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(American Journal of Pathology. 2005;166:831-841.)
© 2005 American Society for Investigative Pathology

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Verena von Felbert*, Francisco Córdoba{dagger}, Jakob Weissenberger{dagger}, Claudio Vallan{ddagger}, Masashi Kato§, Izumi Nakashima, Lasse Roger Braathen* and Joachim Weis{dagger}||

From the Department of Dermatology,* Inselspital, the Division of Neuropathology,{dagger} Institute of Pathology, and the Department of Clinical Research,{ddagger} University of Bern, Bern, Switzerland; the Department of Environmental and Preventive Medicine,§ Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan; the Department of Immunology, Nagoya University, Nagoya, Japan; and the Institute of Neuropathology,|| Technical University (RWTH), Aachen, Germany

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.




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