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 journalArticle (Academic Journal)peer-review

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 languageEnglish
Pages (from-to)42959-70
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number50
DOIs
Publication statusPublished - 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

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