Interleukin-4 (IL-4) is a typical pleiotropic T helper 2 (Th2) cytokine. This cytokine is a critical mediator of the Th1/Th2 balance and apoptosis potential and involved in the process of inflammation-mediated carcinogenesis in human organs. IL-4 gene polymorphisms influence IL-4 transcription and have been implicated in cancer risks. However, current published data show conflicts among of them. To assess the relationship between IL-4 polymorphisms and cancer risks, we performed a meta-analysis which includes 14 studies involving 3,562 cancer cases for IL-4 rs2243250 polymorphism, 6 studies involving 2,052 subjects for IL-4 rs2070874 polymorphism, and 5 studies involving 791 subjects for IL-4 intron-3 polymorphism. As for rs2243250 polymorphism, no significant association of cancer risk was found in the overall analysis. When stratified by cancer type, we observed that the IL-4 rs2243250 polymorphism was significantly associated with decreased oral cancer risk and increased renal cell cancer risk (for oral cancer, TT vs. CC: odds ratio (OR) = 0.40, 95 % confidence interval (95 % CI) 0.19-0.84, P heterogeneity = 0.662, P = 0.016; TT/CT vs. CC: OR = 0.45, 95 % CI 0.22-0.94, P heterogeneity = 0.407, P = 0.033; and for renal cell cancer, TT vs. CC: OR = 1.98, 95 % CI 1.06-3.69, P heterogeneity = 0.535, P = 0.031; TT vs.
Cc/ct: OR = 1.43, 95 % CI 1.05-1.95, P heterogeneity = 0.959, P = 0.022). For rs2070874 and intron-3 polymorphisms, no significant association of cancer risk was found in the overall analysis. However, in the subgroup analysis by source of controls and ethnicities, a significant association between cancer risk and rs2070874 polymorphism was found in population-based studies (A allele vs. G allele: OR = 1.18, 95 % CI 1.03-1.35, P heterogeneity = 0.621, P = 0.0172; AA vs.
Ag/gg: OR = 1.23, 95 % CI 1.03-1.47, P heterogeneity = 0.196, P = 0.024) and Caucasian populations (A allele vs. G allele: OR = 1.24, 95 % CI 1.03-1.48, P heterogeneity = 0.925, P = 0.022), but not in Asian populations. Taken together, our results indicated that IL-4 rs2243250 polymorphism was associated with decreased oral cancer risk in both the homozygote contrasts and the dominant genetic model, as well as increased renal cell cancer risk in both the homozygote contrasts and the recessive genetic model. The A allele of rs2070874 polymorphism in the IL-4 gene may be a risk factor for cancer development among Caucasians. Further larger, preferably prospective studies are needed to confirm these results.