title: IL-1 alpha, innate immunity, and skin carcinogenesis: the effect of constitutive expression of IL-1 alpha in epidermis on chemical carcinogenesis.
abstract: Tumor promoters such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are proinflammatory agents, and their mechanism of action in epithelial carcinogenesis has been linked to the release of IL-1 alpha and the induction of chronic inflammation in skin. To test the role of IL-1 alpha and inflammation in models of cutaneous carcinogenesis, we used our previously described FVB/N transgenic mice overexpressing 17-kDa IL-1 alpha in the epidermis under the keratin 14 (K14) promoter. Strikingly, the K14/IL-1 alpha mice were completely resistant to papilloma and carcinoma formation induced by a two-stage DMBA/TPA protocol, while littermate controls developed both tumor types. K14/IL-1 alpha mice crossed with the highly sensitive TG.AC mice, constitutively expressing mutant Ha-Ras, also failed to develop papillomas or carcinomas. When the K14/IL-1 alpha transgene was bred onto a recombinase-activating gene-2-deficient background, the resistance persisted, indicating that innate, but not acquired, mechanisms may be involved in the resistance to the initiation/promotion model. As an alternative approach, a complete carcinogenesis protocol using repetitive application of DMBA alone was applied. Surprisingly, although the IL-1 alpha mice still did not develop papillomas, they did develop carcinomas de novo at an accelerated rate compared with controls. We conclude that constitutive IL-1 alpha expression rendered FVB mice completely resistant to carcinomas that required evolution from prior papillomas, but facilitated carcinomas that did not evolve from papillomas, as in the complete carcinogenesis protocol. Thus, the role of IL-1 alpha and, by extension that of other proinflammatory factors, in epithelial carcinogenesis are more complex than previously appreciated. These mice may provide a mechanism to investigate the validity of these models of human skin tumorigenesis.
authors.affiliation: Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Jo-Ellen
authors.initials: JE
authors.lastname: Murphy
authors.forename: Romeo E
authors.initials: RE
authors.lastname: Morales
authors.forename: Jordan
authors.initials: J
authors.lastname: Scott
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kupper
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004817:Epidermis / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D053547:Keratin-14; D007633:Keratins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D019076:Transgenes / Q000276:immunology
chemical_list: D002273:Carcinogens; D004268:DNA-Binding Proteins; D007375:Interleukin-1; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; D013755:Tetradecanoylphorbol Acetate