Interleukin-6 receptor signaling. I. gp80 and gp130 receptor interaction in the absence of interleukin-6.
Interleukin-6 (IL-6) is used as a growth factor by various tumor cells. It binds to a gp80 specific receptor (IL-6R) and then to a gp130 transducing chain. Both receptor chains are released as soluble functional proteins which circulate in biological fluids. To study the physiological role of these soluble receptors, both proteins were purified from human plasma and the kinetic constants of equilibria between IL-6 and its natural soluble IL-6R (sIL-6R) and gp130 receptor (sgp130) were measured using surface plasmon resonance analysis. Unexpectedly, natural sIL-6R and natural sgp130 were found to interact (Kd = 2.8 nM) in the absence of IL-6. No interaction was seen between the recombinant soluble receptors or between either natural soluble receptor and its recombinant partner. This binary complex was not due to copurification of IL-6 and was detected in human plasma of healthy donors. It results from either direct interaction between the two natural soluble receptors or indirect binding mediated by a yet unidentified copurified plasma molecule playing the role of an IL-6 antagonist. Once formed, the binary complex was found to be unable to bind IL-6. Soluble gp130 had already been shown to inhibit IL-6 signaling by inactivating the IL-6/IL-6R complex. In addition we show that, in the absence of IL-6, circulating natural sgp130 is able to inhibit directly the circulating sIL-6R that is a strong synergic molecule of IL-6 signaling.
Gaillard
J P
JP
INSERM U. 475, 99, rue Puech-Villa, 34197 Montpellier, Cedex 05 France.
Mani
J C
JC
Liautard
J
J
Klein
B
B
Brochier
J
J
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000097:blood / Q000302:isolation & purification / Q000502:physiology*; D050822:Cytokine Receptor gp130; D004591:Electrophoresis, Polyacrylamide Gel; D000939:Epitopes / Q000032:analysis; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000097:blood / Q000302:isolation & purification / Q000502:physiology*; D008875:Middle Aged; D010265:Paraproteinemias / Q000097:blood / Q000276:immunology*; D011485:Protein Binding; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000302:isolation & purification / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000939:Epitopes; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130