Signal transduction in response to interleukin‐6 (IL‐6) requires binding of the cytokine to its receptor (IL‐6R) and subsequent homodimerization of the signal transducer gp130. The complex of IL‐6 and soluble IL‐6R (sIL‐6R) triggers dimerization of gp130 and induces responses on cells that do not express 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 inhibited IL‐6/sIL‐6R induced proliferation of BAF/3 cells expressing gp130. Surprisingly, sgp130 proteins did not affect IL‐6 stimulated proliferation of BAF/3 cells expressing gp130 and membrane bound IL‐6R, indicating that sgp130 did not interfere with IL‐6 bound to IL‐6R on the cell surface. Additionally, sgp130 partially inhibited proliferation induced by leukemia inhibitory factor (LIF) and oncostatin M (OSM) albeit at higher concentrations. Recombinant sgp130 protein could be used to block the anti‐apoptotic effect of sIL‐6R on lamina propria cells from Crohn disease patients. We conclude that sgp130 is the natural inhibitor of IL‐6 responses dependent on sIL‐6R. Furthermore, recombinant sgp130 is expected to be a valuable therapeutic tool to specifically block disease states in which sIL‐6R transsignaling responses exist, e.g. in morbus Crohn disease.
IL-6 is a multifactorial cytokine mediating acute inflammatory responses in the liver. When IL-6 binds to a specific receptor (IL-6R), the IL-6/IL-6R complex associates with the signal transducer gp130, initiating intracellular signaling. A soluble form of the IL-6R (sIL-6R) renders target cells sensitive to IL-6 that do not express the IL-6R on their surfaces. A designer cytokine, termed Hyper-IL-6, consisting of IL-6 covalently linked to the sIL-6R was fully active on gp130-expressing cells at 100- to 1000-fold lower concentrations than unlinked IL-6 and IL-6R. Mice were injected i.p. with Hyper-IL-6 or IL-6. Upon injection of Hyper-IL-6 into mice, the acute phase response, as measured by haptoglobin mRNA expression in the liver, was markedly increased and lasted significantly longer compared with that in mice injected with a 10-fold higher dose of IL-6 alone. On human hepatoma cells, Hyper-IL-6 caused similar effects, indicating that the longer lasting response to the fusion protein could not only be explained by the longer plasma half-life of the fusion protein. Experiments using iodinated IL-6 and Hyper-IL-6 revealed that Hyper-IL-6 bound with high affinity to gp130 and was less efficiently internalized. This effect might explain the longer lasting activity of this protein on cells. The highly active IL-6/sIL-6R designer protein might be of significant clinical importance for the stimulation of cells that are more responsive to the IL-6/sIL-6R complex than to IL-6 alone. Such cells include hemopoietic progenitor cells and hepatocytes.
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