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Fukata M , Shang LM , Santaolalla R , Sotolongo J , Pastorini C , Espana C , Ungaro R , Harpaz N , Cooper HS , Elson G , Kosco-Vilbois M , Zaias J , Perez MT , Mayer L , Vamadevan AS , Lira SA , Abreu MT
Constitutive Activation of Epithelial TLR4 Augments Inflammatory Responses to Mucosal Injury and Drives Colitis-associated Tumorigenesis
Inflammatory Bowel Diseases. 2011 Jul;17(7) :1464-1473
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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.
Fukata, Masayuki Shang, Limin Santaolalla, Rebeca Sotolongo, John Pastorini, Cristhine Espana, Cecilia Ungaro, Ryan Harpaz, Noam Cooper, Harry S. Elson, Greg Kosco-Vilbois, Marie Zaias, Julia Perez, Maria T. Mayer, Lloyd Vamadevan, Arunan S. Lira, Sergio A. Abreu, Maria T. NIH[AI05226607]; NCI[CA137869-2]; Crohn's and Colitis Foundation of America Supported by NIH grant AI05226607 (to M.T.A.), NCI grant CA137869-2 (to M.T.A.), and Career Development Award from the Crohn's and Colitis Foundation of America (to M.F.). 26 Wiley-blackwell Malden 787zm Nese v, 2007, v3, p287