[HTML][HTML] An antitumorigenic role for the IL-33 receptor, ST2L, in colon cancer

C O'donnell, A Mahmoud, J Keane, C Murphy… - British journal of …, 2016 - nature.com
C O'donnell, A Mahmoud, J Keane, C Murphy, D White, S Carey, M O'riordain, MW Bennett
British journal of cancer, 2016nature.com
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 …
Abstract
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.
Main
Interleukin (IL)-33 is a member of the IL-1 superfamily, identified in 2005 as the ligand for the receptor ST2. Differential mRNA processing within the ST2 gene generates three isoforms of ST2 proteins: a transmembrane receptor (ST2L), a secreted soluble form (sST2) and a variant form (ST2V; Garlanda et al, 2013). Initial studies on the role of ST2L in the immune system demonstrated that ST2L is expressed on many immune cells, including macrophages, mast cells, innate lymphoid cells and T cells, in particular Th2 cells (Lu et al, 2015). Moreover, signalling through ST2L promotes the development of Th2 cells, and the induction of the Th2 cytokines IL-4, IL-5 and IL-13. sST2 is thought to act as a decoy receptor, binding to IL-33, whereas the function of ST2V is unclear. More recently, research on IL-33/ST2 has predominantly focused on their role in chronic disorders, with IL-33 and ST2 involved a role in the pathogenesis of several human inflammatory diseases including inflammatory bowel disease (Pastorelli et al, 2010; Sedhom et al, 2013).
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