- 作者: Junya Ono, Hiroaki Shime, Hiromi Takaki, Ken Takashima, Kenji Funami, Sumito Yoshida, Yohei Takeda, Misako Matsumoto, Masanori Kasahara and Tsukasa Seya
- 作者服務機構: 1.Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan
- 中文摘要:
- 英文摘要:
Background: Intestinal 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.
Methods: We 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.
Results: We 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.
Conclusion: These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in ApcMin/+ mice. - 中文關鍵字:
- 英文關鍵字: TLR3, TICAM-1 (TRIF), c-Myc, Intestinal polyposis