title: Different Soluble Forms of the Interleukin-6 Family Signal Transducer gp130 Fine-tune the Blockade of Interleukin-6 Trans-signaling.
abstract: Soluble forms of the IL-6 receptor (sIL-6R) bind to the cytokine IL-6 with similar affinity as the membrane-bound IL-6R. IL-6·sIL-6R complexes initiate IL-6 trans-signaling via activation of the ubiquitously expressed membrane-bound β-receptor glycoprotein 130 (gp130). Inhibition of IL-6 trans-signaling has been shown to be favorable in numerous inflammatory diseases. Furthermore, different soluble forms of gp130 (sgp130) exist that, together with the sIL-6R, are thought to form a buffer for IL-6 in the blood. However, a functional role for the different sgp130 forms has not been described to date. Here we demonstrate that the metalloproteases ADAM10 and ADAM17 can produce sgp130 by ectodomain shedding of gp130, even though this mechanism only accounts for a minor proportion of sgp130 in the circulation. We further show that full-length sgp130 and the shorter forms sgp130-rheumatoid arthritis-associated peptide (RAPS) and sgp130-E10 are differentially expressed in a cell type- specific manner. Remarkably, full-length sgp130 is expressed by monocytes, but this expression is completely lost during differentiation into macrophages in vitro Using genetically engineered murine pre-B cells that secrete different forms of sgp130, we found that these secreted sgp130 proteins are able to prevent trans-signaling-driven cell proliferation of the secreting cells, whereas conditioned supernatant from these cells failed to block IL-6 trans-signaling in other cells. Thus, our data suggest that the different sgp130 forms are released from cells into their immediate surroundings and appear to form cell-associated gradients to modulate their own susceptibility for IL-6 trans-signaling.
authors.affiliation: From the Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Wolf
authors.affiliation: CONARIS Research Institute AG, 24118 Kiel, Germany.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
authors.affiliation: From the Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.affiliation: Non-Clinical Development, Ferring Pharmaceuticals A/S, 2300 Copenhagen, Denmark, and.
authors.forename: Torsten M
authors.initials: TM
authors.lastname: Reinheimer
authors.affiliation: the Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Wege
authors.affiliation: From the Institute of Biochemistry, Kiel University, 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: From the Institute of Biochemistry, Kiel University, 24098 Kiel, Germany, cgarbers@biochem.uni-kiel.de.
authors.forename: Christoph
authors.identifier: 0000-0003-4939-6950
authors.initials: C
authors.lastname: Garbers
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C508600:IL6 protein, human; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008565:Membrane Proteins; C577686:interleukin-6, mouse; D050822:Cytokine Receptor gp130; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: Janus kinase (JAK); STAT3; gp130; interleukin 6 (IL-6); interleukin 6 receptor (IL6R); proteolysis; sgp130; trans-signaling