Cargando…
The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice
BACKGROUND: Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc (Min/+) mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor ada...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646017/ https://www.ncbi.nlm.nih.gov/pubmed/29041928 http://dx.doi.org/10.1186/s12929-017-0387-z |
Sumario: | BACKGROUND: Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc (Min/+) 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 (Min/+) Ticam1 (−/−) mice and their survival was compared to survival of Apc (Min/+) 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 (Min/+) mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc (Min/+) background. Polyps were more frequently formed in the distal intestine of Apc (Min/+) Ticam1 (−/−) mice than in Apc (Min/+) 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 (Min/+) Ticam1 (−/−) mice compared to Apc (Min/+) mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc (Min/+) Ticam1 (−/−) mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc (Min/+) Ticam1 (−/−) mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc (Min/+) 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 (Min/+) mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12929-017-0387-z) contains supplementary material, which is available to authorized users. |
---|