Department of Vaccine Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.
Department of Microbiology Immunology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
J Biomed Sci. 2017 Oct 17;24(1):79. doi: 10.1186/s12929-017-0387-z.
Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc 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.
We established Apc Ticam1 mice and their survival was compared to survival of Apc Myd88 and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis.
We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc background. Polyps were more frequently formed in the distal intestine of Apc Ticam1 mice than in Apc 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 Ticam1 mice compared to Apc mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, CXCL9 and IL-12p40 was increased in polyps of Apc Ticam1 mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc Ticam1 mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc mice.
These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc mice.
髓样分化初级反应基因 88（MyD88）在 Apc 小鼠中对微生物群的组成成分作出反应而被激活，从而促进肠道肿瘤发生。微生物群还包含双链 RNA（dsRNA），dsRNA 是 Toll 样受体 3（TLR3）的配体，可激活 toll 样受体衔接分子 1（TICAM-1，也称为 TRIF）途径。
我们建立了 Apc Ticam1 小鼠，并比较了它们的存活情况与 Apc Myd88 小鼠和野生型（WT）小鼠的存活情况。使用免疫荧光染色和 RT-PCR 分析研究了息肉的特性。
我们证明 TICAM-1 对于抑制 Apc 小鼠中的息肉形成是必不可少的。与 WT 小鼠或 Apc 背景下 MyD88 基因敲除的小鼠相比，TICAM-1 基因敲除的小鼠存活时间更短。与 Apc 小鼠相比，Apc Ticam1 小鼠的远端肠道中更频繁地形成息肉。在组织学上检测到免疫细胞（如 CD11b 和 CD8α 细胞）浸润到息肉中。与 Apc 小鼠相比，Apc Ticam1 小鼠的息肉中 CD11b 和 CD8α 的 mRNA 增加。Apc Ticam1 小鼠息肉中诱导型一氧化氮合酶（iNOS）、干扰素（IFN）-γ、CXCL9 和 IL-12p40 的基因表达增加。Apc Ticam1 小鼠息肉中 c-Myc 的 mRNA 和蛋白表达增加，c-Myc 是炎症相关息肉形成的关键转录因子。在 Apc 小鼠的粪便中检测到产生 dsRNA 的乳杆菌菌株。
这些结果表明 TLR3/TICAM-1 途径通过抑制 c-Myc 表达抑制息肉形成，并支持 Apc 小鼠的长期存活。
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