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



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.



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.



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.
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
M S
MS
Islam
Department of Anatomy, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
K
K
Horiguchi
Department of Anatomy, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
S
S
Iino
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
N
N
Kaji
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
S
S
Mikawa
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
M
M
Hori
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
H
H
Ozaki
D000818:Animals; D001397:Azoxymethane / Q000008:administration & dosage; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000008:administration & dosage; D066255:EGF Family of Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000378:metabolism; D000067596:Interleukin-33 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats
D066255:EGF Family of Proteins; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D016264:Dextran Sulfate; D001397:Azoxymethane