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An antitumorigenic role for the IL-33 receptor, ST2L, in colon cancer
Charlotte O'Donnell1, Amr Mahmoud2, Jonathan Keane1,3
1Department of Medicine, University College Cork, Cork, Ireland.
Background:
Despite the importance of inflammation in cancer, the role of the cytokine IL-33, and its receptor ST2, in colon cancer is unclear. The aim of this study was to investigate the role of IL-33, and its receptor isoforms (ST2 and ST2L), in colon cancer.
Methods:
Serum levels of IL-33 and sST2 were determined with ELISA. ST2 and IL-33 expression was detected with quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. ST2 expression in CT26 cells was stably suppressed using ST2-specific shRNA. Cytokine and chemokine gene expression was detected with qRT-PCR.
Results:
Human colon tumours showed lower expression of ST2L as compared with adjacent non-tumour tissue (P<0.01). Moreover, the higher the tumour grade, the lower the expression of ST2L (P=0.026). Colon cancer cells expressed ST2 and IL-33 in vitro. Functional analyses showed that stimulation of tumour cells with IL-33 induced the expression of chemokine (C-C motif) ligand 2 (CCL2). Knockdown of ST2 in murine colon cancer cells resulted in enhanced tumour growth (P<0.05) in BALB/c mice in vivo. This was associated with a decrease in macrophage infiltration, with IL-33-induced macrophage recruitment reduced by antagonising CCL2 in vitro.
Conclusion:
The IL-33/ST2 signalling axis may have a protective role in colon carcinogenesis.
Insights
The IL-33/ST2 signaling pathway may protect against colon cancer. Lower ST2L expression correlates with higher tumor grade, and blocking ST2 accelerates tumor growth by reducing macrophage infiltration.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Inflammation plays a critical role in cancer development.
- The specific role of the cytokine IL-33 and its receptor ST2 in colon cancer remains largely unknown.
- Investigating IL-33 and its receptor isoforms (ST2 and ST2L) is crucial for understanding colon carcinogenesis.
Purpose of the Study:
- To elucidate the role of the IL-33/ST2 signaling axis in colon cancer.
- To analyze the expression of IL-33, ST2, and ST2L in human colon tumors and cell lines.
- To determine the functional impact of IL-33/ST2 signaling on colon cancer cell behavior and tumor growth.
Main Methods:
- Quantification of serum IL-33 and soluble ST2 (sST2) using ELISA.
- Assessment of ST2 and IL-33 gene and protein expression via qRT-PCR, western blotting, and immunohistochemistry.
- In vitro and in vivo experiments involving ST2 knockdown in colon cancer cells and analysis of tumor growth and immune cell infiltration.
Main Results:
- Human colon tumors exhibited significantly lower ST2L expression compared to adjacent non-tumor tissues, with decreased expression correlating with higher tumor grade.
- Colon cancer cells expressed both ST2 and IL-33 in vitro.
- IL-33 stimulation induced chemokine (C-C motif) ligand 2 (CCL2) expression in tumor cells. ST2 knockdown in murine colon cancer cells led to accelerated tumor growth, reduced macrophage infiltration, and impaired IL-33-induced macrophage recruitment.
Conclusions:
- The IL-33/ST2 signaling axis appears to possess a protective function in colon carcinogenesis.
- Reduced ST2L expression may serve as a biomarker for advanced colon cancer.
- Targeting the IL-33/ST2 pathway could offer a novel therapeutic strategy for colon cancer.
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