Lack of interleukin-4 receptor α chain-dependent signalling promotes azoxymethane-induced colorectal aberrant crypt focus formation in Balb/c mice

• Published in: The Journal of pathology Vol. 214; no. 5; pp. 603 - 609
• Main Authors: Ko, CWS, Cuthbert, RJ, Orsi, NM, Brooke, DA, Perry, SL, Markham, AF, Coletta, PL, Hull, MA
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-04-2008; Wiley
• Subjects: aberrant crypt focus; Animals; Azoxymethane; Biological and medical sciences; Carcinogens; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - pathology; colorectal cancer; Colorectal Neoplasms - chemically induced; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Disease Models, Animal; Female; Gastroenterology. Liver. Pancreas. Abdomen; Interleukin-13 - blood; Interleukin-4 - blood; interleukin-4 receptor; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; mouse models; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Precancerous Conditions - chemically induced; Precancerous Conditions - immunology; Precancerous Conditions - pathology; Receptors, Cell Surface - deficiency; Receptors, Cell Surface - immunology; Signal Transduction - immunology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transforming Growth Factor beta1 - metabolism; transforming growth factor β; Tumor Necrosis Factor-alpha - blood; Tumors; mouse models; Animal model; Rectal disease; Transforming growth factor β; Colorectal cancer; Signal transduction; interleukin-4 receptor; Intestinal disease; Anomaly; Interleukin 4 receptor; Colon; Digestive system; Gut; Rodentia; Malignant tumor; Colonic disease; Carcinogen; Vertebrata; Anatomic pathology; Mammalia; Mouse; Animal; Rectum; Digestive diseases; Alpha-Peptide chain; aberrant crypt focus; Cancer
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2316

Interleukin (IL)-4 receptor (IL-4R) α chain-dependent signalling by IL-4 and IL-13 promotes tumour growth and metastasis in mouse models of colorectal cancer. However, the role of IL-4Rα-dependent signalling during the early, pre-malignant stages of colorectal carcinogenesis has not been investigated. Therefore, we investigated the effect of deletion of the IL-4Rα gene on azoxymethane-induced colorectal aberrant crypt focus (ACF) multiplicity and size in Balb/c mice. IL-4Rα⁻/⁻ mice developed significantly more ACFs [median 8, inter-quartile range (IQR) 4-11.5; n = 9] than wild-type (WT) animals (median 4, IQR 1-6; n = 9; p = 0.04, Mann-Whitney U-test). There were significantly higher levels of IL-4 in serum from azoxymethane- and sham-treated IL-4Rα⁻/⁻ mice than WT animals, but no difference in serum IL-13 levels. In the absence of functional IL-4Rs, IL-13 can also signal via the IL-13Rα2 receptor, leading to induction of transforming growth factor (TGF) β, which has pro-tumourigenic activity at early stages of intestinal tumourigenesis. We found that mucosal TGFβ mRNA levels and intestinal epithelial cell TGFβ immunoreactivity were significantly higher in IL-4Rα⁻/⁻ mice than inWT animals. In summary, IL-4Rα-dependent signalling has a protective, anti-neoplastic role during the post-initiation phase of azoxymethane-induced colorectal carcinogenesis in Balb/c mice. Our data should prompt thorough investigation of the role of IL-4Rα-dependent signalling during human colorectal carcinogenesis, particularly as antagonism of IL-4R signalling represents a therapeutic strategy for asthma and other allergic diseases. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.