IL-6 receptor independent stimulation of human gp130 by viral IL-6.
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.
Müllberg
J
J
I. Medizinische Klinik, Abteilung Pathophysiologie, Johannes Gutenberg-Universität Mainz, Mainz, Germany.
Geib
T
T
Jostock
T
T
Hoischen
S H
SH
Vollmer
P
P
Voltz
N
N
Heinz
D
D
Galle
P R
PR
Klouche
M
M
Rose-John
S
S
D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism*; D019556:COS Cells; D011232:Chemical Precipitation; D003001:Cloning, Molecular; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D005822:Genetic Vectors; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D019947:Receptors, Interleukin-6 / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D012514:Sarcoma, Kaposi / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014764:Viral Proteins; D050822:Cytokine Receptor gp130