LAUSR

BackgroundIntestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in ApcMin/+ 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.MethodsWe established ApcMin/+Ticam1−/− mice and their survival was compared to survival of ApcMin/+Myd88−/− and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis.ResultsWe demonstrate that TICAM-1 is essential for suppression of polyp formation in ApcMin/+ mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the ApcMin/+ background. Polyps were more frequently formed in the distal intestine of ApcMin/+Ticam1−/− mice than in ApcMin/+ 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 ApcMin/+Ticam1−/− mice compared to ApcMin/+ mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of ApcMin/+Ticam1−/− mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of ApcMin/+Ticam1−/− mice. A Lactobacillus strain producing dsRNA was detected in feces of ApcMin/+ mice.ConclusionThese results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in ApcMin/+ mice.