Reduced type II interleukin-4 receptor signalling drives initiation, but not progression, of colorectal carcinogenesis: evidence from transgenic mouse models and human casecontrol epidemiological observations

We investigated the role of interleukin (IL)-4 receptor (IL-4R) signalling during mouse carcinogen-induced colorectal carcinogenesis and in a casecontrol genetic epidemiological study of IL-4R single nucleotide polymorphisms (SNPs). Azoxymethane-induced aberrant crypt focus (ACF; 6 weeks) and tumours (32 weeks) were analysed in wild-type (WT) BALB/c mice, as well as in IL-4R(/), IL-13(/) and double-knockout (DKO) animals. Colorectal cancer (CRC) cases (1502) and controls (584) were genotyped for six coding IL-4R SNPs. The association with CRC risk and CRC-specific mortality was analysed by logistic regression. Lack of IL-4R expression was associated with increased ACFs [median 8.5 ACFs per mouse (IL-4R(/)) versus 3 (WT); P 0.007], but no difference in the number of colorectal tumours [mean 1.4 per mouse (IL-4R(/)) versus 2 (WT)], which were smaller and demonstrated reduced nuclear/cytoplasmic -catenin translocation compared with WT tumours. Tumour-bearing IL-4R(/) mice had fewer CD11b/Gr1 myeloid-derived suppressor splenocytes than WT animals. IL-13(/) mice developed a similar number of ACFs to IL-4R(/) and DKO mice. There was a significant increase in CRC risk associated with the functional SNP Q576R [odds ratio 1.54 (95% confidence interval 0.942.54), P-trend 0.03 for the minor G allele]. There was no effect of IL-4R genotype on either CRC-specific or all-cause mortality. These combined pre-clinical and human data together demonstrate that reduced IL-4R signalling has stage-specific effects on colorectal carcinogenesis (increased CRC initiation and risk but reduced tumour progression and no effect on CRC mortality). These results should prompt evaluation of the effect of pharmacological manipulation of IL-4R signalling on future CRC risk and for CRC treatment.