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Volume 272, Number 6, Issue of February 7, 1997 pp. 3376-3383
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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Interleukin-1-induced Growth Inhibition of Human Melanoma Cells
INTERLEUKIN-1-INDUCED ANTIZYME EXPRESSION IS RESPONSIBLE FOR ORNITHINE DECARBOXYLASE ACTIVITY DOWN-REGULATION

(Received for publication, October 11, 1995, and in revised form, September 9, 1996)

From the Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya 467, Japan

Interleukin (IL)-1 is a multi-functional cytokine and regulates cell growth either positively or negatively. Previous studies have shown that IL-1-induced ornithine decarboxylase (ODC) activity down-regulation is involved in the anti-proliferative effect of IL-1 on human A375 melanoma cells. In this study, we examined the IL-1-induced molecular events resulting in ODC activity down-regulation in C2-1, a A375 cell line stably transfected with human type I IL-1 receptor. Recombinant human (rh) IL-1 inhibited the growth and down-regulated the ODC activity of C2-1 cells in a dose-dependent manner. Kinetics studies showed that both the DNA synthesis and ODC activity of C2-1 cells progressively decreased from 12 h after IL-1 addition. Northern hybridization showed that IL-1 had no influence on ODC mRNA level. However, rhIL-1 induced both a decrease of ODC protein and an ODC-inhibiting activity in IL-1-treated C2-1 cells. IL-1 specifically up-modulated the mRNA level of antizyme, a protein essential for ODC regulation, but had little effect on its stability. IL-1-induced antizyme up-modulation preceded IL-1-induced down-regulation of ODC protein, ODC activity, and DNA synthesis in C2-1 cells. Run-on transcription analysis confirmed that the increased antizyme mRNA expression was due to elevated antizyme gene transcription. Furthermore, the action of IL-1 to inhibit the ODC activity and growth of C2-1 cells was blocked by expressing the antisense RNA of human antizyme in C2-1 cells. These results suggest that IL-1-induced antizyme expression is responsible for IL-1-induced ODC activity down-regulation in human melanoma cells.

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