Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor

Christoph Garbers; Wolfgang Thaiss; Gareth W Jones; Georg H Waetzig; Inken Lorenzen; Florence Guilhot; Rami Lissilaa; Walter G Ferlin; Joachim Grötzinger; Simon A Jones; Stefan Rose-John; Jürgen Scheller

doi:10.1074/jbc.M111.295758

Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor

Christoph Garbers, Wolfgang Thaiss, Gareth W Jones, Georg H Waetzig, Inken Lorenzen, Florence Guilhot, Rami Lissilaa, Walter G Ferlin, Joachim Grötzinger, Simon A Jones, Stefan Rose-John, Jürgen Scheller

Research output: Contribution to journal › Article (Academic Journal) › peer-review

140 Citations (Scopus)

Abstract

IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) plays a critical role in chronic inflammation and cancer. Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling but was described to not interfere with classic signaling via the membrane-bound IL-6R. Physiological and most pathophysiological conditions are characterized by a molar excess of serum sIL-6R over IL-6 characterized by free IL-6 and IL-6 found in IL-6·sIL-6R complexes allowing both classic and trans-signaling. Surprisingly, under these conditions, sgp130 was able to trap all free IL-6 molecules in IL-6·sIL-6R·sgp130 complexes, resulting in inhibition of classic signaling. Because a significant fraction of IL-6 molecules did not form complexes with sIL-6R, our results demonstrate that compared with the anti-IL-6R antibody tocilizumab or the anti-trans-signaling monoclonal antibody 25F10, much lower concentrations of the dimeric sgp130Fc were sufficient to block trans-signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, indicating that the colon is a prominent target of IL-6 trans-signaling. Our results point to a so far unanticipated role of sgp130 in the blockade of classic signaling and indicate that in vivo only low therapeutic concentrations of sgp130Fc guarantee blockade of IL-6 trans-signaling without affecting IL-6 classic signaling.

Original language	English
Pages (from-to)	42959-70
Number of pages	12
Journal	Journal of Biological Chemistry
Volume	286
Issue number	50
DOIs	https://doi.org/10.1074/jbc.M111.295758
Publication status	Published - 16 Dec 2011

Keywords

Animals
Antibodies, Monoclonal/pharmacology
Antibodies, Monoclonal, Humanized/pharmacology
Blotting, Western
Cell Line
Cell Proliferation/drug effects
Cytokine Receptor gp130/antagonists & inhibitors
Flow Cytometry
Humans
Immunohistochemistry
Interleukin-6/metabolism
Male
Mice
Mice, Inbred C57BL
Receptors, Interleukin-6/antagonists & inhibitors
Signal Transduction/drug effects

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1074/jbc.M111.295758

Handle.net

Persistent link

Cite this

Garbers, C., Thaiss, W., Jones, G. W., Waetzig, G. H., Lorenzen, I., Guilhot, F., Lissilaa, R., Ferlin, W. G., Grötzinger, J., Jones, S. A., Rose-John, S., & Scheller, J. (2011). Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. Journal of Biological Chemistry, 286(50), 42959-70. https://doi.org/10.1074/jbc.M111.295758

@article{7d869eb916a4416f8535165577743247,

title = "Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor",

abstract = "IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) plays a critical role in chronic inflammation and cancer. Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling but was described to not interfere with classic signaling via the membrane-bound IL-6R. Physiological and most pathophysiological conditions are characterized by a molar excess of serum sIL-6R over IL-6 characterized by free IL-6 and IL-6 found in IL-6·sIL-6R complexes allowing both classic and trans-signaling. Surprisingly, under these conditions, sgp130 was able to trap all free IL-6 molecules in IL-6·sIL-6R·sgp130 complexes, resulting in inhibition of classic signaling. Because a significant fraction of IL-6 molecules did not form complexes with sIL-6R, our results demonstrate that compared with the anti-IL-6R antibody tocilizumab or the anti-trans-signaling monoclonal antibody 25F10, much lower concentrations of the dimeric sgp130Fc were sufficient to block trans-signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, indicating that the colon is a prominent target of IL-6 trans-signaling. Our results point to a so far unanticipated role of sgp130 in the blockade of classic signaling and indicate that in vivo only low therapeutic concentrations of sgp130Fc guarantee blockade of IL-6 trans-signaling without affecting IL-6 classic signaling.",

keywords = "Animals, Antibodies, Monoclonal/pharmacology, Antibodies, Monoclonal, Humanized/pharmacology, Blotting, Western, Cell Line, Cell Proliferation/drug effects, Cytokine Receptor gp130/antagonists & inhibitors, Flow Cytometry, Humans, Immunohistochemistry, Interleukin-6/metabolism, Male, Mice, Mice, Inbred C57BL, Receptors, Interleukin-6/antagonists & inhibitors, Signal Transduction/drug effects",

