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Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model
Abstract
OBJECTIVE: The pleiotropic cytokine interleukin (IL)-6 seems to play a pivotal role in sepsis, but contradictory findings in animal models impede a rationale for therapies directed against IL-6. IL-6 signals by two mechanisms via the ubiquitous transmembrane glycoprotein 130 (gp130): "classic" signaling using membrane-bound IL-6 receptor (IL-6R) and trans-signaling using soluble IL-6R (sIL-6R). Trans-signaling is selectively inhibited by soluble gp130 (sgp130). The aim of this study was to systematically compare complete blockade of IL-6 signaling (using a neutralizing anti-IL-6 antibody) and selective blockade of IL-6 trans-signaling (using a fusion protein of sgp130 and the crystallizable fragment of immunoglobulin G1, sgp130Fc) in a standardized cecal ligation and puncture (CLP) sepsis model. DESIGN: Animal study. SETTING: Animal laboratory. SUBJECTS: C57BL/6J mice. INTERVENTIONS: We performed a 96-hr dose-response study and a 24-hr study to investigate short-term mechanisms. In the 96-hr study, CLP was performed in 120 randomized mice (20 mice received vehicle, 10 mice per dose group). Mice were treated with equimolar doses of sgp130Fc (0.01/0.1/1/10 mg/kg) or anti-IL-6 (0.008/0.08/0.8/8 mg/kg) 24 hrs before CLP. Two additional groups received 0.5 mg/kg sgp130Fc 24 hrs before or 1 mg/kg sgp130Fc 24 hrs after CLP. Survival and activity scores were obtained daily until 96 hrs after CLP. In the 24-hr study, mice were randomized into four groups with 10 animals each (sham/vehicle, CLP/vehicle, CLP/anti-IL-6 [0.8 mg/kg], and CLP/sgp130Fc [1 mg/kg]) and killed after 24 hrs. MEASUREMENTS AND MAIN RESULTS: In contrast to anti-IL-6, pretreatment with sgp130Fc significantly and dose-dependently increased survival from 45% to 100%. In addition, 1 mg/kg sgp130Fc administered 24 hrs after CLP increased survival from 45% to 80%. Mechanistically, sgp130Fc efficacy was reflected by complete prevention of epithelial cell apoptosis in the jejunum after CLP, which was not achieved with anti-IL-6. CONCLUSION: Selective inhibition of IL-6 trans-signaling by sgp130Fc has considerable potential for the treatment of sepsis and related disorders.
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“Inhibition of trans signaling via gp130 blockade in murine sepsis models rescues mice from widespread inflammation and death (41).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [41]
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“T he cytokine interleukin-6 (IL-6) appears to be an important player in sepsis (1, 2), and a correlation between high IL-6 plasma levels and mortality in septic patients has been observed (3, 4).”
BackgroundSoluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses.
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The pro- and anti-inflammatory properties of the cytokine interleukin-6
Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.034 · Cited by 3,212
Self-citationMacrophage Cytokines: Involvement in Immunity and Infectious Diseases
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“Inhibition of trans signaling via gp130 blockade in murine sepsis models rescues mice from widespread inflammation and death (41).”
BackgroundIL-6 as a keystone cytokine in health and disease
Hunter, C. A., & Jones, S. A. (2015) · Nature Immunology · doi:10.1038/ni.3153 · Cited by 2,511
Role of interleukin-6 in cancer progression and therapeutic resistance
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Self-citation
Metadata
- Authors
- Barkhausen, T., Tschernig, T., Rosenstiel, P., van Griensven, M., Vonberg, R.-P., Dorsch, M., Mueller-Heine, A., Chalaris, A., Scheller, J., Rose-John, S., Seegert, D., Krettek, C., & Waetzig, G. H.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- ORCID
- Venue
- Critical Care Medicine
- Published
- 2011-06
- Volume
- 39
- Issue
- 6
- Pages
- 1407-1413
- ISSN
- 0090-3493 (ISSN-L)
- OpenAlex
- W2319958192
- Cited by
- 169
- References
- 50
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 11 · 2023: 13 · 2022: 10 · 2021: 20 · 2020: 10 · 2019: 15 · 2018: 9 · 2017: 15 · 2016: 9 · 2015: 8 · 2014: 7 · 2013: 9 · 2012: 8
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- interleukin-6, IL-6 trans-signaling, soluble gp130, sgp130Fc, soluble IL-6 receptor, anti-IL-6 antibody, polymicrobial sepsis, cecal ligation and puncture, sepsis mortality, cytokine inhibition, IL-6 receptor signaling, dose-response relationship
- MeSH terms
- Interleukin-6 Inhibitors, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Mice, Inbred C57BL, Recombinant Fusion Proteins, Signal Transduction, Interleukin-6, Sepsis, Mice, Antibodies, Neutralizing
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