Unmasking by soluble IL-6 receptor of IL-6 effect on metastatic melanoma: growth inhibition and differentiation of B16-F10.9 tumor cells

Abstract

Interleukin-6 (IL-6) inhibits the growth of melanocytes and of early stage melanoma cells, but not that of advanced melanoma cells. The in vitro IL-6 response can be restored in the highly metastatic melamona B16-F10.9 by addition of recombinant soluble IL-6 receptor α-chain (sIL-6R). The F10.9 cells then undergo irreversible growth-arrest and show increased adherence with changes from epithelioid to spindleoid morphology. The sIL-6R is required for IL-6 to induce a sustained activation of the various Stat transcription factors which bind to specific IL-6 inducible enhancers. The sIL-6R and IL-6 combination causes an increase in the level of the anti-oncogenic transcription factor IRF-1 protein and DNA-binding, which remain elevated for 24 h. The promoter activity of the anti-oncogenic p21/Waf-1/Cip-1 gene is induced and accumulation of the p21 protein is observed. These results illustrate the potent agonist activity of sIL-6R on molecular pathways which could mediate the growth-arrest and differentiation of the metastatic melanoma cells. Previously observed antimetastatic effects of IL-6 therapy in mice bearing F10.9 tumors may be at least partly due to direct growth inhibition and differentiation elicited by sIL-6R present in biological fluids.