A fusion protein of interleukin-11 and soluble interleukin-11 receptor acts as a superagonist on cells expressing gp130.

Interleukin-11 is a hematopoietic cytokine that signals via the signal transducer gp130. Although gp130 is ubiquitously expressed, interleukine-11 responsiveness is restricted to cells that express the interleukine-11 receptor alpha-subunit. The interleukine-11 receptor alpha-subunit can be functionally replaced by its soluble form indicating that the transmembrane and cytoplasmic parts are not required for signal transduction. Here, we show that a recombinant fusion protein of a fragment of the human interleukine-11 receptor alpha-subunit ectodomain linked to human interleukine-11 acts as a superagonist on cells expressing gp130 but lacking the membrane-bound interleukine-11 receptor alpha-subunit. It induces acute phase protein synthesis in hepatoma cells and efficiently promotes proliferation of Ba/F3 cells stably, transfected with gp130. In these bioassays, the fusion protein of a fragment of the human interleukine-11 receptor alpha-subunit ectodomain linked to human interleukine-11 is 50 times more potent than the combination of interleukine-11 and the soluble interleukine-11 receptor alpha-subunit. Thus, our findings support the concept that covalent fusion of two soluble proteins required for receptor activation dramatically increases their bioactivity.