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Endogenous Interleukin-18 Modulates Immune Escape of Murine Melanoma Cells by Regulating the Expression of Fas Ligand and Reactive Oxygen Intermediates¹

Laboratory of Immunology, Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon 305-333, Republic of Korea [D. C., H. S., Y. M. K., D. Y., K. H. P., I. C.]; Department of Dermatology, Kangdong Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 134-701, Republic of Korea [D. H.]; Department of Anatomy, Inje University College of Medicine, Pusan 614-735, Republic of Korea [D. Y. H.]; Department of Dermatology, Holy Family Hospital, College of Medicine, The Catholic University of Korea, Pucheon 422-717, Republic of Korea [H. P.]; Department of Anatomy, Seoul National University, Seoul 110-799, Republic of Korea [W. J. L.]; Department of Biochemistry, College of Natural Sciences, Chungnam National University, Taejon 305-764, Republic of Korea [H. S., Y. S. K.]; Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan [M. K.]; Department of Microbiology and Immunology, Finch University of Health Science/The Chicago Medical School, Illinois 60064, [Y. B. K.]

It has been known that melanoma cells can suppress the immune system by the Fas ligand. The present study investigated whether interleukin (IL)-18, which can enhance Fas ligand expression, is produced by B16F10 melanoma cells and is involved in immune escape of tumor cells. Immunohistology, reverse transcription-PCR, intracellular fluorescence-activated cell-sorting analysis, and immunoblotting demonstrated that melanoma cells express IL-18. C57BL/6 splenocytes cultured with culture supernatants of B16F10 melanoma cells enhanced IFN- production, which was blocked by anti-IL-18 antibody, indicating that IL-18 in the culture supernatants is functional. In addition to IL-18, the IL-18 receptor was also detected in B16F10 melanoma cells, suggesting a role of this cytokine in regulating the functions of B16F10 melanoma cells. The functional effect of IL-18 on B16F10 melanoma cells was shown by reduction of Fas ligand expression in cells treated with anti-IL-18 antibody or transfected with IL-18 antisense cDNA. In addition, the same treatments decreased intracellular reactive oxygen intermediate levels in B16F10 melanoma cells, indicating that IL-18 regulates reactive oxygen intermediate production, which is involved in Fas ligand expression. Furthermore, transfection of IL-18 antisense cDNA into melanoma cells increased the susceptibility of tumor cells to natural killer cells in vitro. When IL-18 antisense transfectants were implanted into syngeneic mice, severe reduction of tumor cell growth was observed with concomitant infiltrated natural killer cells in the tumor area. Taken together, these results demonstrate that IL-18 has a critical role as a survival factor for B16F10 melanoma cells.

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