Melanoma-Derived Interleukin 6 Inhibits In Vivo Melanoma Growth

Abstract

Malignant melanomas are capable of producing a wide range of cytokines with multiple biologic functions, including interleukin 6 (IL-6). We have observed an inverse relationship between IL-6 production of three B16-derived murine melanoma cell lines (NP133, HFH18, and HFH(M)) and the tumorigenicity of these melanoma cells in syngeneic mice. To further test the effect of IL-6 on melanoma growth, a non-IL-6-producing murine B16-derived melanoma cell line (HFH18) was transfected with a murine IL-6 expression vector, resulting in stable transfectants (HFH18/IL-6(+)) that expressed significant amounts of IL-6 mRNA and secreted high levels of bioactive IL-6. Syngeneic C57BL/6 mice inoculated subcutaneously with HFH18/IL-6(+) cells developed tumors that reached a final mean diameter of less than half the size of tumors that developed in mice inoculated with either HFH18 parental or HFH18 cells transfected with the IL-6 cDNA in the non-coding 3'-5' orientation (HFH18/IL-6(-) cells). In addition, mice bearing IL-6-producing HFH18/IL-6(+) tumors survived twice as long as mice bearing HFH18 parental or HFH18/IL-6(-) tumors. The specificity of melanoma growth inhibition by IL-6 was confirmed by the reversal of the slow-growing phenotype of HFH18/IL-6(+) cells by local peritumoral administration of neutralizing alpha-murine IL-6 antibody. IL-6-producing melanoma cells exerted a growth-inhibitory effect on distant parental tumors in a dose-dependent manner. The growth of HFH18/IL-6(+) melanomas was also decreased in nude mice, suggesting that melanoma-derived IL-6 may mediate this anti-tumor effect independently of a normal host B- and T-cell immune response. Thus, melanoma-derived IL-6 exerts a significant inhibitory effect on cutaneous melanoma growth and progression. These results indicate that melanoma cytokines may have a profound effect on tumor pathogenesis.