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Epidermal growth factor is a critical regulator of the cytokine IL-33 in intestinal epithelial cells

Epidermal growth factor is a critical regulator of the cytokine IL-33 in intestinal epithelial cells

Authors :
Noriyuki Kaji
Kazuhide Horiguchi
Hiroshi Ozaki
Shoma Mikawa
Md. Shafiqul Islam
Satoshi Iino
Masatoshi Hori
Source :
British Journal of Pharmacology. 173:2532-2542
Publication Year :
2016
Publisher :
Wiley, 2016.

Abstract

Background and purpose IL-33 is a novel cytokine that is believed to be involved in inflammation and carcinogenesis. However, its source, its production and its secretion process remain unclear. Recently, we have reported that IL-33 is up-regulated in dextran sulfate sodium (DSS) colitis in mice. Experimental approach Production of IL-33 from intestinal tissue was studied in a murine cancer model induced by azoxymethane (AOM) and DSS in vivo and in cultures of IEC-6 epithelial cells. Cytokine levels were measured by real time PCR, immunohistochemistry and elisa. Key results Mice with AOM/DSS-induced colitis expressed all the characteristic symptoms of colon cancer pathology. Immunohistochemical analysis demonstrated epithelial cell-derived IL-33 in colon tissues from mice with AOM/DSS colitis. Real time PCR and quantitative PCR analysis revealed that AOM/DSS colitis tissues expressed up-regulated IL-1β, IL-33, TGF-β, and EGF mRNA. Gefitinib, an EGFR inhibitor, inhibited IL-33 mRNA expression in AOM/DSS colitis mice. The pathophysiological role of IL-33 in the rat intestinal epithelial cell line (IEC-6 cells) was then investigated. We found that EGF, but not TGF-β1 or PDGF, greatly enhanced mRNA expression of IL-33 and its receptor ST2. In accordance with the gene expression and immunohistochemical analysis of IL-33 levels, elisa-based analysis of cytoplasmic and nuclear extracts showed increased IL-33 protein levels in IEC-6 cells after treatment with EGF. Conclusions and implications Our results suggest that EGF is a key growth factor that increased IL-33 production and ST2 receptor expression during intestinal inflammation and carcinogenesis. The EGF/IL-33/ST2 axis represents a novel therapeutic target in colon cancer.

Details

ISSN :
00071188
Volume :
173
Database :
OpenAIRE
Journal :
British Journal of Pharmacology
Accession number :
edsair.doi...........8ab4d23ba8d724066a66508f92dc541c
Full Text :
https://doi.org/10.1111/bph.13535