RRC ID 64531
Author Islam MS, Horiguchi K, Iino S, Kaji N, Mikawa S, Hori M, Ozaki H.
Title Epidermal growth factor is a critical regulator of the cytokine IL-33 in intestinal epithelial cells.
Journal Br J Pharmacol
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.
Volume 173(16)
Pages 2532-42
Published 2016-8-1
DOI 10.1111/bph.13535
PMID 27300306
PMC PMC4959955
MeSH Animals Azoxymethane / administration & dosage Cells, Cultured Colitis / chemically induced Colitis / metabolism* Colitis / pathology Dextran Sulfate / administration & dosage EGF Family of Proteins / metabolism* Epithelial Cells / drug effects Epithelial Cells / metabolism* Epithelial Cells / pathology Interleukin-1 Receptor-Like 1 Protein / metabolism Interleukin-33 / genetics Interleukin-33 / metabolism* Intestinal Mucosa / metabolism Intestines / drug effects Intestines / pathology* Male Mice Mice, Inbred C57BL Rats
IF 7.73
Human and Animal Cells IEC 6(RCB0993)