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 sarco ma, encodes proteins with similarities to cytokines and chemokines includin g a homologue of IL-6, Although the function of these viral proteins is unc lear, they might have the potential to modulate the immune system. For vira l 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 t he 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 t ype of signaling has been shown for hematopoietic progenitor cells, endothe lial cells, and smooth muscle cells. In this paper we show that purified re combinant vIL-6 binds to gp130 and stimulates primary human smooth muscle c ells, 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 d ata demonstrate that vIL-6 is the first cytokine which directly binds and a ctivates gp130. This property points to a possible role of this viral cytok ine in the pathophysiology of human herpes virus 8.