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.
“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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- 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 › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › 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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