ArticleCell communication and signaling : CCS2019
Response to IL-6 trans- and IL-6 classic signalling is determined by the ratio of the IL-6 receptor α to gp130 expression: fusing experimental insights and dynamic modelling.
Article in Cell communication and signaling : CCS, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers, 2 of them syntheses that pooled it.
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Who cites it
112 citing papers in PubMed, 2 syntheses or guidelines pooled it, 171 citations in OpenAlex.
- A dual-database bibliometric analysis of post-COVID-19 condition and cognitive dysfunction (2021-2025).Frontiers in neurology · 2026Pooled it
- Pooled it
- Hematoma Interleukin-1 Receptor Antagonist Concentrations Predict Long-Term Outcome in Acute Human Intracerebral Hemorrhage.Annals of neurology · 2026Trial
- Safety and Pharmacokinetics of Olamkicept Doses up to 2400 mg in Healthy Japanese Men: Phase I, Randomized, Placebo-Controlled, and Double-Blind Trial.Clinical and translational science · 2026Trial
- Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials.Clinical and translational science · 2024Trial
- Selective inhibition of IL-6 trans-signalling reveals distinct mechanisms of human classic and trans-signalling receptor-complex formation.Communications biology · 2026Article
- Myogenic IL-6 Mediates Myofiber Type Transition in Porcine Skeletal Muscle Satellite Cells via the STAT3/Veterinary sciences · 2026Article
- Mesenchymal stromal cells immunosuppress osteoarthritis synovial fluid modulated monocytes via IL-6 and CCL2.Cell death & disease · 2026Article
- Article
- Regulation of Renal Transporters by Pro-Inflammatory Cytokines in Human Proximal Tubular Epithelial Cells: Identification of the Perpetrator and Mechanisms.ACS pharmacology & translational science · 2026Article
- Exercise-induced myokines in metabolic regulation: mechanisms, mimetics, and translational potential.Archives of pharmacal research · 2026Review
- Gut-liver axis molecular mechanisms in alcohol-associated liver disease.Alcohol (Fayetteville, N.Y.) · 2026Review
- Peripheral inhibition of IL-6 signaling with tocilizumab improves stroke outcomes in aged mice but requires sex-specific dosing.bioRxiv : the preprint server for biology · 2026Article
- Effect of Interleukin-6 Inhibitors on Rheumatoid Arthritis Pain: Overview of Evidence and Mechanistic Pathways.Pharmacology research & perspectives · 2026Review
- Evaluating tocilizumab in ischemic stroke: Findings from the SPAN multicenter trial.Neuropharmacology · 2026Article
- Role of Interleukin-6 in Atherothrombosis and Myocardial Infarction.Current atherosclerosis reports · 2026Review
- The Heterogeneity and Function of Stromal Cells in the Tumor Microenvironment.Research (Washington, D.C.) · 2026Review
- An Overview on T-Cell Engagers: The Current Position in Both the Biological and Mathematical Context.Computational and structural biotechnology journal · 2026Review
- IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis.The American journal of pathology · 2026Article
- Stress-induced IL-6 regulation in pediatric bone growth disorders: current insights and therapeutic strategies.Frontiers in endocrinology · 2026Review
52 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundInterleukin-6 is a pleiotropic cytokine with high clinical relevance and an important mediator of cellular communication, orchestrating both pro- and anti-inflammatory processes. Interleukin-6-induced signalling is initiated by binding of IL-6 to the IL-6 receptor α and subsequent binding to the signal transducing receptor subunit gp130. This active receptor complex initiates signalling through the Janus kinase/signal transducer and activator of transcription pathway. Of note, IL-6 receptor α exists in a soluble and a transmembrane form. Binding of IL-6 to membrane-bound IL-6 receptor α induces anti-inflammatory classic signalling, whereas binding of IL-6 to soluble IL-6 receptor α induces pro-inflammatory trans-signalling. Trans-signalling has been described to be markedly stronger than classic signalling. Understanding the molecular mechanisms that drive differences between trans- and classic signalling is important for the design of trans-signalling-specific therapies. These differences will be addressed here using a combination of dynamic mathematical modelling and molecular biology.
methodsWe apply an iterative systems biology approach using set-based modelling and validation approaches combined with quantitative biochemical and cell biological analyses.
resultsThe combination of experimental analyses and dynamic modelling allows to relate the observed differences between IL-6-induced trans- and classic signalling to cell-type specific differences in the expression and ratios of the individual subunits of the IL-6 receptor complex. Canonical intracellular Jak/STAT signalling is indifferent in IL-6-induced trans- and classic signalling.
conclusionThis study contributes to the understanding of molecular mechanisms of IL-6 signal transduction and underlines the power of combined dynamical modelling, model-based validation and biological experiments. The opposing pro- and anti-inflammatory responses initiated by IL-6 trans- and classic signalling depend solely on the expression ratios of the subunits of the entire receptor complex. By pointing out the importance of the receptor expression ratio for the strength of IL-6 signalling this study lays a foundation for future precision medicine approaches that aim to selectively block pro-inflammatory trans-signalling. Furthermore, the derived models can be used for future therapy design.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.