Abstract
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.
Highlights
Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in ApcMin/+ mice
These results imply that the TLR3/TIR domaincontaining adapter molecule 1 (TICAM-1) pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in ApcMin/+ mice
We addressed the mechanism by which TLR3/TICAM-1 participates in polyp formation in ApcMin/+ mice
Summary
Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in ApcMin/+ mice. Microbiota contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, known as TRIF) pathway. The intestine contains microorganisms that influence the incidence of inflammation-associated cancer via toll-like receptors (TLRs) expressed in gut mucosal cells. TLR2/4 and Nod-like receptor (NLR) are expressed in mucosa and detect intestinal bacterial patterns [2]. Nod is reportedly important for maintaining the Several reports have suggested that lactobacillus produces partial or structural double-stranded (ds) RNA, Ono et al Journal of Biomedical Science (2017) 24:79 which can activate TLR3 in the intestine [8]. TLR3 couples with the adaptor TICAM-1 (TRIF) to activate transcription factors, IRF3 and AP1. If this is the case, both MyD88 and TICAM-1 pathways participate in polyposis under the presence of complex innate stimulation. We addressed the mechanism by which TLR3/TICAM-1 participates in polyp formation in ApcMin/+ mice
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