IL-6 Receptor Independent Stimulation of Human gp130 by Viral IL-6

• Published in: The Journal of immunology (1950) 2000-05, Vol.164 (9), p.4672-4677
• Main Authors: Mullberg, Jurgen, Geib, Till, Jostock, Thomas, Hoischen, Susanne H, Vollmer, Petra, Voltz, Nicole, Heinz, David, Galle, Peter R, Klouche, Mariam, Rose-John, Stefan
• Format: Article
• Language: English
• Subjects: Aged; Animals; Antigens, CD - biosynthesis; Antigens, CD - metabolism; Chemical Precipitation; Cloning, Molecular; COS Cells; Cytokine Receptor gp130; DNA-Binding Proteins - metabolism; Genetic Vectors; glycoprotein gp130; Growth Inhibitors - pharmacology; Human herpesvirus 8; Humans; Interleukin 6 receptors; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukin-6 - physiology; Male; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - metabolism; Phosphorylation; Protein Binding; Receptors, Interleukin-6 - metabolism; Receptors, Interleukin-6 - physiology; Recombinant Proteins - isolation & purification; Recombinant Proteins - pharmacology; Sarcoma, Kaposi - chemistry; Sarcoma, Kaposi - immunology; Sarcoma, Kaposi - pathology; Signal Transduction - immunology; STAT3 Transcription Factor; Trans-Activators - metabolism; Tumor Cells, Cultured; Viral Proteins - genetics; Viral Proteins - metabolism; Viral Proteins - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.164.9.4672

The genome of human herpes virus 8, which is associated with Kaposi's sarcoma, encodes proteins with similarities to cytokines and chemokines including a homologue of IL-6. Although the function of these viral proteins is unclear, they might have the potential to modulate the immune system. For viral IL-6 (vIL-6), it has been demonstrated that it stimulates IL-6-dependent cells, indicating that the IL-6R system is used. IL-6 binds to IL-6R, and the IL-6/IL-6R complex associates with gp130 which dimerizes and initiates intracellular signaling. Cells that only express gp130 but no IL-6R cannot be stimulated by IL-6 unless a soluble form of the IL-6R is present. This type of signaling has been shown for hematopoietic progenitor cells, endothelial cells, and smooth muscle cells. In this paper we show that purified recombinant vIL-6 binds to gp130 and stimulates primary human smooth muscle cells. IL-6R fails to bind vIL-6 and is not involved in its signaling. A Fc fusion protein of gp130 turned out to be a potent inhibitor of vIL-6. Our data demonstrate that vIL-6 is the first cytokine which directly binds and activates gp130. This property points to a possible role of this viral cytokine in the pathophysiology of human herpes virus 8.