interleukin (IL)-11 from tissue resident cells in the muscularis mucosae, concurrent with epithelial activation of the transcription factor STAT3. Addition of exogenous IL-11 protected against the lethal colitis in TLR2-deficient mice via STAT3 activation in intestinal epithelial cells.
  
  
  CONCLUSIONS
  TLR2-dependent cytoprotective responses from tissue resident cells maintain mucosal integrity against the ultimately lethal TLR4-dependent inflammatory responses of hematopoietic cells. Whereas TLR2 protects against various noxious agents, the role of TLR4 during colitis can be either protective or damaging, depending on the stimulus. Therefore, therapeutics that reduce innate immunity (TLR2 signaling in particular) may not be beneficial to patients with colitis; they could worsen symptoms. Therapies that stimulate cytoprotective responses, like IL-11, could have benefits for patients with colitis.
authors.affiliation: Division of Gastroenterology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Gibson
authors.forename: Marinieve
authors.initials: M
authors.lastname: Montero
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ropeleski
authors.forename: Kirk S B
authors.initials: KS
authors.lastname: Bergstrom
authors.forename: Caixia
authors.initials: C
authors.lastname: Ma
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Ghosh
authors.forename: Helen
authors.initials: H
authors.lastname: Merkens
authors.forename: Jingtian
authors.initials: J
authors.lastname: Huang
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Månsson
authors.forename: Ho Pan
authors.initials: HP
authors.lastname: Sham
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McNagny
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Vallance
mesh_terms: D000818:Animals; D003092:Colitis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy; D017370:Interleukin-11 / Q000502:physiology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology*
chemical_list: D017370:Interleukin-11; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4