author = "Christoph Garbers and Wolfgang Thaiss and Jones, {Gareth W} and Waetzig, {Georg H} and Inken Lorenzen and Florence Guilhot and Rami Lissilaa and Ferlin, {Walter G} and Joachim Gr{\"o}tzinger and Jones, {Simon A} and Stefan Rose-John and J{\"u}rgen Scheller",

year = "2011",

month = dec,

day = "16",

doi = "10.1074/jbc.M111.295758",

language = "English",

volume = "286",

pages = "42959--70",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology Inc.",

number = "50",

}

Garbers, C, Thaiss, W, Jones, GW, Waetzig, GH, Lorenzen, I, Guilhot, F, Lissilaa, R, Ferlin, WG, Grötzinger, J, Jones, SA, Rose-John, S & Scheller, J 2011, 'Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor', Journal of Biological Chemistry, vol. 286, no. 50, pp. 42959-70. https://doi.org/10.1074/jbc.M111.295758

Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. / Garbers, Christoph; Thaiss, Wolfgang; Jones, Gareth W et al.
In: Journal of Biological Chemistry, Vol. 286, No. 50, 16.12.2011, p. 42959-70.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor

AU - Garbers, Christoph

AU - Thaiss, Wolfgang

AU - Jones, Gareth W

AU - Waetzig, Georg H

AU - Lorenzen, Inken

AU - Guilhot, Florence

AU - Lissilaa, Rami

AU - Ferlin, Walter G

AU - Grötzinger, Joachim

AU - Jones, Simon A

AU - Rose-John, Stefan

AU - Scheller, Jürgen

PY - 2011/12/16

Y1 - 2011/12/16

N2 - IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) plays a critical role in chronic inflammation and cancer. Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling but was described to not interfere with classic signaling via the membrane-bound IL-6R. Physiological and most pathophysiological conditions are characterized by a molar excess of serum sIL-6R over IL-6 characterized by free IL-6 and IL-6 found in IL-6·sIL-6R complexes allowing both classic and trans-signaling. Surprisingly, under these conditions, sgp130 was able to trap all free IL-6 molecules in IL-6·sIL-6R·sgp130 complexes, resulting in inhibition of classic signaling. Because a significant fraction of IL-6 molecules did not form complexes with sIL-6R, our results demonstrate that compared with the anti-IL-6R antibody tocilizumab or the anti-trans-signaling monoclonal antibody 25F10, much lower concentrations of the dimeric sgp130Fc were sufficient to block trans-signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, indicating that the colon is a prominent target of IL-6 trans-signaling. Our results point to a so far unanticipated role of sgp130 in the blockade of classic signaling and indicate that in vivo only low therapeutic concentrations of sgp130Fc guarantee blockade of IL-6 trans-signaling without affecting IL-6 classic signaling.

AB - IL-6 trans-signaling via the soluble IL-6 receptor (sIL-6R) plays a critical role in chronic inflammation and cancer. Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling but was described to not interfere with classic signaling via the membrane-bound IL-6R. Physiological and most pathophysiological conditions are characterized by a molar excess of serum sIL-6R over IL-6 characterized by free IL-6 and IL-6 found in IL-6·sIL-6R complexes allowing both classic and trans-signaling. Surprisingly, under these conditions, sgp130 was able to trap all free IL-6 molecules in IL-6·sIL-6R·sgp130 complexes, resulting in inhibition of classic signaling. Because a significant fraction of IL-6 molecules did not form complexes with sIL-6R, our results demonstrate that compared with the anti-IL-6R antibody tocilizumab or the anti-trans-signaling monoclonal antibody 25F10, much lower concentrations of the dimeric sgp130Fc were sufficient to block trans-signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, indicating that the colon is a prominent target of IL-6 trans-signaling. Our results point to a so far unanticipated role of sgp130 in the blockade of classic signaling and indicate that in vivo only low therapeutic concentrations of sgp130Fc guarantee blockade of IL-6 trans-signaling without affecting IL-6 classic signaling.

KW - Animals

KW - Antibodies, Monoclonal/pharmacology

KW - Antibodies, Monoclonal, Humanized/pharmacology

KW - Blotting, Western

KW - Cell Line

KW - Cell Proliferation/drug effects

KW - Cytokine Receptor gp130/antagonists & inhibitors

KW - Flow Cytometry

KW - Humans

KW - Immunohistochemistry

KW - Interleukin-6/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Receptors, Interleukin-6/antagonists & inhibitors

KW - Signal Transduction/drug effects

U2 - 10.1074/jbc.M111.295758

DO - 10.1074/jbc.M111.295758

M3 - Article (Academic Journal)

C2 - 21990364

SN - 0021-9258

VL - 286

SP - 42959

EP - 42970

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 50

ER -

Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor

Abstract

Keywords

UN SDGs

Access to Document

Handle.net

Fingerprint

Cite this