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 |
_version_ | 1783272003536420864 |
---|---|
author | Ono, Junya Shime, Hiroaki Takaki, Hiromi Takashima, Ken Funami, Kenji Yoshida, Sumito Takeda, Yohei Matsumoto, Misako Kasahara, Masanori Seya, Tsukasa |
author_facet | Ono, Junya Shime, Hiroaki Takaki, Hiromi Takashima, Ken Funami, Kenji Yoshida, Sumito Takeda, Yohei Matsumoto, Misako Kasahara, Masanori Seya, Tsukasa |
author_sort | Ono, Junya |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5646017 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-56460172017-10-26 The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice Ono, Junya Shime, Hiroaki Takaki, Hiromi Takashima, Ken Funami, Kenji Yoshida, Sumito Takeda, Yohei Matsumoto, Misako Kasahara, Masanori Seya, Tsukasa J Biomed Sci Research 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. BioMed Central 2017-10-17 /pmc/articles/PMC5646017/ /pubmed/29041928 http://dx.doi.org/10.1186/s12929-017-0387-z Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Ono, Junya Shime, Hiroaki Takaki, Hiromi Takashima, Ken Funami, Kenji Yoshida, Sumito Takeda, Yohei Matsumoto, Misako Kasahara, Masanori Seya, Tsukasa The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice |
title | The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice |
title_full | The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice |
title_fullStr | The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice |
title_full_unstemmed | The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice |
title_short | The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc(Min/+) mice |
title_sort | tlr3/ticam-1 signal constitutively controls spontaneous polyposis through suppression of c-myc in apc(min/+) mice |
topic | Research |
url | 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 |
work_keys_str_mv | AT onojunya thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT shimehiroaki thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT takakihiromi thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT takashimaken thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT funamikenji thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT yoshidasumito thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT takedayohei thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT matsumotomisako thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT kasaharamasanori thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT seyatsukasa thetlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT onojunya tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT shimehiroaki tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT takakihiromi tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT takashimaken tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT funamikenji tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT yoshidasumito tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT takedayohei tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT matsumotomisako tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT kasaharamasanori tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice AT seyatsukasa tlr3ticam1signalconstitutivelycontrolsspontaneouspolyposisthroughsuppressionofcmycinapcminmice |