Introduction We have previously demonstrated that genetic deletion of interleukin-4 receptor α (IL-4Rα) in BALB/c mice leads to an increase in azoxymethane (AOM)-induced aberrant crypt focus (ACF) multiplicity. Therefore, we tested the hypothesis that absence of IL-4Rα signalling also promotes adenoma growth and development in AOM-induced colorectal carcinogenesis.

Methods BALB/c IL-4Rα^−/− and IL-4Rα^+/+ mice (wild-type) were injected twice with 10 mg/kg AOM, for methylene blue stained ACF counting at 6 weeks or with 6 injections, for tumour phenotype analysis at 32 weeks. Lymphocyte (CD4+, CD8+, CD25+ and FoxP3+) and myeloid-derived suppressor cell (CD11b+, GR-1+; MDSC) splenocyte populations were analysed by flow cytometry. Blood cell populations were measured using a Vet abc blood analyser.

Results Loss of IL-4Rα signalling was associated with an increase in ACF multiplicity (median 8.5, IQR 7.25–12, n=8) compared with wild-type mice (median 3, IQR 1–3.5, n=9) (p=0.007 Mann Whitney U-test) confirming our previous observation of an anti-neoplastic role of IL-4Rα signalling in AOM-induced tumour initiation. At 32 weeks, the number of ACFs detected in AOM-treated IL-4Rα^−/− mice (median 8, IQR 6–10, n=16) remained higher than wild-type mice (median 3, IQR 2–7, n=19) (p=0.0017). However, loss of IL-4Rα signalling did not promote macroscopic tumour development (incidence=25%, mean number per tumour-bearing mouse=2 tumours/colon) compared with wild-type animals (incidence=26.3%, mean=1.4 tumours/colon). All tumours apart from one case of mild dysplasia were adenomas that exhibited severe dysplasia. Adenomas were only detected in female mice. Adenomas were smaller in IL-4Rα^−/− mice (mean (SD) 2.3 (1.0) mm) compared with wild-type tumours (3.7 (1.3) mm, p=0.06). There was no significant difference in routine haematological parameters between IL-4Rα^−/− mice and wild-type animals at both time points. However, there was an increase in CD4+ and FoxP3+ splenocytes (but not MDSCs) in IL-4Rα^−/− mice compared with wild-type animals at 32 weeks after AOM treatment.

Conclusion IL-4Rα signalling has stage-specific roles during AOM-induced colorectal carcinogenesis in BALB/c mice. Although absence of IL-4Rα signalling promotes initiation, it does not appear to be protective for progression to adenoma and may even have a pro-tumorigenic role during adenoma growth. Smaller tumour size in IL-4Rα^−/− mice is associated with an increase in splenic regulatory T cells.