title: Lack of interleukin-4 receptor alpha chain-dependent signalling promotes azoxymethane-induced colorectal aberrant crypt focus formation in Balb/c mice.
abstract: Interleukin (IL)-4 receptor (IL-4R) alpha 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-4R alpha-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-4R alpha gene on azoxymethane-induced colorectal aberrant crypt focus (ACF) multiplicity and size in Balb/c mice. IL-4R alpha(-/-) 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-4R alpha(-/-) 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-13R alpha2 receptor, leading to induction of transforming growth factor (TGF) beta, which has pro-tumourigenic activity at early stages of intestinal tumourigenesis. We found that mucosal TGFbeta mRNA levels and intestinal epithelial cell TGFbeta immunoreactivity were significantly higher in IL-4R alpha(-/-) mice than in WT animals. In summary, IL-4R alpha-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-4R alpha-dependent signalling during human colorectal carcinogenesis, particularly as antagonism of IL-4R signalling represents a therapeutic strategy for asthma and other allergic diseases.
authors.affiliation: Section of Molecular Gastroenterology, Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds LS9 7TF, UK. mrpcwsk@leeds.ac.uk
authors.forename: C W S
authors.initials: CW
authors.lastname: Ko
authors.forename: R J
authors.initials: RJ
authors.lastname: Cuthbert
authors.forename: N M
authors.initials: NM
authors.lastname: Orsi
authors.forename: D A
authors.initials: DA
authors.lastname: Brooke
authors.forename: S L
authors.initials: SL
authors.lastname: Perry
authors.forename: A F
authors.initials: AF
authors.lastname: Markham
authors.forename: P L
authors.initials: PL
authors.lastname: Coletta
authors.forename: M A
authors.initials: MA
authors.lastname: Hull
mesh_terms: D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018793:Interleukin-13 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D001397:Azoxymethane; D002273:Carcinogens; D018793:Interleukin-13; D015847:Interleukin-4; D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit