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: 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
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 17 Issue 7 Pg. 1464-73 (Jul 2011) ISSN: 1536-4844 [Electronic] England
• PMID: 21674704 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.

Chemical References

• Carcinogens
• Inflammation Mediators
• Microfilament Proteins
• RNA, Messenger
• TLR4 protein, human
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• villin
• Dextran Sulfate
• Azoxymethane

Topics

• Animals
• Azoxymethane (toxicity)
• Blotting, Western
• Carcinogens (toxicity)
• Colitis, Ulcerative (chemically induced, complications)
• Colonic Neoplasms (etiology, metabolism)
• Dextran Sulfate (toxicity)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunoenzyme Techniques
• Inflammation (complications, immunology, pathology)
• Inflammation Mediators (metabolism)
• Intestinal Mucosa (immunology, injuries, pathology)
• Mice
• Mice, Transgenic
• Microfilament Proteins (genetics)
• Promoter Regions, Genetic (genetics)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Toll-Like Receptor 4 (genetics, metabolism, physiology)