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 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.
Jostock
T
T
I. Medizinische Klinik, Section Pathophysiologie, Johannes Gutenberg Universität Mainz, Germany.
Müllberg
J
J
Ozbek
S
S
Atreya
R
R
Blinn
G
G
Voltz
N
N
Fischer
M
M
Neurath
M F
MF
Rose-John
S
S
D000210:Acute-Phase Reaction; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003424:Crohn Disease / Q000473:pathology; D050822:Cytokine Receptor gp130; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D012995:Solubility; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130