title: IL-13 but not IL-4 signaling via IL-4Rα protects mice from papilloma formation during DMBA/TPA two-step skin carcinogenesis.
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.
authors.affiliation: Institute of Immunology, Charité Campus Buch, 13125, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.forename: David
authors.initials: D
authors.lastname: Quarcoo
authors.forename: Anna A
authors.initials: AA
authors.lastname: Chashchina
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Bozrova
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Qin
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Kammertoens
authors.forename: Marina S
authors.initials: MS
authors.lastname: Drutskaya
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000235:genetics; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010212:Papilloma / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012878:Skin Neoplasms / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; D002273:Carcinogens; D016207:Cytokines; D053661:Interleukin-13 Receptor alpha1 Subunit; D008748:Methylcholanthrene; D011956:Receptors, Cell Surface; D013755:Tetradecanoylphorbol Acetate; C508183:Il13ra1 protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
keywords: Carcinogenesis; DMBA TPA; IL-13; IL-4 receptor alpha; TH2; papilloma