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.
Pflanz
S
S
Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
Tacken
I
I
Grötzinger
J
J
Jacques
Y
Y
Minvielle
S
S
Dahmen
H
H
Heinrich
P C
PC
Müller-Newen
G
G
D000209:Acute-Phase Proteins / Q000096:biosynthesis; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism* / Q000494:pharmacology; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics* / Q000378:metabolism; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D010843:Pichia / Q000235:genetics; D011480:Protease Inhibitors / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D053702:Receptors, Interleukin-11; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D015703:Antigens, CD; D004268:DNA-Binding Proteins; C508428:IL11RA protein, human; C494199:IL6ST protein, human; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130