Abstract
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-1alpha-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-1alpha 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.
Highlights
Interleukin (IL)-1 is a multi-functional cytokine and regulates cell growth either positively or negatively
IL-1 Treatment Caused Growth Inhibition, Decrease in DNA Synthesis, and ornithine decarboxylase (ODC) Activity Down-regulation of C2-1 Cells— Treatment with rhIL-1␣ for 3 days dose-dependently inhibited the growth of C2-1 cells (Fig. 1A) in a manner similar to those of other IL-1-sensitive A375 melanoma cells [8, 34, 40]
As reported previously that ODC activity down-regulation was important for IL-1-induced inhibition of growth and DNA synthesis in human melanoma cells [34, 40], we subsequently investigated the effect of IL-1 on the ODC activity of C2-1 cells
Summary
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. 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. The first intracellular alteration probably associated with the anti-proliferative effect of IL-1 in A375 human melanoma cells was reported to be down-regulation of ornithine decarboxylase (ODC) activity [34]. We transfected A375–5 cells, a twin subclone of A375– 6 expressing no detectable IL-1R [33], with a human
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