title: Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis.
abstract: BACKGROUND
  Chronic intestinal inflammation culminates in cancer and a link to Toll-like receptor-4 (TLR4) has been suggested by our observation that TLR4 deficiency prevents colitis-associated neoplasia. In the current study we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis-associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa.
  
  
  METHODS
  Mice transgenic for a constitutively active TLR4 under the intestine-specific villin promoter (villin-TLR4 mice) were treated with dextran sodium sulfate (DSS) for acute colitis and azoxymethane (AOM)-DSS TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis (UC) and UC-associated cancer. The effect of an antagonist TLR4 antibody (Ab) was tested in prevention of colitis-associated neoplasia in the AOM-DSS model.
  
  
  RESULTS
  Villin-TLR4 mice were highly susceptible to both acute colitis and colitis-associated neoplasia. Villin-TLR4 mice had increased epithelial expression of COX-2 and mucosal PGE₂ production at baseline. Increased severity of colitis in villin-TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all colitis-associated cancer and progressively increased with grade of dysplasia. As a proof of principle, a TLR4/MD-2 antagonist antibody inhibited colitis-associated neoplasia in the mouse model.
  
  
  CONCLUSIONS
  Our results show that regulation of TLRs can affect the outcome of both acute colitis and its consequences, cancer. Targeting TLR4 and other TLRs may ultimately play a role in prevention or treatment of colitis-associated cancer.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fukata
authors.forename: Limin
authors.initials: L
authors.lastname: Shang
authors.forename: Rebeca
authors.initials: R
authors.lastname: Santaolalla
authors.forename: John
authors.initials: J
authors.lastname: Sotolongo
authors.forename: Cristhine
authors.initials: C
authors.lastname: Pastorini
authors.forename: Cecilia
authors.initials: C
authors.lastname: España
authors.forename: Ryan
authors.initials: R
authors.lastname: Ungaro
authors.forename: Noam
authors.initials: N
authors.lastname: Harpaz
authors.forename: Harry S
authors.initials: HS
authors.lastname: Cooper
authors.forename: Greg
authors.initials: G
authors.lastname: Elson
authors.forename: Marie
authors.initials: M
authors.lastname: Kosco-Vilbois
authors.forename: Julia
authors.initials: J
authors.lastname: Zaias
authors.forename: Maria T
authors.initials: MT
authors.lastname: Perez
authors.forename: Lloyd
authors.initials: L
authors.lastname: Mayer
authors.forename: Arunan S
authors.initials: AS
authors.lastname: Vamadevan
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000150:complications* / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000293:injuries / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
chemical_list: D002273:Carcinogens; D018836:Inflammation Mediators; D008840:Microfilament Proteins; D012333:RNA, Messenger; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C026615:villin; D016264:Dextran Sulfate; D001397:Azoxymethane