Selective inhibition of IL-6 trans-signalling reveals distinct mechanisms of human classic and trans-signalling receptor-complex formation
Abstract
The cytokine interleukin-6 orchestrates inflammation through two distinct pathways of receptor activation: anti-inflammatory classic signalling via membrane-bound interleukin-6 receptor and pro-inflammatory trans-signalling via soluble interleukin-6 receptor. Current interleukin-6-targeted therapies block both pathways, thereby disrupting essential homeostatic functions initiated by classic signalling. We here show a high-affinity, human-specific antibody that selectively inhibits interleukin-6 trans-signalling. This antibody maintains classic signalling-induced expression of hepatic acute phase genes while completely blocking trans-signalling-induced activation of endothelial cells. By targeting the domain D2 of membrane-bound and soluble human interleukin-6 receptor, the antibody selectively prevents formation of the trans-signalling receptor complex without interfering with ligand binding. This selective blockade demonstrates that human interleukin-6 classic and trans-signalling proceed through distinct receptor assemblies. Our findings describe mechanistic insight into interleukin-6 receptor assembly and provide a strategy to suppress inflammatory interleukin-6 activity while preserving regenerative and anti-inflammatory signalling, thus offering both conceptual and potential therapeutic advances in the targeted modulation of cytokine signalling networks.
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BibTeX
@article{rieneck2026selective,
title = {{Selective inhibition of IL-6 trans-signalling reveals distinct mechanisms of human classic and trans-signalling receptor-complex formation}},
author = {Emelie Rieneck and Jan René Haak and Kamal Asgarov and Jean-René Pallandre and Nicole Wundrack and Julia Ettich and Niloufarsadat Miri and Doreen M. Floss and Jürgen Scheller and Christoph Garbers and Andy Clark and John Wijdenes and Fred Schaper and Anna Dittrich},
journal = {Communications Biology},
year = {2026},
month = oct,
doi = {10.1038/s42003-026-11014-0},
url = {https://www.nature.com/articles/s42003-026-11014-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Selective inhibition of IL-6 trans-signalling reveals distinct mechanisms of human classic and trans-signalling receptor-complex formation
AU - Emelie Rieneck
AU - Jan René Haak
AU - Kamal Asgarov
AU - Jean-René Pallandre
AU - Nicole Wundrack
AU - Julia Ettich
AU - Niloufarsadat Miri
AU - Doreen M. Floss
AU - Jürgen Scheller
AU - Christoph Garbers
AU - Andy Clark
AU - John Wijdenes
AU - Fred Schaper
AU - Anna Dittrich
PY - 2026
DA - 2026/10/14
JO - Communications Biology
DO - 10.1038/s42003-026-11014-0
UR - https://www.nature.com/articles/s42003-026-11014-0
AB - The cytokine interleukin-6 orchestrates inflammation through two distinct pathways of receptor activation: anti-inflammatory classic signalling via membrane-bound interleukin-6 receptor and pro-inflammatory trans-signalling via soluble interleukin-6 receptor. Current interleukin-6-targeted therapies block both pathways, thereby disrupting essential homeostatic functions initiated by classic signalling. We here show a high-affinity, human-specific antibody that selectively inhibits interleukin-6 trans-signalling. This antibody maintains classic signalling-induced expression of hepatic acute phase genes while completely blocking trans-signalling-induced activation of endothelial cells. By targeting the domain D2 of membrane-bound and soluble human interleukin-6 receptor, the antibody selectively prevents formation of the trans-signalling receptor complex without interfering with ligand binding. This selective blockade demonstrates that human interleukin-6 classic and trans-signalling proceed through distinct receptor assemblies. Our findings describe mechanistic insight into interleukin-6 receptor assembly and provide a strategy to suppress inflammatory interleukin-6 activity while preserving regenerative and anti-inflammatory signalling, thus offering both conceptual and potential therapeutic advances in the targeted modulation of cytokine signalling networks.
SN - 2399-3642
ER -