Abstract
Interleukin 4 (IL-4) was shown to be tumor-promoting in full carcinogenesis studies using 3-methylcholanthrene (MCA). Because heretofore the role of IL-4 in DMBA/TPA (9,10-dimethyl-1,2-benz-anthracene/12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis was not studied, we performed such experiments using either IL-4−/− or IL-4Rα−/− mice. We found that IL-4Rα−/− but not IL-4−/− mice have enhanced papilloma formation, suggesting that IL-13 may be involved. Indeed, IL-13−/− mice developed more papillomas after exposure to DMBA/TPA than their heterozygous IL-13-competent littermate controls. However, when tested in a full carcinogenesis experiment, exposure of mice to 25 μg of MCA, both IL-13−/− and IL-13+/− mice led to the same incidence of tumors. While IL-4 enhances MCA carcinogenesis, it does not play a measurable role in our DMBA/TPA carcinogenesis experiments. Conversely, IL-13 does not affect MCA carcinogenesis but protects mice from DMBA/TPA carcinogenesis. One possible explanation is that IL-4 and IL-13, although they share a common IL-4Rα chain, regulate signaling in target cells differently by employing distinct JAK/STAT-mediated signaling pathways downstream of IL-13 or IL-4 receptor complexes, resulting in different inflammatory transcriptional programs. Taken together, our results indicate that the course of DMBA/TPA- and MCA-induced carcinogenesis is affected differently by IL-4 versus IL-13-mediated inflammatory cascades.
Highlights
The first experimental carcinogenesis protocols were established a century ago by Yamagiva and Ichikawa [1], who painted coal tar on rabbit ears
Because Interleukin 4 (IL-4) and IL-4Ra were locally upregulated upon TPA treatment, we addressed the role of IL-4 and the IL-4Ra chain in two-step carcinogenesis
It still remains unclear how exactly the inflammatory responses orchestrate tumor development in this carcinogenesis protocol. It was not known whether IL-4 or IL-13 affect DMBA/ TPA carcinogenesis. We addressed this question and found that IL-4Ra and IL-13 but not IL-4 affects two-step skin carcinogenesis
Summary
The first experimental carcinogenesis protocols were established a century ago by Yamagiva and Ichikawa [1], who painted coal tar on rabbit ears. Various factors affecting chemical skin carcinogenesis have been described, such as wounding [5], diet [6, 7], composition of skin surface lipids [8], glucocorticoid levels [9], and genetic background [4, 10] Because tumor promoters, such as TPA, cause a local inflammatory response, it is not surprising that immune cells and inflammatory processes can influence skin carcinogenesis. While in the FVB (an inbred strain of mice) genetic background CD8+ T cells are thought to be more important in tumor promotion [13], in the C3H background, CD4+ T cells are thought to be tumor-promoting while CD8+ T cells are considered to be protective [14] Cytokines such as interferon c (IFN-c) and interleukin 12 (IL-12) have both been shown to promote tumor development [15, 16], and systemic administration of recombinant mouse IFN-c resulted in increased numbers of papillomas [17]. We addressed the role of IL-4 and IL-13 in two-step skin carcinogenesis in this study
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