The IL-6/sIL-6R treatment of a malignant melanoma cell line enhances susceptibility to TNF-alpha-induced apoptosis.

Abstract

Melanoma is an intractable tumor that has shown very impressive and promising response to local administration of high dose recombinant TNF-alpha in combination with IFN-gamma in clinical studies. In this study, we investigated the effect of IL-6/sIL-6R on TNF-alpha-resistant B16/F10.9 melanoma cells. A low dose of TNF-alpha or IL-6/sIL-6R had minimal affect on the cell growth. However, the highly active fusion protein of sIL-6R and IL-6 (IL6RIL6), covalently linked by a flexible peptide, sensitized TNF-alpha-resistant F10.9 melanoma cells to TNF-alpha-induced apoptosis. Stimulation of the cells with IL6RIL6 plus TNF-alpha resulted in both the activation of caspase-3 and the reduction of bcl-2 expression. Flow cytometry analysis showed that IL6RIL6-upregulated TNF-R55 and TNF-R75 expression, suggesting an increase in TNF-alpha responsiveness by IL6RIL6 resulting from the induction of TNF receptors. Moreover, exposure of F10.9 cells to neutralizing antibody to TNF-R55 significantly inhibited IL6RIL6/TNF-alpha-induced cytotoxicity. These results suggest that the IL6/sIL6R/gp130 system, which sensitizes TNF-alpha-resistant melanoma cells to TNF-alpha-induced apoptosis, may provide a new target for immunotherapy.

• Authors: Yadav Wagley, Yung-Choon Yoo, Han Geuk Seo, Man Hee Rhee, Tae-Hyoung Kim, Keon Wook Kang, Seung-Yeol Nah, Jae-Wook Oh
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 354 Issue 4 Pg. 985-91 (Mar 23 2007) ISSN: 0006-291X [Print] United States
• PMID: 17274948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Interleukin-6
• Receptors, Tumor Necrosis Factor, Type II
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• interleukin 6-interleukin 6 receptor fusion protein, recombinant
• Cytokine Receptor gp130

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytokine Receptor gp130 (physiology)
• Drug Synergism
• Interleukin-6 (therapeutic use)
• Melanoma (drug therapy)
• Mice
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Receptors, Interleukin-6 (therapeutic use)
• Receptors, Tumor Necrosis Factor, Type II (biosynthesis, immunology)
• Recombinant Fusion Proteins (therapeutic use)
• Solubility
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation