title: Interleukin-6 gene ablation in a transgenic mouse model of malignant skin melanoma.
abstract: Interleukin (IL)-6 is a pleiotropic cytokine that has been shown to inhibit the growth of early stage and to promote the proliferation of advanced stage melanoma cells in vitro. In patients with metastasizing melanomas, highly increased IL-6 blood levels correlate with a poor response to chemotherapy and a worse overall prognosis, suggesting that IL-6 promotes melanoma progression in vivo. Here, we analyzed the role of IL-6 in melanoma development and progression in a transgenic mouse model. We bred IL-6-deficient mice with MT-ret transgenic animals predisposed for melanomas. While MT-ret transgenic animals develop severe melanosis of the skin and subcutis and subsequent melanomas at an incidence of 80% during their first year of life, MT-ret mice devoid of IL-6 developed preneoplastic melanosis and consecutive melanomas significantly less frequently (47%; P < 0.05). Moreover, the tumors were significantly smaller in the groups of MT-ret mice lacking one (P < 0.05) or both (P < 0.01) copies of the IL-6 gene. Immunoblot analysis revealed that ret transgene expression was not reduced in the skin of mice lacking IL-6, indicating that the observed decrease of melanoma incidence and of tumor sizes was not because of a down-regulation of transgene expression. Taken together, these results indicate that IL-6 enhances both the development of melanoma precursor lesions and the subsequent growth of the resulting tumors in the MT-ret model of melanoma development.
authors.affiliation: Department of Dermatology, University of Bern, Bern, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: von Felbert
authors.forename: Francisco
authors.initials: F
authors.lastname: Córdoba
authors.forename: Jakob
authors.initials: J
authors.lastname: Weissenberger
authors.forename: Claudio
authors.initials: C
authors.lastname: Vallan
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakashima
authors.forename: Lasse Roger
authors.initials: LR
authors.lastname: Braathen
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
mesh_terms: D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005838:Genotype; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D037102:Lectins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011230:Precancerous Conditions; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D037102:Lectins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D019869:Phosphatidylinositol 3-Kinases
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