IL-13 but not IL-4 signaling via IL-4Rα protects mice from papilloma formation during DMBA/TPA two-step skin carcinogenesis

Cancer Med. 2013 Dec;2(6):815-25. doi: 10.1002/cam4.145. Epub 2013 Oct 22.


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.

Keywords: Carcinogenesis; DMBA TPA; IL-13; IL-4 receptor alpha; TH2; papilloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Carcinogens
  • Cytokines / blood
  • Cytokines / genetics*
  • Interleukin-13 Receptor alpha1 Subunit / genetics
  • Methylcholanthrene
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Papilloma / blood
  • Papilloma / chemically induced
  • Papilloma / genetics*
  • Receptors, Cell Surface / genetics*
  • Skin Neoplasms / blood
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics*
  • Tetradecanoylphorbol Acetate


  • Carcinogens
  • Cytokines
  • Il13ra1 protein, mouse
  • Il4ra protein, mouse
  • Interleukin-13 Receptor alpha1 Subunit
  • Receptors, Cell Surface
  • Methylcholanthrene
  • 9,10-Dimethyl-1,2-benzanthracene
  • Tetradecanoylphorbol Acetate