The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc mice.

Background: Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway.

Methods: We established Apc Ticam1 mice and their survival was compared to survival of Apc Myd88 and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis.

Results: We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc background. Polyps were more frequently formed in the distal intestine of Apc Ticam1 mice than in Apc mice. Infiltration of immune cells such as CD11b and CD8α cells into the polyps was detected histologically. CD11b and CD8α mRNAs were increased in polyps of Apc Ticam1 mice compared to Apc mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc Ticam1 mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc Ticam1 mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc mice.

Conclusion: These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc mice.