The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling
Open accessAbstract
Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram/ml serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram/ml range. Calculations based on intermolecular affinities have suggested that systemic IL-6 is immediately trapped in IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, indicating that sIL-6R and sgp130 constitute a buffer system that increases the serum half-life of IL-6 or restricts systemic IL-6 signaling. However, this scenario has not been experimentally validated. Here, we quantified IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes over a wide concentration range. The amounts of IL-6 used in this study reflect concentrations found during active inflammatory events. Our results indicated that most IL-6 is free and not complexed with sIL-6R or sgp130, indicating that the level of endogenous sgp130 in the bloodstream is not sufficient to block IL-6 trans-signaling via sIL-6R. Importantly, addition of the single-domain antibody VHH6, which specifically stabilizes IL-6·sIL-6R complexes but did not bind to IL-6 or sIL-6R alone, drove free IL-6 into IL-6·sIL-6R complexes and boosted trans-signaling but not classic signaling, demonstrating that endogenous sIL-6R has at least the potential to form complexes with IL-6. Our findings indicate that even though high concentrations of sIL-6R and sgp130 are present in human serum, the relative ratio of free IL-6 to IL-6·sIL-6R allows for simultaneous classic and trans-signaling.
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Acutely elevated muscle-derived IL-6 acts directly on the liver to promote gluconeogenesis and stimulates adipose tissue lipolysis to increase free fatty acid mobilization and oxidation.
“It acts directly on the liver to promote gluconeogenesis, maintaining blood glucose stability, while simultaneously stimulating adipose tissue lipolysis to increase free fatty acid mobilization and oxidation for contracting muscles [32,33].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [33]
The paper’s introductory discussion of IL-6 signaling says that hepatocytes have IL-6 receptors and describes an acute-phase response, but it does not address hepatic gluconeogenesis. Searches for gluconeogenesis, glucose, adipose lipolysis, fatty-acid oxidation, and muscle found no passage supporting the attributed metabolic effects. (LLM, conf=0.75)
Experimental — accuracy not yet measuredThe in vivo biological half-life of IL-6 is approximately 2 h, which may explain the observed, relatively low, effect size of IL-6 modulation by 5-MeO-DMT.
“Furthermore, the in vivo biological half-life of IL-6 is approximately 2 h (Baran et al. 2018), which may explain the observed, relatively low, effect size of IL-6 modulation by 5-MeO-DMT (Fig. 2b).”
From Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment (2020) · cites this paper as Baran et al. 2018
The Abstract discusses a proposed serum buffer system that could increase IL-6 half-life, but gives no measured in vivo half-life. Searches for “half-life,” “2 h,” and “two hours” found no passage stating that IL-6 has an approximately two-hour biological half-life. The cited paper is not offered as evidence for the sentence’s separate interpretation of the 5-MeO-DMT result. (LLM, conf=0.75)
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“It acts directly on the liver to promote gluconeogenesis, maintaining blood glucose stability, while simultaneously stimulating adipose tissue lipolysis to increase free fatty acid mobilization and oxidation for contracting muscles [32,33].”
- Authors
- Baran, P., Hansen, S., Waetzig, G. H., Akbarzadeh, M., Lamertz, L., Huber, H. J., Ahmadian, M. R., Moll, J. M., & Scheller, J.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Conaris (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Corresponding author
- Scheller, Jürgen
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 293
- Issue
- 18
- Pages
- 6762-6775
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5936821
- OpenAlex
- W2791599654
- Cited by
- 235
- References
- 31
- Citations by year
- 2026: 32 · 2025: 33 · 2024: 37 · 2023: 36 · 2022: 24 · 2021: 28 · 2020: 24 · 2019: 16 · 2018: 5
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (DFG) (AH 92/8–1)
- Bundesministerium für Bildung und Forschung (BMBF) (InTraSig)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- interleukin-6, soluble IL-6 receptor, soluble gp130, trans-signaling, IL-6 family cytokines, gp130, inflammation
- MeSH terms
- Epitopes, Cell Line, Enzyme-Linked Immunosorbent Assay, Humans, Recombinant Proteins, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, Cytokine Receptor gp130, Single-Domain Antibodies
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