Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis

Masayuki Fukata, Limin Shang, Rebeca Santaolalla, John Sotolongo, Cristhine Pastorini, Cecilia España, Ryan Ungaro, Noam Harpaz, Harry S. Cooper, Greg Elson, Marie Kosco-Vilbois, Julia Zaias, Maria T. Perez, Lloyd Mayer, Arunan S. Vamadevan, Sergio A. Lira, Maria T. Abreu

Research output: Contribution to journalArticle

111 Scopus citations

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 PGE 2 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. (Inflamm Bowel Dis 2010;)

Original languageEnglish (US)
Pages (from-to)1464-1473
Number of pages10
JournalInflammatory bowel diseases
Volume17
Issue number7
DOIs
StatePublished - Jul 1 2011

Keywords

  • cancer
  • innate immunity
  • Toll-like receptor
  • ulcerative colitis
  • villin

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

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    Fukata, M., Shang, L., Santaolalla, R., Sotolongo, J., Pastorini, C., España, C., Ungaro, R., Harpaz, N., Cooper, H. S., Elson, G., Kosco-Vilbois, M., Zaias, J., Perez, M. T., Mayer, L., Vamadevan, A. S., Lira, S. A., & Abreu, M. T. (2011). Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflammatory bowel diseases, 17(7), 1464-1473. https://doi.org/10.1002/ibd.21527