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

Oncogene. 1997 Jul 31;15(5):569-77. doi: 10.1038/sj.onc.1201213.


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 melanoma B16-F10.9 by addition of recombinant soluble IL-6 receptor alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / chemistry
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cricetinae
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / drug effects
  • Cyclins / genetics
  • Cyclins / metabolism
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Interferon Regulatory Factor-1
  • Interleukin-6 / pharmacology*
  • Melanoma / drug therapy
  • Melanoma / metabolism
  • Melanoma / pathology*
  • Mice
  • Phosphoproteins / drug effects
  • Phosphoproteins / metabolism
  • Receptors, Interleukin / chemistry
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism*
  • Receptors, Interleukin-6
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • STAT1 Transcription Factor
  • Solubility
  • Trans-Activators / drug effects
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured


  • Antigens, CD
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Interleukin-6
  • Irf1 protein, mouse
  • Phosphoproteins
  • Receptors, Interleukin
  • Receptors, Interleukin-6
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Stat1 protein, mouse
  • Trans-Activators