Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses

Signal transduction in response to interleukin-6 (IL-6) requires binding of the cytokine to its receptor (IL-6R) and subsequent homodimerization of th e signal transducer gp130. The complex of IL-6 and soluble IL-6R (sIL-6R) t riggers dimerization of gp130 and induces responses on cells that do not ex press membrane bound IL-6R. Naturally occurring soluble gp130 (sgp130) can be found in a ternary complex with IL-6 and sIL-6R. We created recombinant sgp130 proteins that showed binding to IL-6 in complex with sIL-6R and inhi bited IL-6/sIL-6R induced proliferation of BAF/3 cells expressing gp130. Su rprisingly, sgp130 proteins did not affect IL-6 stimulated proliferation of BAF/3 cells expressing gp130 and membrane bound IL-6R, indicating that sgp 130 did not interfere with IL-6 bound to IL-6R on the cell surface. Additio nally, sgp130 partially inhibited proliferation induced by leukemia inhibit ory factor (LIF) and oncostatin M (OSM) albeit at higher concentrations. Re combinant sgp130 protein could be used to block the anti-apoptotic effect o f sIL-6R on lamina propria cells from Crohn disease patients. We conclude t hat sgp130 is the natural inhibitor of IL-6 responses dependent on sIL-6R. Furthermore, recombinant sgp130 is expected to be a valuable therapeutic to ol to specifically block disease states in which sIL-6R transsignaling resp onses exist, e.g. in morbus Crohn disease.