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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Expression of IRAK‑3 is associated with colitis‑associated tumorigenesis in mice
Dingting Xu1, Hanyun Zhang1, Xiaoying Wang1
1Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China.
Abstract:
Interleukin‑1 receptor‑associated kinase‑3 (IRAK‑3) is a negative regulator in Toll‑like receptor (TLR) pathways. The present study investigated the importance of IRAK‑3 in a mouse model of chemically‑induced colitis‑associated tumorigenesis. The colitis‑associated tumorigenesis was induced in ICR mice by the administration of 1,2‑dimethyl hydrazine (DMH) and dextran sodium sulfate (DSS), termed the DMH + DSS group. In the DSS group, mice were administered with DSS; in the DMH group, mice were injected with DMH; in the control group, mice were injected with physiological saline. The clinical signs were examined for 20 weeks; tissue samples were analyzed at week 4, 9, 13 and 20. At week 20, the levels of IRAK‑3 were analyzed using immunohistochemistry, western blot analysis, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis, and methylation‑specific PCR. At week 20, the DMH + DSS group mice exhibited a decrease in total body weight and had developed canalicular adenoma or adenocarcinoma. The mice in the DSS group and DMH group presented with significant colitis at week 20. The mice with colitis‑associated tumorigenesis were found to have decreased levels of IRAK‑3, compared with the mice in the other groups, as evidenced by the results of the immunohistochemistry (P=0.002), RT‑qPCR analysis (P<0.001) and western blot analysis (P<0.001). IRAK‑3 methylation was observed in all experimental groups. Taken together, DMH + DSS induction in colitis led to increased inflammation and risk of tumorigenesis. IRAK‑3 methylation may be a predictive factor in the transition from colitis to cancer.
Insights
Interleukin-1 receptor-associated kinase-3 (IRAK-3) levels decrease during colitis-associated tumorigenesis. IRAK-3 methylation may predict cancer development from colitis.
Area of Science:
- Immunology
- Gastroenterology
- Oncology
Background:
- Toll-like receptor (TLR) pathways regulate inflammation.
- Interleukin-1 receptor-associated kinase-3 (IRAK-3) acts as a negative regulator in TLR pathways.
- The role of IRAK-3 in colitis-associated tumorigenesis requires further investigation.
Purpose of the Study:
- To investigate the role of IRAK-3 in a mouse model of chemically-induced colitis-associated tumorigenesis.
- To analyze IRAK-3 expression and methylation in the context of inflammation and tumor development.
Main Methods:
- Colitis-associated tumorigenesis was induced in ICR mice using 1,2-dimethyl hydrazine (DMH) and dextran sodium sulfate (DSS).
- Mice were divided into DMH + DSS, DSS, DMH, and control groups.
- Clinical signs were monitored for 20 weeks, with tissue analysis at weeks 4, 9, 13, and 20.
- IRAK-3 levels were assessed using immunohistochemistry, western blot, and RT-qPCR.
- IRAK-3 methylation was analyzed using methylation-specific PCR.
Main Results:
- DMH + DSS group mice showed decreased body weight and developed tumors (adenoma or adenocarcinoma).
- DSS and DMH groups exhibited significant colitis.
- Mice with colitis-associated tumorigenesis had significantly decreased IRAK-3 levels compared to other groups (P<0.001 for RT-qPCR and western blot, P=0.002 for immunohistochemistry).
- IRAK-3 methylation was detected in all experimental groups.
Conclusions:
- DMH + DSS induction promotes inflammation and increases the risk of tumorigenesis in colitis.
- Decreased IRAK-3 levels are associated with colitis-associated tumorigenesis.
- IRAK-3 methylation may serve as a predictive biomarker for the progression from colitis to cancer.
